WO2019125184A1 - Utilisation de biomarqueur en thérapie du cancer - Google Patents

Utilisation de biomarqueur en thérapie du cancer Download PDF

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Publication number
WO2019125184A1
WO2019125184A1 PCT/NZ2018/050180 NZ2018050180W WO2019125184A1 WO 2019125184 A1 WO2019125184 A1 WO 2019125184A1 NZ 2018050180 W NZ2018050180 W NZ 2018050180W WO 2019125184 A1 WO2019125184 A1 WO 2019125184A1
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Prior art keywords
methyl
amino
pyrimidin
dimethyl
hap
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PCT/NZ2018/050180
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English (en)
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Christopher Paul Guise
Adam Vorn Patterson
Cristin Gregor Print
Shevan SILVA
Jeffrey Bruce Smaill
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Auckland Uniservices Limited
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/255—Esters, e.g. nitroglycerine, selenocyanates of sulfoxy acids or sulfur analogues thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present disclosure relates to the role played by Six-Transmembrane Epithelial Antigen of Prostate 4 (STEAP4) in the metabolism of certain hypoxia-activated prodrugs (HAPs), and the application of such in cancer therapies.
  • STEAP4 Six-Transmembrane Epithelial Antigen of Prostate 4
  • STEAP4 has been shown to be associated with certain cancers (Gomes et al, 2012; Xue et al, 2017). STEAP4 has also been shown to be highly induced by hypoxia, i.e., low oxygen at the tissue level. Moreover, hypoxia within tumours is associated with poor prognosis of cancer patients and with treatment failure (Hunter et al., 2016), such as resistance to radiotherapy and traditional chemotherapy.
  • High levels of STEAP4 expression are associated with certain cancers.
  • the inventors surprisingly found that when STEAP4 is highly expressed in cancers, STEAP4 can catalyse a reaction in HAPs leading to release of the drug payload and/or modification of the HAP to a form that is able to penetrate the cell membrane and cause cell death.
  • cancers with elevated STEAP4 expression levels respond to treatment by HAPs. Accordingly, the inventors have surprisingly found an effective treatment for STEAP4-associated cancers. Accordingly, in one aspect of the present disclosure there is provided a method of treating cancer in an individual in need thereof, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the present disclosure provides a method of treating cancer in an individual in need thereof, where tumour cells of the individual exhibit an elevated level of STEAP4 expression, the method comprising :
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • the present disclosure also provides kits for performing the disclosed methods.
  • HAPs for example, a HAP having the structures of Compound A, Compound C, and Compound E. .
  • Figure 1 shows the amino acid sequence SEQ ID NO: l, which is isoform 1 of the
  • STEAP4 protein (NCBI Acc No. NM_024636.3), and comprises 459 amino acids.
  • Figure 2 shows the nucleotide sequence SEQ ID NO:2, which is variant 1 (and the predominant variant) encoding isoform 1 of the STEAP4 protein, and comprises 4488 base pairs.
  • Figure 3 shows the nucleotide sequence SEQ ID NO:3, which is variant 2 (and an alternative to variant 1) encoding isoform 1 of the STEAP4 protein, and comprises 4587 base pairs.
  • Figure 4 shows the amino acid sequence SEQ ID NO:4, which is isoform 2 of the STEAP4 protein (NCBI Acc No. NM_001205315.1), and comprises 283 amino acids.
  • Figure 5 shows the nucleotide sequence SEQ ID NO: 5, which is variant 3 encoding isoform 2 of the STEAP4 protein, and comprises 3960 base pairs.
  • Figure 6 shows the effect of siRNA knockdown in HCC1954 and SiHa cells of five reductase genes ( STEAP4 , SDHA, DCXR, COQ6 and FOXRED1 ) on Compound A metabolism, as described in Example 3.
  • Figure 7 shows the enforced overexpression expression of STEAP4 in H1299 and C33A cells by western blot and the effect of STEAP4 overexpression in H1299 and C33A cells on Compound A metabolism under aerobic (oxic) and anoxic conditions, as described in Example 4.
  • Figure 8 shows the structures for the prodrugs TH-302 (also known as evofosfamide), tirapazamine (TPZ or SR4233), and Compound C (also known as PR-104A or SN27858), as referred to in Example 5.
  • Figure 9 is a graphic showing the layout of the 96-well plate, as described in Example 5.
  • Figure 10 shows the IC50 values for TH-302, TPZ, and Compound C in wild-type (WT) and STEAP4-expressing cells, where the concentration of prodrug required to inhibit cell growth by 50% (IC50) is shown, as described in Example 5.
  • Figure 11 shows the metabolism of the prodrugs Compound A and Compound C in wild-type A431 cells (A431 WT ) and in cells over-expressing cytochrome P450 oxidoreductase (A431 por ) under aerobic (oxic) and anoxic conditions, and metabolism of the prodrugs Compound A by cell-free recombinant POR under anoxia in the presence of NADPH, as described in Example 6.
  • Figure 12 shows the nucleotide sequence SEQ ID NOs: 6-l l, which may be used as probes to detect STEAP4 mRNA sequences, including as PCR primers, as herein described.
  • Figure 13 shows the results of the RT-PCR study demonstrating the feasibility of using selected primers for qPCR detection of STEAP4, as described further in Example 7.
  • Figure 14 shows the results of the qPCR where STEAP4 expression was normalised in reference to GAPDH expression, across a panel of human cancer cell lines, as described in Example 7.
  • Figure 15 shows the results of the Western blot for STEAP4 in H 1299 WT cells (lane 2) and H 1299 STEAP4 cells (lane 3), as described in Example 7.
  • Figure 16 shows the results of the functional assay for STEAP4 based on the ferrireductase activity of the STEAP4 enzyme in parental C33A WT and C33A STEAP4 cells, as described in Example 7.
  • Figure 17 shows the rate of Compound B production under aerobic and anoxic conditions in C33A WT , C33A STEAP4 , H 1299 WT , and H 1299 STEAP4 cells following exposure to 10pM Compound A for 90 minutes, as described in Example 7.
  • Figure 18 shows the expression of STEAP4 relative to GAPDH and HPRT expression in SiHa clones derived following transfection with the STEAP4 gRNA containing px458 plasmid, as described in Example 8.
  • Figure 19 shows the measured Compound A metabolism under anoxic conditions in parental SiHa WT cells and SiHa clone #50 cells as measured by the rate of Compound B formation in each cell line, as described in Example 8.
  • Figure 20 shows the fold-change in STEAP4 expression in each isogenic cell line pairs relative to each parental (WT) cell line, as described in Example 9.
  • Figure 21 shows the Compound A metabolism under anoxic conditions in parental (WT) and STEAP4-overexpressing C33A and PC9 isogenic cell line pairs, as described in Example 9.
  • Figure 24 shows the mean ⁇ SEM Compound B concentrations in the same parental and STEAP4 k/o SiHa tumours as shown in Figure 23, and as described in Example 10.
  • Figure 25 shows the intratumour ratios of Compound B: Compound A in parental and STEAP4 k/o SiHa tumours, as described in Example 10.
  • Figure 26 shows STEAP4 expression by qPCR in 5/6 parental SiHa and 5/6 STEAP4 k/o SiHa tumours, as described in Example 10.
  • Figure 27 shows the products from the qPCR reaction run on a 2% agarose gel, as described in Example 10.
  • Figure 28 shows STEAP4 expression by immunohistochemical detection in parental C33A WT tumours and C33A STEAP4 tumour xenograft tissue sections engineered to overexpress STEAP4, as described in Example 7.
  • Figure 29 shows STEAP4 expression by immunohistochemical detection in parental SiHa WT tumours and SiHa STEAP4 nu " tumour xenograft tissue sections where the STEAP4 gene has been genomically disrupted and results in the absence of protein expression, overexpress STEAP4, as described in Example 10.
  • Figure 30 shows a schematic depicting an exemplary STEAP4-mediated activation of Compound A.
  • Figure 31 shows anti-tumour activity of tarloxotinib when administered as a single dose (48 mg/kg) in C33A WT (WT) and STEAP4 overexpressing C33A STEAP4 (STEAP4) tumours.
  • the top three (3) lines correspond to WT #1, WT #2, and WT #3.
  • the bottom three (3) lines correspond to STEAP4 #1, STEAP4 #2, and STEAP4 #3.
  • composition of matter, group of steps or group of compositions of matter shall be taken to encompass one and a plurality (i.e., one or more) of those steps, compositions of matter, groups of steps or group of compositions of matter.
  • alkyl include both straight chain and branched chain groups, and unsubstituted and substituted groups.
  • the optional substituents may include, without limitation, halogen, C1-C6 alkoxy, CN, OH, NH 2 , N0 2 , NH(CI-C 6 alkyl), N(CI-C 6 alkyl) 2 , CONH 2 , CO(Ci-C 6 alkyl), S0 2 NH 2 and S0 2 (Ci-C 6 alkyl).
