WO2012009475A1 - Méthodes de traitement du cancer par inhibition de la déméthylase 1 spécifique de la lysine - Google Patents

Méthodes de traitement du cancer par inhibition de la déméthylase 1 spécifique de la lysine Download PDF

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WO2012009475A1
WO2012009475A1 PCT/US2011/043911 US2011043911W WO2012009475A1 WO 2012009475 A1 WO2012009475 A1 WO 2012009475A1 US 2011043911 W US2011043911 W US 2011043911W WO 2012009475 A1 WO2012009475 A1 WO 2012009475A1
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inhibitor
lsdl
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cancer
parp
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Joshi Alumkal
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Oregon Health & Science University
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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
    • 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
    • A61K31/13—Amines
    • A61K31/132—Amines having two or more amino groups, e.g. spermidine, putrescine
    • 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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • A61K31/502—Pyridazines; Hydrogenated pyridazines ortho- or peri-condensed with carbocyclic ring systems, e.g. cinnoline, phthalazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This disclosure concerns inhibitors of lysine-specific demethylase 1 (LSD1), inhibitors of HDAC, and DNA damaging agents or inhibitors of PARP, and methods of their use for treating human diseases, such as cancer.
  • LSD1 lysine-specific demethylase 1
  • HDAC lysine-specific demethylase 1
  • PARP DNA damaging agents or inhibitors of PARP
  • Cancer of the prostate is the most commonly diagnosed cancer in men and is the second most common cause of cancer death (Carter and Coffey, Prostate 16:39- 48, 1990; Armbruster et al, Clinical Chemistry 39: 181, 1993). If detected at an early stage, prostate cancer is potentially curable. However, a majority of cases are diagnosed at later stages when metastasis of the primary tumor has already occurred (Wang et al, Meth. Cancer Res. 19: 179, 1982). Even early diagnosis is problematic because not all individuals who test positive in these screens develop cancer.
  • ADT androgen deprivation therapy
  • ADT works by lowering levels of androgens or interfering with androgen binding to and activation of the androgen receptor (AR).
  • AR androgen receptor
  • ADT is not curative, and "castration-resistance" is common (Scher and Sawyers, /. Clin. Oncol. 23:8253-8261, 2005).
  • Chemotherapy agents, such as docetaxel, and combination chemotherapy regimens are used to treat castration-resistant prostate cancer (CRPC; also referred to as hormone-refractory prostate cancer).
  • CRPC castration-resistant prostate cancer
  • the prognosis remains poor for individuals with CRPC.
  • LSDl lysine-specific demethylase 1
  • PARP poly (ADP-ribose) polymerase
  • HDAC histone deacetylase
  • the methods include administering a therapeutically effective amount of an LSDl inhibitor to a subject with cancer.
  • the cancer is prostate cancer (such as CRPC or small cell prostate carcinoma).
  • the methods include administering a
  • the LSDl inhibitor includes any inhibitor of LSDl, such as a small organic molecule, an RNA interference molecule, a peptide, or an antibody.
  • the LSDl inhibitor is a polyamine analog, such as XB154, PG11144, PG11047.
  • the LSDl inhibitor decreases the expression of one or more BRCA or Fanconi anemia (FA) gene(s), such as BRCA1, BRCA2, FANCA, FANCB, FANCC, FANCD2, FANCG, or, FANCM.
  • the PARP inhibitor includes any inhibitor of PARP, such as a small organic molecule (for example, olaparib).
  • the disclosed methods include administering a therapeutically effective amount of an HDAC inhibitor and a therapeutically effective amount of a PARP inhibitor to a subject with cancer (such as prostate cancer, breast cancer, or ovarian cancer).
  • the HDAC inhibitor includes any inhibitor of HDAC, such as a small organic molecule, an RNA interference molecule, a peptide, or an antibody.
  • the HDAC inhibitor is vorinostat (SAHA), trichostatin A, or valproic acid.
  • SAHA vorinostat
  • the HDAC inhibitor decreases the expression of one or more androgen-independent androgen receptor-regulated genes, such as UBE2C and CDC20.
  • the PARP inhibitor includes any inhibitor of PARP, such as a small organic molecule (for example, olaparib).
  • FIG. 1 is a pair of digital images showing immunob lotting of LNCaP cells treated with XB154 (left) or LSDl siRNA (right).
  • GAPDH glyceraldehyde-3- phosphate dehydrogenase
  • 2MK4 di-methyl lysine 4
  • 2MK9 di-methyl lysine 9
  • NTC non-targeted control.
  • FIG. 2 is a heatmap of Fanconi anemia (FANC) and BRCA gene expression in LNCaP cells treated with LSDl siRNA, XB154, PGl 1144, or PGl 1047. Darker shading indicates >1.5-fold increase in expression compared to untreated cells; medium shading indicates >1.5-fold decrease in expression compared to untreated cells; and lighter shading indicates ⁇ 1.5-fold change in expression compared to control.
  • FANC Fanconi anemia
  • FIG. 3 is a graph showing relative FANCD2 mRNA expression in LNCaP cells transfected with vector alone (pcDNA3.1) or LSDl.
  • FIG. 4A is a graph showing FANCD2 mRNA expression in LNCaP cells treated with the indicated amount of XB154 for 48 hours.
  • FIG. 4B is a pair of digital images showing FANCD2 and ubiquitinated FANCD2 (ub-FANCD2) protein (upper) and ⁇ -actin (control, lower) in LNCaP cells treated with the indicated amount of XB154 for 24 or 48 hours.
  • ub-FANCD2 ubiquitinated FANCD2
  • ⁇ -actin control, lower
  • FIG. 4C is a series of digital images of immunoblots of LSDl, FANCD2 and GAPDH in LNCaP cells with stable knockdown of LSDl by shRNA. Relative amounts of FANCD2 and ub-FANCD2 are shown below the blot. NTC, non- targeted control shRNA.
  • FIG. 4D is a pair of digital images of immunoblots of FANCD2 and ⁇ -actin in LNCaP cells treated with pargyline. Relative amounts of FANCD2 and ub- FANCD2 are shown below the blot.
  • FIG. 5 is a graph showing relative expression of BRCA1 mRNA in LNCaP cells treated with the indicated amount of XB 154 for 24 or 48 hours.
  • FIG. 6 is a heatmap of Fanconi anemia (FANC) and BRCA gene expression in LNCaP cells treated with histone deacetylase (HDAC) inhibitors sulforaphane (SFN), trichostatin A (TSA), or vorinostat (SAHA) or LSD1 siRNA or XB154. Dark shading indicates > 1.5-fold decrease in expression compared to untreated cells; light shading indicates no change in expression compared to control.
  • HDAC histone deacetylase
  • FIG. 7 is a graph showing effect of LSD1 knockdown (shLSDl) on proliferation of LNCaP cells.
  • FIG. 8 is a graph showing the total cell counts of LNCaP cells pre-treated with the indicated amount of XB154 for 24 hours, followed by 48 hour co-treatment with mitomycin C (MMC).
  • MMC mitomycin C
  • FIG. 9 is a graph showing percent viability of LNCaP cells with LSD1 knockdown (shLSDl) or mock transfected (shNTC) treated with the indicated amount of olaparib.
  • FIG. 10 is a heatmap indicating up or down (1.5 fold) regulation for probe sets from a 16 hour treatment with dihydrotestosterone (DHT) or siRNA to androgen receptor (siAR) in both LNCaP and Abl cells, as well as data with siRNA to LSD1 (siLSDl) in LNCaP cells.
  • Probe sets were selected based on having 1.5 fold change versus control for one of the experiments and having a significant (q-value ⁇ 0.05) AR binding site within 50 kb of the annotated transcriptional start site for the gene associated with the probe set. Dark shading represents at least a 1.5 fold decrease or increase and light shading indicates that there was not a difference meeting the 1.5 fold threshold.
  • FIG. 11 is a series of digital images of immunoblots probed with the indicated antibodies after treatment with siRNA against a non-targeted control (NTC) or LSD1 for 96 hours (left) or increasing amounts of PG11144 (right).
  • NTC non-targeted control
  • FIG. 12 A is a graph showing UBE2C RNA expression in LNCaP cells with RNAi mediated suppression of AR, LSDl, or both AR and LSDl, relative to control.
  • FIG. 12B is a graph showing CCNA2 RNA expression in LNCaP cells with RNAi mediated suppression of AR, LSDl, or both AR and LSDl, relative to control
  • FIG. 12C is a graph showing chromatin immunoprecipitation (ChIP) PCR results for the UBE2C enhancer I (left) and CCNA2 (right) in LNCaP cells with antibodies to AR, LSDl, acetylated histone H3 (AcH3), and IgG. QPCR was performed in triplicate and enrichment was compared with the input sample.
  • ChIP chromatin immunoprecipitation
  • FIG. 13 is a graph showing relative expression of CDC20 (left) and UBE2C (right) mRNA in LNCaP cells treated with LSDl siRNA, XB154, or PGl 1144 at the indicated concentrations.
  • FIG. 14 is a pair of graphs showing proliferation gene expression in PC3 cells treated with siLSDl (top) or XB154 (bottom).
  • FIG. 15 is a graph showing Nkx3.1 mRNA levels in LNCaP cells treated with the indicated amounts of PGl 1144 (top) or siLSDl (bottom).
  • FIG. 16 is a graph showing cell number quantified after trypan blue exclusion in abl (left) and C4-2B (right) cells transfected with control RNAi (RNAiNTC) or siLSDl.
  • FIG. 17A is a graph showing proliferation of LNCaP cells treated with siRNA to LSDl or control and grown in the absence of androgens.
  • FIG. 17B is a digital image of a Western blot showing LSDl expression in the cells.
  • FIG. 18 is a graph showing the change in percentage of cells in the indicated cell cycle phase relative to control in LNCaP LSDl knockdown cells.
  • FIG. 20A is a digital image showing FANCD2 protein expression and ubiquitination and histone methylation (2MK4 and 2MK9) in LNCaP cells treated with PGl 1047 for 96 hours.
  • FIG. 20B is a digital image showing histone methylation (2MK4 and 2MK9) in LNCaP cells treated with vehicle or 1 ⁇ PGl 1047 for 96 hours.
  • FIG. 20C is a digital image showing the effect of LSD 1 suppression on histone methylation (2MK4) in LNCaP cells transfected with the indicated RNAi and then 24 hours later treated with vehicle or 2 ⁇ PGl 1047 for 96 hours.