  • quaternisable nitrogen means a fully substituted nitrogen of sufficient basicity (or nucleophilicity) to react with an electrophilic group such as an a-methyl halide/mesylate/tosylate or triflate to provide a quaternary ammonium salt of the nitrogen.
  • aromatic nitroheterocycle means an aromatic heterocyclic moiety substituted at any ring position by one or more nitro (N0 2 ) groups.
  • the aromatic heterocyclic moiety may be a monocyclic or bicyclic ring containing 4 to 12 atoms of which at least one atom is chosen from nitrogen, sulphur or oxygen.
  • the aromatic heterocyclic moiety may be carbon or nitrogen linked.
  • the aromatic heterocyclic moiety may additionally be substituted by one or more additional substituents at any available ring carbon or heteroatom.
  • the substituents may include, but are not limited to the groups as defined for R 26 in Formula V.
  • aromatic nitrocarbocycle means a benzene moiety substituted at any position by one or more nitro (N0 2 ) groups.
  • two adjacent ring carbon atoms may optionally be linked to form a fused carbocyclic or heterocyclic ring.
  • the benzene moiety (and optional fused ring) may additionally be substituted by one or more additional substituents at any available carbon or heteroatom.
  • the substituents may include, but are not limited to, the groups as defined for R26 in Formula V.
  • pharmaceutically acceptable means that which is useful in preparing a pharmaceutical composition that is generally safe, non-toxic, and neither biologically nor otherwise undesirable and includes that which is acceptable for veterinary as well as human pharmaceutical use.
  • Such salts include: acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like; or formed with organic acids such as acetic acid, methanesulfonic acid, maleic acid, tartaric acid, citric acid and the like; and salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminium ion; or coordinates with an organic or inorganic base.
  • Acceptable organic bases include ethanolamine, diethanolamine, N-methylglucamine, triethanolamine and the like.
  • Acceptable inorganic bases include aluminium hydroxide, calcium hydroxide, potassium hydroxide, sodium carbonate and sodium hydroxide
  • prodrug refers to a compound that, after administration, is metabolised or otherwise converted to a biologically active or more active compound (or drug) with respect to at least one property.
  • a prodrug, relative to the drug is modified chemically in a manner that renders it, relative to the drug, less active or inactive, but the chemical modification is such that the corresponding drug is generated by metabolic or other biological processes after the prodrug is administered.
  • a prodrug may have, relative to the active drug, altered metabolic stability or transport characteristics, fewer side effects or lower toxicity, or improved flavour (for example, see the reference Nogrady, 1985, Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392, incorporated herein by reference).
  • a prodrug may be synthesized using reactants other than the corresponding drug.
  • hypooxic refers to a concentration of oxygen in tissue that is significantly lower the normal physiological concentration of oxygen in healthy well perfused tissue, in particular oxygen tensions below approximately 1% (10,000 parts per million oxygen; 7.6 mmHg).
  • anoxia or “anoxic conditions” (and similar) refers to an absence (or near absence) of oxygen in tissue, and in particular oxygen tensions below approximately 1 parts per million oxygen.
  • treatment refers to an action that occurs while an individual is suffering from the specified cancer, which reduces the severity of the cancer or the symptoms of the cancer, or retards or slows the progression of the cancer.
  • treatment may refer to a 5%, 10%, 25%, 50%, or 100% decrease in the rate of progress of a tumour.
  • treatment may refer to a 5%, 10%, 25%, 50%, or 100% decrease in determined tumour burden (/.e., the number of cancerous cells present in the individual, or the size of the tumour).
  • treatment may refer to a 5%, 10%, 25%, 50%, or 100% decrease in the physical symptoms of a cancer.
  • treatment may refer to a 5%, 10%, 25%, 50%, or 100% increase in the general health of the individual, as determined by any suitable means, such as cell counts, assay results, or other suitable means.
  • the cancer may be any suitable cancer, including those as further defined herein.
  • the term "individual” or “subject” as used interchangeably herein refers to any mammalian animal including a human being. Suitably, the individual is a human being.
  • providing tumour cells may refer to the step of obtaining cells of the individual (e.g., by way of biopsy or otherwise), or may refer to the step of receiving a sample of tumour cells which has previously been obtained from the individual.
  • the tumour cells may comprise a sample.
  • the sample comprises a biological sample and can be, for instance, a cell, a cell culture, a tissue, or a biological fluid.
  • the biological sample may comprise a tumour cell biopsy, a plurality of samples from a clinical trial, or the like.
  • the sample can be a crude sample, or can be purified to various degrees prior to storage, processing, or measurement.
  • determining generally refers to any form of measurement, and includes determining if the Six-Transmembrane Epithelial Antigen of Prostate 4 (STEAP4) protein or mRNA is present or not.
  • the term “determining” includes both quantitative and/or qualitative determination.
  • the STEAP4 expression levels may be determined by any suitable method known to those skilled in the art, including those as further defined herein.
  • the expression “elevated level of STEAP4 expression” is further defined herein.
  • the terms “determining”, “measuring”, “evaluating”, “assessing” and “assaying” are used interchangeably herein.
  • predict generally means to determine or tell in advance.
  • predict can mean that the likelihood of the outcome of the cancer treatment can be determined at the outset, before the treatment has begun, or before the treatment period has progressed substantially.
  • a predictive method may also be described as a prognostic method.
  • “likelihood”, “likely to”, and similar generally refers to an increase in the probability of an event.
  • “likelihood”, “likely to”, and similar when used in reference to responsiveness to cancer therapy generally contemplates an increased probability that the individual will exhibit a reduction in the severity of cancer or the symptoms of cancer or the retardation or slowing of the cancer progression.
  • the term “likelihood”, “likely to”, and similar when used in reference to responsiveness to cancer therapy can also generally mean the increase of indicators, such as mRNA or protein expression, that may evidence an increase in cancer treatment.
  • hypoxia-activated prodrug and HAP refer to any suitable HAP, including those as further defined herein. Suitable administration methods for HAPs are further described herein.
  • a therapeutically effective amount of a HAP refers to an amount of the HAP, alone or in combination with other therapies, which is sufficient to treat a cancer.
  • a therapeutically effective amount of a compound refers to the amount of the compound that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more of the symptoms of the cancer.
  • the term also refers to the amount of the compound that is sufficient to elicit a biological or medical response of a biological molecule (e.g., a protein, enzyme, RNA, or DNA), cell, tissue, system, animal, or human, which is being sought by a researcher, veterinarian, medical doctor, or clinician.
  • a biological molecule e.g., a protein, enzyme, RNA, or DNA
  • a therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, which provides a therapeutic benefit in the treatment or management of the cancer.
  • the term encompasses an amount of the compound that improves overall therapy, reduces, or avoids symptoms or causes of the cancer, or enhances the therapeutic efficacy of another therapeutic agent.
  • level refers to the amount, accumulation, or rate of a biomarker molecule.
  • a level can be represented, for example, by the amount or the rate of synthesis of a messenger RNA (mRNA) encoded by a gene, the amount or the rate of synthesis of a polypeptide or protein encoded by a gene, the amount or the rate of synthesis of a biological molecule accumulated in a cell or biological fluid, or the biological activity of a biological molecule in a cell or biological fluid.
  • mRNA messenger RNA
  • level refers to an absolute amount of a molecule in a sample or to a relative amount of the molecule, determined under steady-state or non-steady-state conditions.
  • responsiveness refers to the degree of effectiveness of the treatment in lessening or decreasing the symptoms of a disease, disorder, or condition being treated.
  • increased responsiveness when used in reference to a treatment of a cell or a subject refers to an increase in the effectiveness in lessening or decreasing the symptoms of the disease when measured using any methods known in the art.
  • the increase in the effectiveness is at least about 5%, at least about 10%, at least about 20%, at least about 30%, at least about 40%, or at least about 50%.
  • the Six-Transmembrane Epithelial Antigen of Prostate (STEAP) protein family contains four members (STEAP1-4) though only STEAP2-4 have oxidoreductase activity.
  • the STEAP4 protein also known as STAMP2 or TIARP, is a metalloreductase that reduces iron and copper ions.
  • STEAP4 has equivalent activity under either physiological or acidic pH (pH5.5 - 7.5).
  • the full length nucleotide sequence encoding the STEAP4 protein (/.e., the STEAP4 gene) and the full length amino acid sequence of the STEAP4 protein are known in the art (see, e.g., NCBI Gene ID: 79689, NCBI Acc. No. NM_024636, NCBI Acc. No. NM_001205315.1, NCBI Acc. No. NM_001205316.1, and UniProt Acc. No. Q687X5).