  • FIG. 20D is a pair of graphs showing relative UBE2C mRNA levels (top) and relative CDC20 mRNA levels (bottom) in LNCaP cells treated with the indicated amounts of PGl 1047 for 96 hours.
  • FIG. 21 is a digital image showing FANCD2 protein expression and ubiquitination, LSD1 protein expression, and histone methylation (2MK4 and 2MK9) in LNCaP cells treated with the indicated amounts of PGl 1044 for 72 hours.
  • FIG. 22 is a series of graphs showing the effect of PGl 1144 treatment for
  • nucleic and amino acid sequences referenced herein are shown using standard letter abbreviations for nucleotide bases, as defined in 37 C.F.R. 1.822. In at least some cases, only one strand of each nucleic acid sequence is shown, but the complementary strand is understood as included by any reference to the displayed strand.
  • Sequence_Listing.txt which was created on July 13, 2011, and is 4715 bytes, which is incorporated by reference herein.
  • SEQ ID NO: 1 is an LSD1 siRNA.
  • SEQ ID NO: 2 is a control luciferase siRNA.
  • SEQ ID NO: 3 is an LSD1 shRNA.
  • SEQ ID NO: 4 is an AR siRNA.
  • SEQ ID NOs: 5-20 are RT-PCR primers.
  • Fanconi anemia is a rare genetic disorder characterized by progressive bone marrow failure, cancer susceptibility, and cellular hypersensitivity to DNA cross-linking agents, such as mitomycin C and cisplatin. Loss of function experiments of FA pathway members point to their role in enhancing chemotherapy sensitivity when depleted in cancer cells (Taniguchi et al, Nature Med. 9:568-574, 2003). Of the 11 pathway members, FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM form a nuclear core complex (Meetei et al, Nature Genet. 36: 1219-1224, 2004; Levitus et al, Nature Genet.
  • FANCA, FANCB, FANCC, FANCE, FANCF, FANCG, FANCL, and FANCM form a nuclear core complex (Meetei et al, Nature Genet. 36: 1219-1224, 2004; Levitus et al, Nature Gene
  • Inhibition of FA genes provides a synthetic lethal approach to treating cancer by enhancing chemosensitivity of cancer cells to DNA damage-inducing agents. It is also disclosed herein that inhibition of LSD1 (for example, by knockdown of LSD1 expression) increases sensitivity of prostate cancer cells to the PARP inhibitor olaparib. Thus, disclosed herein are methods of treating cancer by administering a therapeutically effective amount of an LSD1 inhibitor or an HDAC inhibitor in combination with a PARP inhibitor.
  • the central protein in prostate cancer is the androgen receptor (AR) which is a nuclear hormone receptor that is activatable by androgens.
  • AR androgen receptor
  • Most therapeutic approaches in this disease rest upon depleting androgens or interfering with androgen binding to AR protein.
  • ADT androgen deprivation therapy
  • CRPC castration resistant prostate cancers
  • LSD1 is an AR binding partner which binds to androgen response elements (AREs) along with AR. It is disclosed herein that following inhibition of LSD1 by RNA interference, the top pathways whose expression decline are androgen- independent "AR" signaling pathways that are enriched in CRPC cells and patient samples. This indicates that LSD1 inhibition is a target to prevent or overcome castration-resistance in prostate cancer.
  • methods of treating CRPC by administering a therapeutically effective amount of an LSD1 inhibitor.
  • DNA damaging agent A compound or treatment that causes damage to DNA, such as produces DNA strand breaks (such as single-strand or double-strand breaks) or DNA cross -linking.
  • a DNA damaging agent includes a DNA cross-linking agent, such as mitomycin C (MMC), diepoxybutane (DEB), platinum compounds (such as carboplatin, cisplatin, oxaliplatin, and bbr3464), cyclophosphamide, psoralen, adriamycin, 5-fluorouracil (5FU), etoposide (VP- 16), camptothecin, actinomycin-D, or radiation (such as UVA radiation).
  • MMC mitomycin C
  • DEB diepoxybutane
  • platinum compounds such as carboplatin, cisplatin, oxaliplatin, and bbr3464
  • cyclophosphamide such as carboplatin, cisplatin, oxaliplatin, and b
  • Histone deacetylase A family of proteins that catalyze deacetylation of histone lysine residues. HDACs are classified into at least three families based on structural homology and co-factor dependence. Class I and II HDACs require zinc as a cofactor, while Class III HDACs require nicotinamide adenine dinucleotide (NAD) for enzyme activity. In cancer, HDACs are recruited to the promoter regions of tumor suppressor genes and result in inappropriate transcriptional repression (such as gene silencing), contributing to tumorigenesis.
  • HDAC Histone deacetylase
  • HDAC inhibitors include diverse compounds, such as short-chain fatty acids (for example, sodium butyrate and valproic acid), epoxides (for example, depudecin and trapoxin), cyclic peptides (for example, apicidin and depsipeptide), hydroxamic acids (for example, trichostatin A, suberoylanilide hydroxamic acid (SAHA), oxamflatin, scriptaid, and pyroxamide), benzamides (for example, MS-275 and CI-994), and other hybrid compounds (for example, SK-7068).