  • Variant 1 is the predominant nucleotide sequence encoding isoform 1 of the STEAP4 protein, and is shown in SEQ ID NO:2 (also in Figure 2).
  • Variant 2 is an alternative nucleotide sequence encoding isoform 1 of the STEAP4 protein, and is shown in SEQ ID NO:3 (also in Figure 3).
  • Isoform 2 of the STEAP4 protein is 283 amino acids long, and is shown in SEQ ID NO:4 (also in Figure 4).
  • Variant 3 is a nucleotide sequence encoding this shorter isoform of STEAP4 protein (isoform 2) and is shown in SEQ ID NO: 5 (also in Figure 5).
  • STEAP4 protein refers to isoform 1 (SEQ ID NO: l), isoform 2 (SEQ ID NO:4), a protein encoded by variant 1 (SEQ ID NO:2), a protein encoded by variant 2 (SEQ ID NO:3), or a protein encoded by variant 3 (SEQ ID NO: 5), and/or to any other variant thereof.
  • Variants contemplated within the scope of the present disclosure include protein variants which are substantially homologous to a native STEAP4 protein.
  • substantially homologous refers to a protein having one or more naturally or non-naturally occurring amino acid deletions, insertions, or substitutions (e.g., derivatives, homologs, and fragments), as compared to the amino acid sequence of a native STEAP4 protein.
  • the amino acid sequence of a STEAP4 variant may be at least about 40% identical, at least about 50% identical, at least about 60% identical, at least about 70% identical, at least about 80% identical, at least about 90% identical, or at least about 95% identical to a native STEAP4 protein.
  • a "native STEAP4 protein” refers to the STEAP4 proteins which are found in nature and are not manipulated by man, and includes isoform 1 (SEQ ID NO: l), isoform 2 (SEQ ID NO:4), a protein encoded by variant 1 (SEQ ID NO:2), a protein encoded by variant 2 (SEQ ID NO:3), and a protein encoded by variant 3 (SEQ ID NO: 5).
  • variant 1 SEQ ID NO: l
  • SEQ ID NO:4 isoform 1
  • variant 2 SEQ ID NO:3
  • variant 3 SEQ ID NO: 5
  • Variants contemplated within the scope of the present disclosure also include proteins encoded by polynucleotide variants which have substantial sequence similarity or sequence identity to a native STEAP4 gene.
  • the polynucleotide sequence of a STEAP4 variant may have at least about 40%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95% sequence similarity or sequence identity with a native STEAP4 gene.
  • a "native STEAP4 gene” refers to genes: (a) which are found in nature and are not manipulated by man, and encode STEAP4 proteins; and (b) which encode STEAP4 proteins that are found in nature and are not manipulated by man; and includes the gene having the polynucleotide sequence encoding isoform 1 (SEQ ID NO: l), the gene having the polynucleotide sequence encoding isoform 2 (SEQ ID NO:4), the gene with the polynucleotide sequence of variant 1 (SEQ ID NO:2), the gene with the polynucleotide sequence of variant 2 (SEQ ID NO:3), and the gene with the polynucleotide sequence of variant 3 (SEQ ID NO:5).
  • High levels of STEAP4 expression are associated with certain cancers.
  • the inventors when STEAP4 is highly expressed in a cancer, the inventors have surprisingly found that STEAP4 can catalyse conversion of an administered drug into its active form, such as a reaction leading to release of a drug payload. Accordingly, in some embodiments, high STEAP4 expression leads to release of the drug payload in HAPs.
  • the high STEAP4 expression is associated with hypoxic metabolism.
  • the high STEAP4 expression is associated with a hypoxic environment.
  • the high STEAP4 expression is associated with a hypoxic tumour.
  • the high STEAP4 expression is not associated with low oxygen levels.
  • STEAP4 when STEAP4 is present in hypoxic tumour environments, STEAP4 catalyses one-electron reduction of cell-excluded quaternary ammonium salt HAPs, leading to their fragmentation selectively in pathophysiologically hypoxic tumour tissues, releasing the active drug which can then cross the cell wall and kill the cancer cell. Without wishing to be bound by theory, it is thought that STEAP4 is located on the plasma membrane. As such, in some embodiments, STEAP4 reduces the HAP extracellularly, forming a molecule that is capable of diffusing into the cell (e.g., a reduced form of the molecule).
  • STEAP4 is on the plasma membrane and reduces the HAP extracellularly, at which point the charged molecule undergoes fragmentation and diffuses into the cell to inhibit EGFR.
  • the charged HAP molecule undergoes fragmentation under hypoxic conditions.
  • the charged HAP molecule undergoes fragmentation in the presence of elevated levels of STEAP4.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the HAP is selected from the group consisting of Compound A, Compound C, and Compound E.
  • NMQ prodrugs used in the disclosed methods function by releasing an active molecule having undergone reduction in the extracellular medium
  • other HAPs for use in the disclosed methods do not fragment and release an active molecule, but instead are effective because the reduced form of the molecule is able to penetrate the cell membrane and then cause cell death.
  • the HAPs may have a limiting or low rate of membrane penetration such that extracelluclar metabolism by STEAP4 will contribute a significant proportion of total cellular metabolism and such that intracellular reductases will contribute a less significant proportion of total cellular metabolism.
  • One such class of HAPs is the nitrophenyl mustards.
  • HAPs with a net neutral charge may be hydrophilic in nature, e.g., may have a low partition coefficient, which can result in a limiting rate of cell membrane penetration.
  • extracellular metabolism by STEAP4 contributes a significant proportion of total cellular metabolism, and the remainder of HAP cellular metabolism is due to intracellular reductases.
  • HAPs with a low pKa may be protonated at physiologically relevant pH range and thus carry a net positive charge, resulting in a low partition coefficient, which can result in a limiting rate of cell membrane penetration.
  • extracellular metabolism by STEAP4 contributes a significant proportion of total cellular metabolism, and the remainder of HAP cellular metabolism is due to intracellular reductases.
  • the inventors surprisingly discovered, in part, a previously unidentified role played by the enzyme STEAP4 in hypoxic tumour environments in metabolising HAPs, including cell-excluded HAPs, at the cell surface, having the effect of releasing the active drug from the prodrug. This can enable the active drug to cross the cell membrane and deliver its payload to the intracellular targets and thus kill the cancer cell.
  • This activity appears to be unique to the STEAP4 reductase enzyme, and is not shared with the other STEAP proteins or with other reductases.
  • the present application thus contemplates methods of treating or preventing cancer with a HAP in an individual in need thereof, where the individual exhibits an elevated level of STEAP4 expression, and related methods and uses.
  • the present disclosure provides a method of treating or preventing cancer in an individual in need thereof, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides a method of treating or preventing cancer in an individual in need thereof, the method comprising :
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides a method of treating or preventing cancer in an individual in need thereof, the method comprising :
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E. .
  • the present disclosure provides a method of treating or preventing cancer in an individual in need thereof, where tumour cells of the individual exhibit an elevated level of STEAP4 expression; the method comprising administering a therapeutically effective amount of a HAP to the individual.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides a method of treating or preventing cancer in an individual in need thereof, the method comprising administering to the individual a therapeutically effective amount of a hypoxia -activated prodrug (HAP), wherein the cancer exhibits an elevated level of STEAP4 expression.
  • HAP hypoxia -activated prodrug
  • the level of STEAP4 expression is expression of a STEAP4 gene.
  • the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid.
  • the target nucleic acid is DNA.
  • the target nucleic acid is mRNA.
  • the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the prediction of whether an individual is likely to be responsive to treatment by a HAP may be made by comparing the determined STEAP4 expression levels in the tumour cells to a reference level of STEAP4 expression.
  • the present disclosure provides a method of treating or preventing cancer in an individual in need thereof, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides a method of treating or preventing cancer in an individual in need thereof, the method comprising :
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides a method of treating or preventing cancer in an individual in need thereof, the method comprising :
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the prediction of whether an individual is likely to be responsive to treatment by a HAP may also be made by comparing the determined STEAP4 expression levels in the tumour cells to a level of STEAP4 expression in a control sample.
  • the present disclosure provides a method of treating or preventing cancer in an individual in need thereof, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides a method of treating or preventing cancer in an individual in need thereof, the method comprising :
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides a method of treating or preventing cancer in an individual in need thereof, the method comprising :
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides the use of a HAP in the manufacture of a medicament for the treatment or prevention of cancer in an individual, wherein the cancer exhibits an elevated level of STEAP4 expression.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides the use of a HAP in the manufacture of a composition for the treatment or prevention of cancer in an individual in need thereof, where tumour cells of the individual exhibit an elevated level of STEAP4 expression.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides the use of a HAP in the manufacture of a composition for the treatment or prevention of cancer in an individual in need thereof, where a sample of tumour cells from the individual exhibit an elevated level of STEAP4 expression.
  • the level of STEAP4 expression is expression of a STEAP4 gene.
  • the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid.
  • the target nucleic acid is DNA.
  • the target nucleic acid is mRNA.
  • the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides the use of a HAP for the treatment or prevention of cancer in an individual, wherein the cancer exhibits an elevated level of STEAP4 expression.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides the use of a HAP in the treatment or prevention of cancer in an individual in need thereof, where tumour cells of the individual exhibit an elevated level of STEAP4 expression.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides the use of a HAP in the treatment or prevention of cancer in an individual in need thereof, where a sample of tumour cells of the individual exhibit an elevated level of STEAP4 expression.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides a compound which is a HAP, for use in the treatment or prevention of a cancer exhibiting an elevated level of STEAP4 expression, wherein the treatment comprises administering the HAP to an individual in need thereof.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides a compound which is a HAP for use in the treatment or prevention of cancer in an individual in need thereof, where tumour cells of the individual exhibit an elevated level of STEAP4 expression .
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides a compound which is a HAP for use in the treatment or prevention of cancer in an individual in need thereof, where a sample of tumour cells of the individual exhibit an elevated level of STEAP4 expression .
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides a HAP for use in the treatment or prevention of cancer in an individual in need thereof, where the cancer exhibits an elevated level of STEAP4 expression.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides a HAP for use in the treatment or prevention of cancer in an individual in need thereof, where tumour cells of the individual exhibit an elevated level of STEAP4 expression.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides a HAP for use in the treatment or prevention of cancer in an individual in need thereof, where a sample of tumour cells of the individual exhibit an elevated level of STEAP4 expression.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides a HAP for use in the treatment or prevention of cancer in an individual in need thereof, comprising : a) providing tumour cells of the individual;
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides a HAP for use in the treatment or prevention of cancer in an individual in need thereof, comprising :
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present disclosure provides a HAP for use in the treatment or prevention of cancer in an individual in need thereof, comprising :
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein. In certain embodiments, the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard. In certain embodiments, the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • the present application also contemplates methods of predicting the responsiveness of an individual with cancer to treatment with a HAP, methods of predicting whether an individual with cancer is likely to be responsive to treatment with a HAP, and methods of identifying an individual with cancer who is likely to be responsive to treatment with a HAP.
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the prediction of an individual that is likely to be responsive to treatment by a HAP may be made by comparing the determined STEAP4 expression levels in the tumour cells to a reference level of STEAP4 expression.
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the individual is likely to be responsive to the treatment with a HAP if the level of STEAP4 expression in the tumour cells is elevated relative to the reference level of STEAP4 expression.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • the individual is likely to be responsive to the treatment with a HAP if the level of STEAP4 expression in the tumour cells is elevated relative to the reference level of STEAP4 expression.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • the individual is likely to be responsive to the treatment with a HAP if the level of STEAP4 expression in the tumour cells is elevated relative to the reference level of STEAP4 expression.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • an elevated level of STEAP4 expression in the tumour cells relative to the reference level of STEAP4 expression correlates with an increased likelihood of responsiveness or an increased responsiveness of the individual to the treatment.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • an elevated level of STEAP4 expression in the tumour cells relative to the reference level of STEAP4 expression correlates with an increased likelihood of responsiveness or an increased responsiveness of the individual to the treatment.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the prediction of an individual that is likely to be responsive to treatment by a HAP is made by comparing the determined STEAP4 expression levels in the tumour cells to the level of STEAP4 expression in a control sample.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E..
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • an elevated level of STEAP4 expression in the tumour cells relative to the reference level of STEAP4 expression correlates with an increased likelihood of responsiveness or an increased responsiveness of the individual to the treatment.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • an elevated level of STEAP4 expression in the tumour cells relative to the reference level of STEAP4 expression correlates with an increased likelihood of responsiveness or an increased responsiveness of the individual to the treatment.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • an elevated level of STEAP4 expression in the tumour cells relative to the reference level of STEAP4 expression correlates with an increased likelihood of responsiveness or an increased responsiveness of the individual to the treatment.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure also provides a method of predicting the responsiveness of an individual with cancer to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP comprising : a) providing tumour cells of the individual;
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the identification of an individual that is likely to be responsive to treatment by a HAP may be made by comparing the determined STEAP4 expression levels in the tumour cells to a reference level of STEAP4 expression.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the individual is likely to be responsive to the treatment with a HAP if the level of STEAP4 expression in the tumour cells is elevated relative to the reference level of STEAP4 expression.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • the individual is likely to be responsive to the treatment with a HAP if the level of STEAP4 expression in the tumour cells is elevated relative to the reference level of STEAP4 expression.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • an elevated level of STEAP4 expression in the tumour cells relative to the reference level of STEAP4 expression correlates with an increased likelihood of responsiveness or an increased responsiveness of the individual to the treatment.
  • the method further comprises administration of the HAP to the individual.
  • the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment.
  • the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene.
  • the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid.
  • the target nucleic acid is DNA.
  • the target nucleic acid is mRNA.
  • the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • an elevated level of STEAP4 expression in the tumour cells relative to the reference level of STEAP4 expression correlates with an increased likelihood of responsiveness or an increased responsiveness of the individual to the treatment.
  • the method further comprises administration of the HAP to the individual.
  • the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment.
  • the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene.
  • the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid.
  • the target nucleic acid is DNA.
  • the target nucleic acid is mRNA.
  • the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • an elevated level of STEAP4 expression in the tumour cells relative to the reference level of STEAP4 expression correlates with an increased likelihood of responsiveness or an increased responsiveness of the individual to the treatment.
  • the method further comprises administration of the HAP to the individual.
  • the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment.
  • the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene.
  • the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid.
  • the target nucleic acid is DNA.
  • the target nucleic acid is mRNA.
  • the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the identification of an individual that is likely to be responsive to treatment by a HAP is made by comparing the determined STEAP4 expression levels in the tumour cells to the level of STEAP4 expression in a control sample.
  • the method further comprises administration of the HAP to the individual.
  • the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment.
  • the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene.
  • the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid.
  • the target nucleic acid is DNA.
  • the target nucleic acid is mRNA.
  • the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising : a) determining the level of STEAP4 expression in tumour cells of the individual;
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising : a) determining the level of STEAP4 expression in tumour cells of the individual;
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • an elevated level of STEAP4 expression in the tumour cells relative to the reference level of STEAP4 expression correlates with an increased likelihood of responsiveness or an increased responsiveness of the individual to the treatment.
  • the method further comprises administration of the HAP to the individual.
  • the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment.
  • the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene.
  • the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid.
  • the target nucleic acid is DNA.
  • the target nucleic acid is mRNA.
  • the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising : a) determining the level of STEAP4 expression in tumour cells of the individual;
  • an elevated level of STEAP4 expression in the tumour cells relative to the reference level of STEAP4 expression correlates with an increased likelihood of responsiveness or an increased responsiveness of the individual to the treatment.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising : a) determining the level of STEAP4 expression in a sample of tumour cells from the individual; and
  • an elevated level of STEAP4 expression in the tumour cells relative to the reference level of STEAP4 expression correlates with an increased likelihood of responsiveness or an increased responsiveness of the individual to the treatment.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure also provides a method of identifying an individual with cancer who is likely to be responsive to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is identified as being likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4- expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • a method for determining whether an individual with cancer is sensitive to a treatment with a HAP comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the determination of whether an individual is likely to be responsive to treatment by a HAP may be made by comparing the determined STEAP4 expression levels in the tumour cells to a reference level of STEAP4 expression.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the individual is likely to be sensitive to treatment to the treatment with a HAP if the level of STEAP4 expression in the tumour cells is elevated relative to the reference level of STEAP4 expression.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA.
  • the target nucleic acid is mRNA.
  • the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • the individual is likely to be sensitive to treatment to the treatment with a HAP if the level of STEAP4 expression in the tumour cells is elevated relative to the reference level of STEAP4 expression.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising : a) providing tumour cells of the individual;
  • an elevated level of STEAP4 expression in the tumour cells relative to the reference level of STEAP4 expression correlates with an increased likelihood of responsiveness or an increased responsiveness of the individual to the treatment.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • an elevated level of STEAP4 expression in the tumour cells relative to the reference level of STEAP4 expression correlates with an increased likelihood of responsiveness or an increased responsiveness of the individual to the treatment.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • an elevated level of STEAP4 expression in the tumour cells relative to the reference level of STEAP4 expression correlates with an increased likelihood of responsiveness or an increased responsiveness of the individual to the treatment.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the determination of whether an individual is likely to be responsive to treatment by a HAP is made by comparing the determined STEAP4 expression levels in the tumour cells to the level of STEAP4 expression in a control sample.