  • short-chain fatty acids for example, sodium butyrate and valproic acid
  • epoxides for example, depudecin and trapoxin
  • cyclic peptides for example, apicidin and depsipeptide
  • hydroxamic acids for example, trichostatin A, suberoylanilide hydroxamic acid (SAHA), oxamflatin,
  • HDAC nucleic acid and amino acid sequences are publicly available.
  • GenBank Accession Nos.: NM_004964, NM_001527, NM_003883, NM_006037, and NM_006044 disclose exemplary human HDAC nucleic acid sequences
  • GenBank Accession Nos.: NP_004955, NP_001518, NP_003874, NP_006028, and NP_006035 disclose exemplary human HDAC amino acid sequences, all of which are incorporated by reference as present in GenBank on July 14, 2010.
  • Other HDAC nucleic acid and amino acid sequences can be identified by one of skill in the art.
  • an HDAC has at least 80% sequence identity, for example at least 85%, 90%, 95%, or 98% sequence identity to a publicly available HDAC sequence, such as those provided herein.
  • Inhibitor Any chemical compound, nucleic acid molecule, or peptide, such as a small organic molecule, a nucleic acid (such as an RNAi nucleic acid), or an antibody, specific for a gene product that can reduce activity of a gene product or directly interfere with expression of a gene, such as genes that encode LSD1, HDAC, or PARP, such as in a cancer or a treatment resistant cancer (e.g., a prostate cancer, such as castration-resistant prostate cancer).
  • An inhibitor of the disclosure for example, can inhibit the activity of a protein that is encoded by a gene either directly or indirectly.
  • Direct inhibition can be accomplished, for example, by binding to a protein and thereby preventing the protein from binding a target (such as a receptor or binding partner) or preventing protein activity (such as enzymatic activity). Indirect inhibition can be accomplished, for example, by binding to a protein's intended target, such as a receptor or binding partner, thereby blocking or reducing activity of the protein.
  • an inhibitor of the disclosure can inhibit a gene by reducing or inhibiting expression of the gene, inter alia by interfering with gene expression (transcription, processing, translation, post- translational modification), for example, by interfering with the gene's mRNA and blocking translation of the gene product or by post-translational modification of a gene product, or by causing changes in intracellular localization.
  • Lysine-specific demethylase 1 (LSD1): A histone lysine demethylase that specifically demethylates monomethylated and dimethylated histone H3 at K4 (Shi et al, Cell 119:941-953, 2004) and also demethylates dimethylated histone H3 at K9.
  • LSD1 includes a monoamine oxidase-like domain, which has homology to FAD-dependent oxidases. LSD1 also includes an N-terminal SWRIM domain. There are two transcript variants of LSD 1 produced by alternative splicing.
  • LSD1 Nucleic acid and amino acid sequences for LSD1 are publicly available.
  • GenBank Accession Nos.: NM_015013 and NM_001009999 disclose exemplary human LSD1 nucleic acid sequences
  • GenBank Accession Nos.: NP_055828 and NP_001009999 disclose exemplary human LSD1 amino acid sequences, all of which are incorporated by reference as present in GenBank on July 14, 2010.
  • Other LSDl nucleic acid and amino acid sequences can be identified by one of skill in the art.
  • LSDl includes a full-length wild-type (or native) sequence, as well as LSDl allelic variants that retain lysine-specific demethylase activity.
  • LSDl has at least 80% sequence identity, for example at least 85%, 90%, 95%, or 98% sequence identity to a publicly available LSDl sequence, such as those provided herein.
  • compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compounds, molecules or agents are conventional. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21 st Edition (2005), describes compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic compounds, molecules or agents.
  • parenteral formulations usually comprise injectable fluids that include pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • pharmaceutically and physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like as a vehicle.
  • physiologically acceptable fluids such as water, physiological saline, balanced salt solutions, aqueous dextrose, glycerol or the like
  • solid compositions for example, powder, pill, tablet, or capsule forms
  • conventional non-toxic solid carriers can include, for example, pharmaceutical grades of mannitol, lactose, starch, or magnesium stearate.
  • compositions to be administered can contain minor amounts of non-toxic auxiliary substances, such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
  • non-toxic auxiliary substances such as wetting or emulsifying agents, preservatives, and pH buffering agents and the like, for example sodium acetate or sorbitan monolaurate.
  • PARP Poly (ADP ribose) polymerase
  • PARP1 is the founding member of a large family of poly(ADP-ribose) polymerases with 17 members identified (Ame et ah, Bioessays 26:882-893, 2004). It is the primary enzyme catalyzing the transfer of ADP-ribose units from NAD + to target proteins including PARP1 itself. Under normal physiologic conditions, PARP1 facilitates the repair of DNA base lesions by helping recruit base excision repair proteins XRCC1 and ⁇ (Dantzer et ah,
  • PARP2 contains a catalytic domain and is capable of catalyzing a poly(ADP-ribosyl)ation reaction.
  • This protein has a catalytic domain that is homologous to that of PARPl, but lacks an N-terminal DNA binding domain which activates the C-terminal catalytic domain of PARP.
  • the basic residues within the N-terminal region of this protein may bear potential DNA-binding properties, and may be involved in the nuclear and/or nucleolar targeting of the protein.
  • PARP nucleic acid and amino acid sequences are publicly available.
  • NM_001042618, NM_005485, NM_001003931, and NM_006437 disclose exemplary human PARP nucleic acid sequences
  • GenBank Accession Nos.: NP_001609, NP_005475, NP_001036083, NP_005476, NP_001003931, and NP_006428 disclose exemplary human PARP amino acid sequences, all of which are incorporated by reference as present in GenBank on July 14, 2010. Additional PARP nucleic acid and amino acid sequences can be identified by one of skill in the art.
  • a PARP has at least 80% sequence identity, for example at least 85%, 90%, 95%, or 98% sequence identity to a publicly available PARP sequence, such as those provided herein.
  • Prostate cancer A malignant tumor, generally of glandular origin, of the prostate. Prostate cancers include adenocarcinomas and small cell carcinomas. Many prostate cancers express prostate specific antigen (PSA).
  • PSA prostate specific antigen
  • Prostate cancer initially grows in an androgen-dependent manner, and androgen deprivation therapy (ADT) is an effective treatment in many cases of prostate cancer.
  • ADT androgen deprivation therapy
  • prostate cancer can eventually become refractory to ADT.
  • CRPC Basation-resistant prostate cancer
  • hormone- refractory prostate cancer is prostate cancer that has become androgen-independent and progresses despite low levels of androgens (for example, in a subject undergoing ADT).
  • RNA interference refers to a cellular process that inhibits expression of genes, including cellular and viral genes. RNAi is a form of antisense- mediated gene silencing involving the introduction of double stranded RNA-like oligonucleotides leading to the sequence- specific reduction of RNA transcripts. Double-stranded RNA molecules that inhibit gene expression through the RNAi pathway include small (or short) interfering RNA (siRNA), micro-RNA (miRNA), and short (or small) hairpin RNA (shRNA).
  • siRNA small interfering RNA
  • miRNA micro-RNA
  • shRNA short hairpin RNA
  • Short hairpin RNA An RNA that makes a tight hairpin turn and can be used to silence gene expression via the RNAi pathway.
  • the shRNA hairpin structure is cleaved by the cellular machinery into siRNA.
  • a shRNA molecule is one that reduces or interferes with the biological activity of one or more molecules that encode LSD1, HDAC, or PARP.
  • siRNA Short (or small) interfering RNA: A double stranded nucleic acid molecule capable of RNA interference or "RNAi.”
  • RNAi RNA interference
  • siRNA molecules need not be limited to those molecules containing only RNA, but further encompasses chemically modified nucleotides and non-nucleotides having RNAi capacity or activity.
  • a siRNA molecule is one that reduces or interferes with the biological activity of one or more molecules that encode LSD1, HDAC, or PARP.
  • Subject Living multi-cellular vertebrate organisms, a category that includes both human and non-human mammals.
  • Subjects include veterinary subjects, including livestock such as cows and sheep, rodents (such as mice and rats), and non-human primates.
  • Therapeutically effective amount An amount of a pharmaceutical preparation that alone, or together with a pharmaceutically acceptable carrier or one or more additional therapeutic agents, induces the desired response.
  • a therapeutic agent such as a chemotherapeutic agent, is administered in therapeutically effective amounts.
  • Effective amounts a therapeutic agent can be determined in many different ways, such as assaying for a reduction in tumor size or improvement of
  • physiological condition of a subject having cancer such as prostate cancer.
  • transfected A transfected cell is a cell into which has been introduced a nucleic acid molecule by molecular biology techniques.
  • transfection encompasses all techniques by which a nucleic acid molecule (such as a DNA or siRNA) might be introduced into such a cell, including transfection with viral vectors, transformation with plasmid vectors, and introduction of naked nucleic acid by electroporation, lipofection, and particle gun acceleration.
  • Treating a disease refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition, such as a sign or symptom of prostate cancer. Treatment can also induce remission or cure of a condition, such as prostate cancer. In particular examples, treatment includes preventing a disease, for example by inhibiting the full development of a disease. Prevention of a disease does not require a total absence of disease. For example, a decrease of at least 50% can be sufficient.
  • cancer such as prostate cancer (for example, castration-resistant prostate cancer), breast cancer, or ovarian cancer) including administering a therapeutically effective amount of an inhibitor of lysine-specific demethylase 1 (LSDl) to a subject with cancer.
  • the methods include administering a therapeutically effective amount of an inhibitor of LSDl and a DNA damaging agent or an inhibitor of poly (ADP ribose) polymerase (PARP) to the subject.
  • PARP poly (ADP ribose) polymerase
  • the methods include administering a therapeutically effective amount of an inhibitor of histone deacetylase (HDAC) and a DNA damaging agent or an inhibitor of PARP to the subject.
  • HDAC histone deacetylase
  • the disclosed methods include treating a subject with cancer, such as prostate cancer (for example, CRPC) including administering a therapeutically effective amount of an LSDl inhibitor to the subject.
  • the LSDl inhibitor is any inhibitor of LSDl activity or expression, such as those described in Section V, below.
  • the method includes administering a therapeutically effective amount of a polyamine analog (such as XB154, PG 11047 or PG11144).
  • a polyamine analog such as XB154, PG 11047 or PG11144.
  • the structures of XB 154, PG11047, and PG11144 are provided in FIGS. 19A to 19C. .
  • the LSDl inhibitor inhibits LSDl activity (for example, decreases LSDl histone demethylation activity).