  • the method further comprises administration of the HAP to the individual.
  • the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment.
  • the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene.
  • the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid.
  • the target nucleic acid is DNA.
  • the target nucleic acid is mRNA.
  • the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • an elevated level of STEAP4 expression in the tumour cells relative to the reference level of STEAP4 expression correlates with an increased likelihood of sensitivity of the individual to the treatment.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • an elevated level of STEAP4 expression in the tumour cells relative to the reference level of STEAP4 expression correlates with an increased likelihood of sensitivity of the individual to the treatment.
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the present disclosure provides a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • the method further comprises administration of the HAP to the individual. In another embodiment, the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment. In certain embodiments, the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene. In another embodiment, the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid. In one embodiment, the target nucleic acid is DNA. In another embodiment, the target nucleic acid is mRNA. In another embodiment, the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • Also provided herein is a method of determining whether an individual with cancer is sensitive to treatment with a HAP, the method comprising :
  • tumour cells of the individual a) providing tumour cells of the individual
  • the method is a method of identifying whether the individual with cancer is likely to be sensitive to treatment to the treatment.
  • the method further comprises administration of the HAP to the individual.
  • the method further comprises administration of the HAP to the individual if the individual is predicted to be likely to be responsive to the treatment.
  • the HAP is administered in a therapeutically effective amount.
  • the level of STEAP4 expression is expression of a STEAP4 gene.
  • the level of STEAP4 expression is expression of a STEAP4-expressing target nucleic acid.
  • the target nucleic acid is DNA.
  • the target nucleic acid is mRNA.
  • the level of STEAP4 expression is expression of a STEAP4 protein.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A.
  • the HAP is Compound C.
  • the HAP is Compound E.
  • the method further comprises administering a therapeutically effective amount of a HAP to the individual. In some embodiments, the method further comprises administering a therapeutically effective amount of a HAP to the individual who is likely to be responsive to the treatment.
  • the HAP comprises an NMQ prodrug and/or a nitrophenyl mustard.
  • the HAP is Compound A. In other embodiments, the HAP is Compound C. In other embodiments, the HAP is Compound E.
  • cancer and “cancerous” as used herein may refer to any cancer or cancerous condition and refers to the physiological condition in mammals characterised by unregulated cell growth or a malignant tumour.
  • Suitable cancers include, but are not limited to, prostate cancer (including but not limited to neuroendocrine prostate cancer/NEPC), lung cancer (including but not limited to lung adenocarcinoma, lung squamous cell cancer, small cell lung cancer, non-small cell lung cancer/NSCLC, and mesothelioma), breast cancer, esophageal cancer, head and neck cancer, upper aerodigestive tract cancer, neuroblastoma, cancer of the brain (including but not limited to glioma), cancer of the kidney, leukemia, chronic lymphocytic leukemia (CLL), monoclonal B cell lymphocytosis (MBL), childhood B-cell acute lymphobastic leukemia (B- ALL), chronic myeloid leukemia (CML), T-cell acute lymphobastic leukemia (T-ALL), sarcoma (including but not limited to Ewings sarcoma), pancreatic cancer, gastric cancer (also known as stomach cancer), desmoplastic small-round-cell
  • the cancer is a prostate cancer. In one embodiment, the cancer is a neuroendocrine prostate cancer (NEPC). In another embodiment, the cancer is a lung cancer. In one embodiment, the cancer is a lung adenocarcinoma. In another embodiment, the cancer is a lung squamous cell cancer. In another embodiment, the cancer is a small cell lung cancer. In another embodiment, the cancer is a non-small cell lung cancer (NSCLC). In another embodiment, the cancer is a mesothelioma. In another embodiment, the cancer is a breast cancer. In another embodiment, the cancer is a esophageal cancer. In another embodiment, the cancer is a head and neck cancer. In another embodiment, the cancer is a upper aerodigestive tract cancer.
  • NEPC neuroendocrine prostate cancer
  • the cancer is a lung cancer. In one embodiment, the cancer is a lung adenocarcinoma. In another embodiment, the cancer is a lung squamous cell cancer. In another embodiment, the cancer is
  • the cancer is a neuroblastoma. In another embodiment, the cancer is a cancer of the brain. In one embodiment, the cancer is a glioma). In another embodiment, the cancer is a cancer of the kidney. In another embodiment, the cancer is a leukemia. In another embodiment, the cancer is a chronic lymphocytic leukemia (CLL). In another embodiment, the cancer is a monoclonal B cell lymphocytosis (MBL) . In another embodiment, the cancer is a childhood B-cell acute lymphobastic leukemia (B-ALL). In another embodiment, the cancer is a chronic myeloid leukemia (CML). In another embodiment, the cancer is a T-cell acute lymphobastic leukemia (T-ALL).
  • CLL chronic lymphocytic leukemia
  • MBL monoclonal B cell lymphocytosis
  • B-ALL childhood B-cell acute lymphobastic leukemia
  • CML chronic myeloid leukemia
  • T-ALL T-cell acute lymphob
  • the cancer is a sarcoma. In one embodiment, the cancer is a Ewings sarcoma. In another embodiment, the cancer is a pancreatic cancer. In another embodiment, the cancer is a gastric cancer (also known as stomach cancer) . In another embodiment, the cancer is a desmoplastic small-round-cell tumour (DESM). In another embodiment, the cancer is a uterine cancer. In another embodiment, the cancer is a uterine carcinosarcoma (UCS). In another embodiment, the cancer is a acute myeloid leukemia (AML). In another embodiment, the cancer is a B-cell acute lymphobastic leukemia (B-ALL). In another embodiment, the cancer is a liver cancer.
  • AML acute myeloid leukemia
  • B-ALL B-cell acute lymphobastic leukemia
  • the cancer is a bladder cancer. In another embodiment, the cancer is a cancer of the urinary tract. In another embodiment, the cancer is a childhood acute myeloid leukemia (AML). In another embodiment, the cancer is a renal cancer. In another embodiment, the cancer is a colorectal cancer. In another embodiment, the cancer is a cervical cancer. In another embodiment, the cancer is a multiple myeloma. In another embodiment, the cancer is a endometrial cancer. In another embodiment, the cancer is a ovarian cancer. In another embodiment, the cancer is a lymphoma. In one embodiment, the cancer is a diffuse large B- cell lymphoma (DLBCL). In another embodiment, the cancer is a Hodgkin's lymphoma.
  • DLBCL diffuse large B- cell lymphoma
  • the cancer is a non-Hodgkin's lymphoma. In one embodiment, the cancer is a Burkitt lymphoma. In another embodiment, the cancer is a glioblastoma. In another embodiment, the cancer is a medulloblastoma. In another embodiment, the cancer is a melanoma. In another embodiment, the cancer is a cutaneous T-cell lymphoma (CTCL). In another embodiment, the cancer is a astrocytoma. In another embodiment, the cancer is a bile duct cancer. In one embodiment, the cancer is a cholangiocarcinoma. In another embodiment, the cancer is a osteosarcoma. In another embodiment, the cancer is a meningioma. In another embodiment, the cancer is a thyroid cancer. In another embodiment, the cancer is a soft tissue sarcoma. In another embodiment, the cancer is a and chondrosarcoma.
  • CTCL cutaneous T-cell lymphoma
  • the cancer is
  • the cancer is selected from the group consisting of prostate cancer, lung cancer (including but not limited to lung adenocarcinoma, lung squamous cell cancer, and mesothelioma), breast cancer, esophageal cancer, gastric cancer, cervical cancer, squamous cell carcinoma of the cervix, squamous cell carcinoma of the head and neck, liver cancer, neuroblastoma, chronic myeloid leukemia, and sarcoma.
  • the cancer is a prostate cancer.
  • the cancer is a lung cancer.
  • the cancer is a lung adenocarcinoma.
  • the cancer is a lung squamous cell cancer.
  • the cancer is a mesothelioma. In an embodiment, the cancer is a breast cancer. In another embodiment, the cancer is a esophageal cancer. In another embodiment, the cancer is a gastric cancer. In an embodiment, the cancer is a cervical cancer. In one embodiment, the cancer is a squamous cell carcinoma of the cervix. In another embodiment, the cancer is a squamous cell carcinoma of the head and neck. In another embodiment, the cancer is a liver cancer. In another embodiment, the cancer is a neuroblastoma. In another embodiment, the cancer is a chronic myeloid leukemia. In one embodiment, the cancer is a sarcoma.
  • the combinations disclosed herein are administered to treat cancer.
  • the cancer to be treated comprises lung cancer.
  • the lung cancer comprises non-small cell lung cancer.
  • the cancer comprises gastric cancer.
  • the cancer comprises breast cancer.