  • an LSDl inhibitor may decrease demethylation (increase methylation) of dimethyl lysine 4 of histones or dimethyl lysine 9 of histones in a cell or a subject, for example, as compared to a cell or subject that has not been treated with the LSDl inhibitor.
  • an LSDl inhibitor includes a small organic molecule, including, but not limited to polyamine analogs, such as XB154 (also known as 2d), PG11047, or PG11144.
  • the LSDl inhibitor inhibits LSDl expression (for example, decreases LSDl mRNA and/or LSDl protein levels).
  • an LSDl inhibitor may decrease amounts of LSDl mRNA, LSDl protein, or both, in a cell or subject, as compared to a cell or subject that has not been treated with the LSDl inhibitor.
  • an LSDl inhibitor includes an RNA interference (RNAi) molecule, such as a small interfering RNA (siRNA) or short hairpin RNA (shRNA).
  • RNAi RNA interference
  • the RNAi molecule includes, but is not limited to, SEQ ID NO: 1 or 3.
  • an LSDl inhibitor decreases expression of one or more andro gen-independent androgen receptor-regulated genes.
  • the expression of the one or more andro gen-independent androgen receptor-regulated genes is decreased by at least about 1.5-fold (such as at least about 2-fold, 2.5-fold, 3-fold, 4-fold, 5-fold, or more) as compared to a cell that has not been treated with the LSDl inhibitor.
  • the genes exhibiting decreased expression following treatment of cells with an LSDl inhibitor include at least one of ACYP1, ARL6IP6, BUB3, CDK1, DEPDC1, HMGB2, HMMR, NCAPG, and PRC1.
  • the genes exhibiting decreased expression following treatment of cells with an LSDl inhibitor include UBE2C and/or CDC20
  • the disclosed methods include treating a subject with cancer (such as prostate cancer, breast cancer, or ovarian cancer) with a
  • the method includes administering a therapeutically effective amount of a polyamine analog such as XB154, PG11047, or PG11144 and a therapeutically effective amount of olaparib to a subject.
  • a polyamine analog such as XB154, PG11047, or PG11144
  • the LSDl inhibitor inhibits LSDl activity (for example, decreases LSDl histone demethylation activity).
  • an LSDl inhibitor may decrease demethylation (increase methylation) of dimethyl lysine 4 of histones or dimethyl lysine 9 of histones in a cell or a subject, for example, as compared to a cell or subject that has not been treated with the LSDl inhibitor.
  • an LSDl inhibitor includes a small organic molecule, including, but not limited to polyamine analogs such as XB154 (also known as 2d), PG11047, or PG11144.
  • the LSDl inhibitor inhibits LSDl expression (for example, decreases LSDl mRNA and/or LSDl protein levels).
  • an LSDl inhibitor may decrease amount of LSDl mRNA, LSDl protein, or both, in a cell or subject, as compared to a cell or subject that has not been treated with the
  • an LSDl inhibitor includes an RNA interference (RNAi) molecule, such as a small interfering RNA (siRNA) or short hairpin RNA (shRNA).
  • RNAi RNA interference
  • siRNA small interfering RNA
  • shRNA short hairpin RNA
  • the RNAi molecule includes, but is not limited to, SEQ ID NO: 1 or 3.
  • an LSD1 inhibitor decreases expression of one or more Fanconi anemia (FA) or BRCA genes.
  • the FA genes include FANCA, FANCB, FANCC, FANCD1 (BRACA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, and FANCN.
  • the BRCA genes include BRCAl and BRCA2 (FANCD1).
  • an LSD1 inhibitor decreases expression (such as mRNA expression and/or protein expression) of at least one of BRCAl, BRCA2, FANCA, FANCB, FANCC, FANCD2, FANCG, and FANCM, as compared to a control.
  • the expression of at least one of BRCAl, BRCA2, FANCA, FANCB, FANCC, FANCD2, FANCG, and FANCM is decreased by at least about 1.5-fold (such as at least about 2-fold, 2.5-fold, 3-fold, 4-fold, 5-fold, or more) as compared to a cell that has not been treated with the LSD1 inhibitor.
  • an LSD1 inhibitor decreases expression of FANCD2 protein and/or amount of ubiquitinated FANCD2 (ub-FNACD2) protein as compared to a control.
  • the amount of FANCD2 protein and/or ubFANCD2 is decreased by at least about 1.5-fold (such as at least about 2-fold, 2.5-fold, 3-fold, 4- fold, 5-fold, or more) as compared to a cell that has not been treated with the LSD1 inhibitor.
  • the disclosed methods include treating a subject with cancer (such as prostate cancer, breast cancer, or ovarian cancer) with a cancer (such as prostate cancer, breast cancer, or ovarian cancer) with a cancer (such as prostate cancer, breast cancer, or ovarian cancer) with a subject with cancer (such as prostate cancer, breast cancer, or ovarian cancer) with a subject with cancer (such as prostate cancer, breast cancer, or ovarian cancer) with a subject with cancer (such as prostate cancer, breast cancer, or ovarian cancer) with a subject with cancer (such as prostate cancer, breast cancer, or ovarian cancer) with a cancer (such as prostate cancer, breast cancer, or ovarian cancer) with a cancer (such as prostate cancer, breast cancer, or ovarian cancer) with a subject with cancer (such as prostate cancer, breast cancer, or ovarian cancer) with a subject with cancer (such as prostate cancer, breast cancer, or ovarian cancer) with a subject with cancer (such as prostate cancer, breast cancer, or ovarian cancer) with a subject with cancer
  • the method includes administering a therapeutically effective amount of vorinostat and a therapeutically effective amount of olaparib to a subject.