  • the cancer comprises head and neck squamous cell carcinoma (HNSCC).
  • the cancer comprises gastric/gastroesophageal (GE) junction cancer.
  • the cancer comprises oesophageal cancer.
  • the cancer comprises salivary cancer.
  • the cancer comprises ovarian cancer.
  • the cancer comprises endometrial cancer.
  • the cancer comprises uterine cancer. In yet other embodiments, the cancer comprises pancreatic cancer. In certain embodiments, the cancer comprises biliary tract cancer. In certain embodiments, the cancer comprises bladder cancer. In certain embodiments, the cancer comprises colorectal cancer. In certain embodiments, the cancer comprises renal cancer. In certain embodiments, the cancer comprises brain and/or spinal cord cancer (glioblastoma). In some embodiments, the cancer comprises lymphoma, e.g., primary central nervous system lymphoma. In some embodiments, the cancer comprises leukaemia, e.g., acute lymphoblastic leukaemia.
  • the cancer is selected from the group of lung cancer, gastric cancer, breast cancer, HNSCC, GE junction cancer, oesophageal cancer, salivary cancer, ovarian cancer, endometrial cancer, uterine cancer, prostate cancer, pancreatic cancer, colon cancer, biliary tract cancer, bladder cancer, colorectal, renal, glioblastoma, mesothelioma, adenocarcinoma, lymphoma, and leukaemia.
  • the cancer is selected from bone cancer, lung cancer, breast cancer, cancer of the head and neck, prostate cancer, pancreatic cancer, skin cancer, uterine cancer, ovarian cancer, cancer of the urethra, cancer of the adrenal gland, cancer of the small intestine, cancer of the kidney, cancer of the bladder, cancers of the brain, colorectal cancer, oesophageal cancer, gastric cancer, anal cancer, liver cancer, thyroid cancer, ocular cancer, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland and testicular cancer.
  • the cancer is selected from chronic or acute leukaemia, acute myeloid leukaemia, chronic myeloid leukaemia, acute lymphoblastic leukaemia, chronic lymphocytic leukaemia, carcinoma of the cervix, carcinoma of the vulva, carcinoma of the vagina, Hodgkin's Disease, brain stem glioma, melanoma, Merkel cell carcinoma, Urothelial carcinoma, lymphomas, gliomas, meningiomas, pituitary adenomas, nerve sheath tumours, and retinoblastoma, and non-small cell lung cancer.
  • the cancer is non-small cell lung cancer.
  • the cancer is prostate cancer.
  • the cancer is cervical carcinoma.
  • the cancer is breast cancer.
  • the cancer is brain cancer.
  • the cancer is glioblastoma.
  • the cancer is spinal cord cancer.
  • the cancer is a solid tumour.
  • Solid tumours are abnormal masses of tissue that usually do not contain cysts or liquid areas. Solid tumours can be benign or malignant. Different types of solid tumours are named for the type of cells that form them (such as sarcomas, carcinomas, and lymphomas).
  • the solid tumour can be sarcomas and carcinomas, include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteosarcoma, and other sarcomas, synovioma, mesothelioma, Ewing's tumour, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, lymphoid malignancy, pancreatic cancer, breast cancer, lung cancers, ovarian cancer, prostate cancer, oesophageal adenocarcinoma, oesophageal squamous cell carcinoma, squamous cell carcinoma of the head and neck (HNSCC), oral carcinoma, gastric carcinoma, hepatocellular carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, medullary thyroid carcinoma, papillary thyroid carcinoma, pheochromocytomas sebaceous gland carcinoma, papillary carcinoma,
  • the solid tumour is malignant melanoma, adrenal carcinoma, breast carcinoma, renal cell cancer, carcinoma of the pancreas, non-small-cell lung carcinoma (NSCLC) or carcinoma of unknown primary.
  • NSCLC non-small-cell lung carcinoma
  • the solid tumour is breast cancer, ovarian cancer, brain cancer, gastric cancer, oesophageal cancer prostate cancer, lung cancer, colon cancer, skin cancer, liver cancer, pancreatic cancer, and thyroid cancer.
  • the solid tumour is selected from the groups consisting of carcinoma, melanoma, sarcoma, or chronic granulomatous disease.
  • HAP Hypoxia-Activated Prodrug
  • the hypoxia-activated prodrug may be any suitable HAP that is capable of being converted to an active drug molecule in a hypoxic tumour environment where the active molecule is sufficiently long-lived and able to penetrate the cell membrane in order to kill the cell. Many such HAPs are known. All are potential candidates for use in any of the disclosed methods.
  • the HAPs are nitromethylaryl quaternary ammonium salts (often referred to as NMQ prodrugs) or nitrophenyl mustards.
  • NMQ prodrugs are broadly described in PCT publications WO 2010/104406 and WO 2011/028135. However, it should be appreciated that the NMQ prodrugs for use in the disclosed methods are not limited to the compounds described in WO 2010/104406 and WO 2011/028135.
  • NMQ prodrugs are quaternary ammonium salts where at least one group bound to the ammonium nitrogen atom comprises a moiety capable of being reduced so that following reduction the fragmenting and release of an active molecule is triggered and the active molecule is able to penetrate the cell membrane and then cause cell death.
  • HAPs for example, a HAP having the structures of Compound A.
  • STEAP4 increases and/or causes the metabolism of Compound A to its active metabolite, Compound B: Compound B, or RN-4000E, or TRLX-TKI.
  • Compound B Compound B
  • RN-4000E Compound B
  • TRLX-TKI TRLX-TKI
  • HAPs for example, HAPs having the structure of Compound C and Compound E.
  • NMQ prodrugs of quaternary nitrogen salts of Formula I are provided herein.
  • X is any negatively charged counterion
  • Ri is a group of the formula -(CH2) n Tr, where Tr is an aromatic nitroheterocycle or aromatic nitrocarbocycle and -(CH2) n Tr acts as a reductively-activated fragmenting trigger; and n is an integer from 0 to 6;
  • R 2 , R 3 and R 4 may each independently be selected from aliphatic or aromatic groups of a tertiary amine kinase inhibitor (R 2 )(R 3 )(R 4 )N, or two of R 2 , R 3 , and R 4 may form an aliphatic or aromatic heterocyclic amine ring of a kinase inhibitor, or one of R 2 , R 3 and R 4 may be absent and two of R 2 , R 3 and R 4 form an aromatic heterocyclic amine ring of a kinase inhibitor.
  • the NMQ prodrugs are quaternary ammonium salts of Formula II:
  • X is any negatively charged counterion
  • Y is N or C-R7, where R 7 is selected from the group consisting of H, C1-C6 alkyl, C1-C6 alkoxy and groups of Formula III:
  • T is selected from O, NH, N(C I -C 6 alkyl) and a direct link;
  • n is selected from integers from 0 to 6;
  • U is selected from ORio, CF3, OCF3, CN, NR11R12, pyrrolidinyl, piperidinyl, piperazinyl, Nl-methylpiperazinyl, morpholinyl, CON(Ri3)(Ri 4 ), S02N(Ris)(Ri 6 ), N(RI 7 )CORI S , N(Rig)S02R2o, COR21, SOR22, SO2R23 and COOR24; and Re, R9, Rio, Rll, R12, R13, R14 R15, Rl6, Rl7, Rl8, Rl9, R20, R2I, R22, R23, R24 Q GQ independently selected from H and C 1 -C 6 alkyl;
  • Z is N or C-CN
  • n is an integer from 0 to 6;
  • Ri is a group of the formula (CH 2 ) n Tr where Tr is an aromatic nitroheterocycle or aromatic nitrocarbocycle and -(CH 2 ) n Tr acts as a reductively-activated fragmenting trigger; and n is an integer from 0 to 6;
  • R 2 and R 3 are independently selected from C 1 -C 6 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, CH 2 CH 2 OH, CH 2 CH 2 0(C I -C 6 alkyl), or R 2 and R 3 may together form a non-aromatic carbocyclic ring or non-aromatic heterocyclic ring containing at least one heteroatom;
  • R 5 is selected from anilines, indoles, indolines, amines, aminoindoles and aminoindazoles, each of which may be optionally substituted with one or more substituents selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, C 1 -C 6 alkoxy, F, Cl, Br, I, CN, CH2F, CHF2, CF 3 , OH, NH 2 , N0 2 , NH(CI-C 6 alkyl), N(CI-C 6 alkyl) 2 , CONH 2 , CO(Ci-C 6 alkyl), SO2NH2 and S0 2 (Ci-C 6 alkyl); and
  • R 6 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, NH(CI-C 6 alkyl), N(CI-C 6 alkyl)2 and groups of Formula IV:
  • V is selected from (CH 2 ) k where k is an integer from 0 to 6, O, NH and N(C I -C 6 alkyl);
  • R2 5 is selected from H and C 1 -C 6 alkyl.