  • the structure of olaparib is provided in FIG. 19C.
  • the HDAC inhibitor inhibits HDAC activity (for example, decreases HDAC histone deacetylase activity).
  • HDAC inhibitor may decrease deacetylation of N-acetyl lysine on a histone protein in a cell or a subject, for example, as compared to a cell or subject that has not been treated with the HDAC inhibitor.
  • an HDAC inhibitor includes a small organic molecule, including, but not limited to vorinostat, trichostatin A (TSA), or sulforaphane.
  • the HDAC inhibitor inhibits HDAC expression (for example, decreases HDAC mRNA and/or HDAC protein levels).
  • an HDAC inhibitor may decrease amount of HDAC mRNA, HDAC protein, or both, in a cell or subject, as compared to a cell or subject that has not been treated with the HDAC inhibitor.
  • an HDAC inhibitor includes an RNA interference (RNAi) molecule, such as a small interfering RNA (siRNA) or short hairpin RNA (shRNA).
  • RNAi RNA interference
  • siRNA small interfering RNA
  • shRNA short hairpin RNA
  • an HDAC inhibitor decreases expression of one or more Fanconi anemia (FA) or BRCA genes.
  • the FA genes include FANCA, FANCB, FANCC, FANCD1 (BRACA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANCJ, FANCL, FANCM, and FANCN.
  • the BRCA genes include BRCA1 and BRCA2 (FANCD1).
  • an HDAC inhibitor decreases expression (such as mRNA expression and/or protein expression) of at least one of BRCA1, BRCA2, FANCA, FANCB, FANCC, FANCD2, FANCG, and FANCM, as compared to a control.
  • the expression of at least one of BRCA1, BRCA2, FANCA, FANCB, FANCC, FANCD2, FANCG, and FANCM is decreased by at least about 1.5-fold (such as at least about 2-fold, 2.5-fold, 3-fold, 4-fold, 5- fold, or more) as compared to a cell that has not been treated with the HDAC inhibitor.
  • an HDAC inhibitor decreases expression of FANCD2 protein and/or amount of ubiquitinated FANCD2 (ub-FNACD2) protein as compared to a control.
  • the amount of FANCD2 protein and/or ubFANCD2 is decreased by at least about 1.5-fold (such as at least about 2-fold, 2.5- fold, 3-fold, 4-fold, 5-fold, or more) as compared to a cell that has not been treated with the HDAC inhibitor.
  • the methods disclosed herein are utilized to treat a subject with a solid cancer.
  • solid cancers such as sarcomas and carcinomas
  • solid cancers include fibrosarcoma, myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, and other sarcomas, synovioma, mesothelioma, Ewing's tumor, leiomyosarcoma, rhabdomyosarcoma, colon carcinoma, lymphoid malignancy, pancreatic cancer, breast cancer, lung cancers, ovarian cancer, prostate cancer, hepatocellular carcinoma, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinomas, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, Wilm
  • the disclosed methods are used to treat a subject with a hematological malignancy.
  • hematological malignancies include leukemias, including acute leukemias (such as acute lymphocytic leukemia, acute myelocytic leukemia, acute myelogenous leukemia and myeloblastic,
  • chronic leukemias such as chronic myelocytic (granulocytic) leukemia
  • myelogenous leukemia and chronic lymphocytic leukemia
  • polycythemia vera lymphoma
  • lymphoma lymphoma
  • Hodgkin' s disease non-Hodgkin' s lymphoma (indolent and high grade forms)
  • multiple myeloma Waldenstrom's macroglobulinemia, heavy chain disease, myelodysplasia syndrome, hairy cell leukemia and myelodysplasia.
  • the cancer is prostate cancer, breast cancer, or ovarian cancer.
  • the cancer is castration- resistant prostate cancer.
  • the cancer is small cell prostate carcinoma.
  • the disclosed methods include treating a subject with cancer with a therapeutically effective amount of an LSDl inhibitor, a combination of an LSDl inhibitor and a DNA damaging agent or a PARP inhibitor, or an HDAC inhibitor and a DNA damaging agent or a PARP inhibitor.
  • Inhibitors of LSDl, HDAC, and PARP are known to one of skill in the art including, but are not limited to the inhibitors described below.
  • the disclosed methods include treating a subject with cancer (such as prostate cancer, breast cancer, or ovarian cancer) with an inhibitor of LSDl.
  • Inhibitors of LSDl are known to, or can be identified by, one of skill in the art.
  • an LSDl inhibitor specifically inhibits LSDl activity (such as LSDl histone demethylase activity).
  • an LSDl inhibitor specifically inhibits LSDl expression (such as LSDl mRNA expression or longevity and/or LSDl protein expression or longevity).
  • the LSDl inhibitor is a previously identified small molecule LSDl inhibitor.
  • the inhibitor is a polyamine analog.
  • the polyamine analog is a bisguanidine polyamine analog or a biguanide polyamine analog.