  • X may be selected from halide (fluoride, chloride, bromide, iodide), methanesulfonate, trifluoromethanesulfonate, acetate, trifluoroacetate, tosylate, lactate, citrate and formate.
  • Ri may be selected from groups of Formula V:
  • R2 6 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C2-C 6 alkenyl, C2-C 6 alkynyl, CF 3 , OCF 3 , F, Cl, Br, I, NO2, CN, COOH, COO(Ci-C 6 alkyl), CONH 2 , CONH(CI-C 6 alkyl), CON(CI-C 6 alkyl) 2 , CO(Ci-C 6 alkyl), SO2NH2, S0 2 NH(Ci-C 6 alkyl), S0 2 N(Ci-C 6 alkyl) 2 , S0 2 (Ci-C 6 alkyl) and groups of Formula Ilia as defined above but where * is the point of attachment to a group of Formula V;
  • R 27 is selected from the group consisting of H, C 1 -C 6 alkyl and groups of Formula Ilia as defined above but where * is the point of attachment to a group of Formula V;
  • R2 8 is selected from H and C 1 -C 6 alkyl.
  • Ri is a group of one of the following Formulas Vr-Vae:
  • Ri may be selected from groups of Formula Vc, where R 26 is H and R27 is CH 3 . In certain embodiments, Ri may also be selected from groups of Formula Vd, where
  • R2 6 is selected from H, C 1 -C 6 alkyl (such as methyl), C 1 -C 6 alkoxy (such as OCH 3 ), C2-C 6 alkynyl (such as ethynyl), CONH 2 , CONHMe, CF 3 , OCF 3 , Br, NO 2 and CN, and R 27 is selected from CH 3 , CH2CH2CONH2 and CH2CH2CN.
  • Ri may also be selected from groups of Formula Vd :
  • R 26 is selected from H and C 1 -C 3 alkyl
  • R 27 is selected from H and C1-C6 alkyl .
  • R 26 is H and R 27 is C 1 -C 3 alkyl e.g., methyl .
  • Ri is selected from groups of Formula Vd, where R26 is 1- propynyl and R27 IS CH 3 .
  • Ri is selected from groups of Formula Vq, where R26 is selected from H, C 1 -C 6 alkyl (such as methyl or ethyl) and C 1 -C 6 alkoxy (such as OCH 3 ), and R27 is CH 3 .
  • Ri is a group of Formula Vq, where R26 is selected from H,
  • C 1 -C 6 alkyl e.g., methyl or ethyl
  • C 1 -C 6 alkoxy e.g., OCH 3
  • R27 is CH 3 .
  • Ri is a group of any one of Formulas Vd (1) -Vd (7) :
  • R 27 is selected from methyl, ethyl and propyl . In certain embodiments R 27 is methyl .
  • R 2 and R 3 may form a ring selected from pyrrolidinium, piperidinium, piperazinium, N l -methylpiperazinium and morpholinium.
  • R5 may be selected from groups of Formula VI :
  • R29, R36, R37, R39, R44, R49 and R54 are independently selected from H and C1-C6 alkyl
  • R30 / R31 / R32, R33 / R34, R35 / R38 / R40 / R41, R42, R43 / R45 / R46 / R47, R48 / R50 / Rsi / R52, R53 / R 55 , R 56 , R 57 and R 58 are independently selected from H, C 1 -C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, Ci-C 6 alkoxy, F, Cl, Br, I, CN, CH 2 F, CHF 2 , CF 3 , OH, NH 2 , N0 2 , NH(CI-C 6 alkyl), N(CI-C 6 alkyl) 2 , CONH 2 , CO(Ci-C 6 alkyl), SO2NH2 and S0 2 (Ci-C 6 alkyl); and
  • W is N or C-H.
  • Y is N, Z is N or C-CN;
  • Ri is selected from the following :
  • R 26 is selected from H, C 1 -C 6 alkyl (such as methyl), C 1 -C 6 alkoxy (such as OCH 3 ), C 2 -C 6 alkynyl (such as ethynyl), CF 3 , OCF 3 , Br, NO 2 and CN, and R 27 is selected from CH 3 , CH 2 CH 2 CONH 2 and CH 2 CH 2 CN; or (ii) R 26 is 1-propynyl and R 27 is CH 3 ;
  • R 26 is selected from H, C 1 -C 6 alkyl (such as methyl or ethyl) and C 1 -C 6 alkoxy (such as OCH 3 ), and R 27 is CH 3 ;
  • R 2 and R 3 are independently selected from C 1 -C 6 alkyl, or together form a ring selected from pyrrolidinium, piperidinium, piperazinium, Nl-methylpiperazinium and morpholinium;
  • R. 5 is selected from the following :
  • R 30 , R 31 , R 32 are independently selected from H, C 1 -C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C 1 -C 6 alkoxy, F, Cl, Br, I, CN, CH 2 F, CHF 2 , CF 3 , OH, NH 2 , N0 2 , NH(CI-C 6 alkyl), N(CI-C 6 alkyl) 2 ;
  • R 42 and R 43 are independently selected from H, C 1 -C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C 1 -C 6 alkoxy, F, Cl, Br, I, CN, CH 2 F, CHF 2 , CF 3 , OH, NH 2 , N0 2 , NH(CI-C 6 alkyl), N(CI-C 6 alkyl) 2 ;
  • R 42 and R 43 are independently selected from H, C 1 -C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C 1 -C 6 alkoxy, F, Cl, Br, I, CN, CH 2 F, CHF 2 , CF 3 , OH, NH 2 , N0 2 , NH(CI-C 6 alkyl), N(CI-C 6 alkyl) 2 , W is N
  • Y is C-H or C-(Ci-C 6 alkoxy), Z is N or C-CN;
  • Ri is selected from the following :
  • R2 6 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C2-C 6 alkynyl, CF 3 , OCF 3 , Br, NO2 and CN, and R27 is selected from CH 3 , CH2CH2CONH2 and CH 2 CH 2 CN; or R 26 IS 1-propynyl and R 27 is CH 3 ;
  • R 26 is selected from H, C 1 -C 6 alkyl (such as methyl or ethyl) and C 1 -C 6 alkoxy (such as OCH 3 ), and R27 is CH 3 ;
  • R 2 and R 3 are independently selected from C 1 -C 6 alkyl, or together form a ring selected from pyrrolidinium, piperidinium, piperazinium, Nl-methylpiperazinium and morpholinium;
  • R 5 is selected from the following :
  • R 29 is H
  • R 30 , R 31 , R 32 are independently selected from H, C 1 -C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C 1 -C 6 alkoxy, F, Cl, Br, I, CN, CH 2 F, CHF 2 , CF 3 , OH, NH 2 , N0 2 , NH(CI-C 6 alkyl), N(CI-C 6 alkyl) 2 ;
  • R 39 is H
  • R 40 and R 41 are independently selected from H, C 1 -C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C 1 -C 6 alkoxy, F, Cl, Br, I, CN, CH 2 F, CHF 2 , CF 3 , OH, NH 2 , N0 2 , NH(CI-C 6 alkyl), N(CI-C 6 alkyl) 2
  • R 42 and R 43 are independently selected from H, C 1 -C 6 alkyl, C2-C 6 alkenyl, C2-C 6 alkynyl, C 1 -C 6 alkoxy, F, Cl, Br, I, CN, CH 2 F, CHF 2 , CF 3 , OH, NH 2 , N0 2 , NH(CI-C 6 alkyl), N(CI-C 6 alkyl) 2
  • W is N or C
  • R 6 is H
  • X is any negatively charged counterion
  • n l or 2.
  • Y is C-R7, where R7 is a group of Formula Illb; Z is N or C-
  • Ri is selected from the following :
  • R 26 is selected from H, C 1 -C 6 alkyl, C 1 -C 6 alkoxy, C 2 -C 6 alkynyl, CF 3 , OCF 3 , Br, N0 2 and CN, and R 27 is selected from CH 3 , CH 2 CH 2 CONH 2 and CH 2 CH 2 CN; or R 26 is 1-propynyl; and R 27 is CH 3 ;
  • R 26 is selected from H, C 1 -C 6 alkyl (such as methyl or ethyl) and C 1 -C 6 alkoxy (such as OCH 3 ); and R 27 is CH 3 ;
  • R 2 and R 3 are independently selected from C 1 -C 6 alkyl, or together form a ring selected from pyrrolidinium, piperidinium, piperazinium, Nl-methylpiperazinium and morpholinium;
  • R 5 is selected from the following :
  • R 30 , R 31 , R 32 are independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 alkoxy, F, Cl, Br, I, CN, CH 2 F, CHF 2 , CF 3 , OH, NH 2 , N0 2 , NH(Ci- C 6 alkyl), N(CI-C 6 alkyl) 2 ;
  • R 39 is H; and R 4o and R 4I are independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 alkoxy, F, Cl, Br, I, CN, CH 2 F, CHF 2 , CF 3 , OH, NH 2 , N0 2 , NH(Ci- C 6 alkyl), N(CI-C 6 alkyl) 2 ; R 42 and R 43 are independently selected from H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, Ci-C 6 alkoxy, F, Cl, Br, I, CN, CH 2 F, CHF 2 , CF 3 , OH, NH 2 , N0 2 , NH(Ci- C 6 alkyl), N(C I)
  • R 6 is H
  • X is any negatively charged counterion
  • n l or 2. Also provided herein are compounds of Formula VII as kinase inhibitors released from an NMQ prodrug :
  • R.60 is (3-chlorobenzyl)oxy- and R 6I is chloro;
  • R 6O is 2-pyridinylmethoxy and R 6I is chloro;
  • R 6O and R 6I are both chloro
  • R 6O and R 6I are both bromo
  • R 6O is fluoro and R 6I is ethynyl
  • R 6O is chloro and R 6I is ethynyl
  • R 6O is bromo and R 6I is ethynyl
  • R 6O is 2-pyridinylmethoxy and R 6I is fluoro
  • R 6O is 2-pyridinylmethoxy and R 6I is bromo
  • R59, R60 and R 6I is selected from benzyloxy, 3-chlorobenzyloxy and 2- pyridinylmethoxy and when at least one of R59, R60 and R 6I is not benzyloxy, 3- chlorobenzyloxy or 2-pyridinylmethoxy, each of the others is independently selected from H, halogen, and C2-C4 alkynyl, with the proviso that when one of R59, R60 and R 6 I is benzyloxy or 2-pyridinylmethoxy, the other two of R59, R60 and R 6I are not H;
  • the compound of Formula VII is a compound according to Formula VIII:
  • R 6 2 is H, and either
  • R.63 is (3-chlorobenzyl)oxy- and R 6 4 is chloro;
  • R 6 3 is 2-pyridinylmethoxy and R 6 4 is chloro;
  • R 6 3 and R 6 4 are both chloro
  • R 6 3 is chloro and R 6 4 is bromo
  • R 6 3 and R 6 4 are both bromo
  • R 6 3 is fluoro and R 6 4 is ethynyl
  • R 6 3 is chloro and R 6 4 is ethynyl
  • R 6 3 is bromo and R 6 4 is ethynyl
  • R 6 3 is bromo and R 6 4 is fluoro
  • R 6 3 is 2-pyridinylmethoxy and R 6 4 is fluoro;
  • R 6 3 is 2-pyridinylmethoxy and R 6 4 is bromo.
  • the compound of Formula VII is selected from the group consisting of:
  • the NMQ prodrugs are quaternary ammonium salts of Formula X:
  • Formula X wherein X is any negatively charged counterion, R59, R60 and R 6 I are as defined for Formula VII, R 6 5 is selected from H, methyl, ethyl, trifluoromethyl, -CN, -CONH2 and propyn-l-yl, and R 66 is C1-C6 alkyl.
  • the NMQ prodrugs are quaternary ammonium salts of
  • R59, R60 and R 6 I are as defined for Formula VII and R 6 7 is selected from H, methyl, ethyl, trifluoromethyl, -CN, -CONH2 and propyn-l-yl.
  • the NMQ prodrugs are quaternary ammonium salts of
  • Formula XII wherein X is any negatively charged counterion, R 6 2, R63 and R 6 4 are as defined for Formula VIII and R 68 is selected from H, methyl, ethyl, trifluoromethyl, -CN, -CONH2 and propyn-l-yl.
  • X is selected from halide (fluoride, chloride, bromide, iodide), methanesulfonate, trifluoromethanesulfonate, acetate, trifluoroacetate, tosylate, lactate, citrate and formate.
  • the NMQ prodrugs are quaternary ammonium salts selected from the group consisting of:
  • the compounds are selected from the group consisting of:
  • the HAP is a nitrophenyl mustard compound.
  • Certain nitrophenyl mustards are broadly described in PCT publications WO 2005/042471 and WO 2014/031012. These compounds include compounds of Formula XIII:
  • Xi represents at any available ring position -CONH-, -SO2NH-, -0-, -CH2-, -NHCO- or -NHSO2-;
  • R.69 represents a lower Ci- 6 alkyl optionally substituted with one or more groups including hydroxy, amino and N-oxides therefrom or dialkylamino and N-oxides therefrom;
  • Yi represents at any available ring position -N-aziridinyl, -N(CH2CH2W I )2 or
  • each Wi is independently selected from halogen or -OSC ⁇ Me;
  • Zi represents at any available ring position -NO 2 , -halogen, -CN, -CF 3 or -S0 2 Me.
  • the compound of Formula (XIII) is selected from a compound represented by Formula XIV, Formula XV or Formula XVI:
  • n 1 to 6
  • Z 2 represents -NO 2 , -halogen, -CN, -CF 3 or -S0 2 Me;
  • each W2 is independently selected from halogen or -OSC ⁇ Me.
  • the phosphate compound of Formula XIII is selected from the group consisting of:
  • nitrophenyl mustards also include compounds of Formula XVII:
  • X 3 represents at any available ring position -CONH-, -SO2NH-, -0-, -CH2-, -NHCO- or -NHSO2-;
  • Y 3 represents at any available ring position -N-aziridinyl, -N(CH 2 CH 2 W 3 ) 2 , or
  • each W 3 is independently selected from halogen or - 0S0 2 Me;
  • Z 3 represents at any available ring position -NO 2 , -halogen, -CN, -CF 3 or -S0 2 Me;
  • R 70 represents a lower Ci- 6 alkyl optionally substituted with one or more groups including hydroxy, amino and N-oxides therefrom or dialkylamino and N-oxides therefrom.
  • the alcohol compound of Formula XVII is selected from a compound represented by Formulae XVIII, Formula XIX or Formula XX:
  • Y 4 may represent or N
  • n 1 to 6
  • Z 4 represents -NO 2 , -halogen, -CN, -CF 3 or -S0 2 Me;
  • each W 4 is independently selected from halogen or -OSC ⁇ Me.
  • the compound of Formula XVII is selected from the group consisting of:
  • the nitrophenyl mustards are compounds of the Formula
  • X 5 represents Cl, Br, I, OSO2R7 1 ,
  • Y 5 represents H, CN, SO2R7 1 ,
  • each R71 independently represents a C1-6 alkyl group
  • Z 5 is selected from any of the radicals of Formula XXII:
  • R72 represents H, or a Ci- 6 alkyl group
  • R7 3 and R7 4 may independently represent H, or a C 1 -C 6 alkyl group, or R 73 and R 74 together may be linked to form a substituted or unsubstituted heterocyclic ring comprising 5 or 6 members;
  • n 2 to 6;
  • Nitrophenyl mustards of WO 2014/031012 include compounds of Formula XXIII:
  • Y 6 represents H, CN, SO2R75,
  • R 75 represents a methyl or ethyl group
  • Z 6 is selected from any of the radicals of Formula XXIV:
  • R76 represents H, or a C1-C6 alkyl group
  • R77 and R78 may independently represent H, or a C1-C6 alkyl group, or
  • R77 and R78 together may be linked to form a substituted or unsubstituted heterocyclic ring comprising 5 or 6 members;
  • n 2 to 6;
  • Nitrophenyl mustards of WO 2014/031012 also include compounds of Formula XXV:
  • n 2 to 6
  • W 7 represents Cl, Br, I, OSO2R79,
  • X7 represents Cl, Br, I, OSO2R79,
  • each R79 independently represents a C1-C6 alkyl group
  • Rso represents H, or a C1-C6 alkyl group.
  • W 7 may be bromine or iodine.
  • X7 may be bromine or OS0 2 Me.

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Abstract

Dans certains aspects, l'invention concerne des procédés d'utilisation d'un antigène épithélial six transmembranaire de la prostate 4 (STEAP4) dans le métabolisme de certains promédicaments activés par l'hypoxie (HAP), et leur application dans des thérapies anticancéreuses, y compris des procédés de prédiction de la réactivité d'un individu atteint d'un cancer à un traitement avec un HAP sur la base de niveaux d'expression STEAP4..
PCT/NZ2018/050180 2017-12-19 2018-12-18 Utilisation de biomarqueur en thérapie du cancer WO2019125184A1 (fr)

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WO2019229195A1 (fr) * 2018-05-30 2019-12-05 Convert Pharmaceuticals S.A. Promédicaments et leurs utilisations médicales
WO2020205627A1 (fr) * 2019-03-29 2020-10-08 Rain Therapeutics Inc. Utilisation de biomarqueur dans la thérapie du cancer

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