  • the LSDl inhibitor is a biguanide analog, such as XB154 (also known as 2d; Huang et al., Proc. Natl. Acad. Sci. 104:8023-8028, 2007).
  • the polyamine analog is an oligoamine analog, such as a pentamine (for example, PGl 1122, PGl 1128, or PGl 1141), hexamine (for example, PGl 1231, PGl 1287, or PGl 1288), octamine (for example, PGl 1157, PGl 1158, or PGl 1160), or decamine (such as PGl 1144, PGl 1150, or PGl 1159).
  • a pentamine for example, PGl 1122, PGl 1128, or PGl 1141
  • hexamine for example, PGl 1231, PGl 1287, or PGl 1288
  • octamine for example, PGl 1157, PGl 1158, or PGl 1160
  • decamine such as PGl 1144, PGl 1150, or PGl 1159. See, e.g., Huang et al, Clin. Cancer Res.
  • the LSDl inhibitor is a decamine oligoamine analog, such as PGl 1144 or PGl 1150.
  • the LSDl inhibitor is a conformationally restricted polyamine analog, such as PGl 1047 (see, e.g., Casero and Marton, Nature Rev. Drug Discovery 6:373- 390, 2007; U.S. Pat. No. 5,889,061).
  • the LSDl inhibitor is a monoamine oxidase inhibitor, such as pargyline, trans-2-phenylcyclorpropylamine (tranylcypromine), phenelzine, nialamide, clorgyline, or deprenyl. See, e.g., Lee et al., Chem. Biol. 13:563-567, 2006.
  • the LSDl inhibitor is pargyline.
  • the LSDl inhibitor is an antisense compound. Any type of antisense compound that specifically targets and regulates expression of LSDl is contemplated for use.
  • An antisense compound is one which specifically hybridizes with and modulates expression of a target nucleic acid molecule (such as LSDl).
  • the agent is an antisense compound selected from an antisense oligonucleotide, a siRNA, a miRNA, a shRNA or a ribozyme.
  • these compounds can be introduced as single- stranded, double-stranded, circular, branched or hairpin compounds and can contain structural elements such as internal or terminal bulges or loops.
  • Double- stranded antisense compounds can be two strands hybridized to form double- stranded compounds or a single strand with sufficient self complementarity to allow for hybridization and formation of a fully or partially double-stranded compound.
  • an antisense oligonucleotide is a single stranded antisense compound, such that when the antisense oligonucleotide hybridizes to a target mRNA, the duplex is recognized by RNaseH, resulting in cleavage of the mRNA.
  • a miRNA is a single- stranded RNA molecule of about 21-23 nucleotides that is at least partially complementary to an mRNA molecule that regulates gene expression through an RNAi pathway.
  • a shRNA is an RNA oligonucleotide that forms a tight hairpin, which is cleaved into siRNA.
  • siRNA molecules are generally about 20-25 nucleotides in length and may have a two nucleotide overhang on the 3' ends, or may be blunt ended. Generally, one strand of a siRNA is at least partially complementary to a target nucleic acid.
  • Antisense compounds specifically targeting LSDl can be prepared by designing compounds that are complementary to an LSDl nucleotide sequence, such as an LSDl mRNA sequence. Antisense compounds need not be 100%
  • the antisense compound, or antisense strand of the compound if a double- stranded compound can be at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% complementary to the selected LSDl nucleic acid sequence, such as about 20-25 contiguous nucleotides of an LSDl nucleic acid.
  • LSDl nucleic acid sequences are provided above.
  • Exemplary LSDl antisense compounds are commercially available (for example, catalog numbers sc-60970, sc-60970-SH, and sc-60970- V, Santa Cruz Biotechnologies (Santa Cruz, CA); or catalog numbers L-0092223-00, M-009223-01, E-009223-00, SH-009223-01, Thermo Scientific Dharmacon (Lafayette, CO)).
  • the RNAi molecule includes, but is not limited to, SEQ ID NO: 1 or 3. Methods of screening antisense compounds for specificity are well known in the art.
  • LSD1 inhibitors for use in the present disclosure also include novel LSD1 inhibitors developed in the future.
  • the disclosed methods include treating a subject with cancer (such as prostate cancer, breast cancer, or ovarian cancer) with an inhibitor of HDAC.
  • Inhibitors of HDAC are known to, or can be identified by, one of skill in the art.
  • an HDAC inhibitor specifically inhibits HDAC activity (such as histone deacetylase activity).
  • an HDAC inhibitor specifically inhibits HDAC expression (such as HDAC mRNA expression or longevity and/or HDAC protein expression or longevity).
  • the HDAC inhibitor is a previously identified small molecule HDAC inhibitor.
  • the HDAC inhibitor includes short-chain fatty acids (for example, sodium butyrate and valproic acid), epoxides (for example, depudecin and trapoxin), cyclic peptides (for example, apicidin and depsipeptide), hydroxamic acids (for example, trichostatin A, suberoylanilide hydroxamic acid (SAHA, also known as vorinostat), oxamflatin, scriptaid, and pyroxamide), benzamides (for example, MS-275 and CI-994), and other hybrid compounds (for example, SK-7068).
  • short-chain fatty acids for example, sodium butyrate and valproic acid
  • epoxides for example, depudecin and trapoxin
  • cyclic peptides for example, apicidin and depsipeptide
  • hydroxamic acids for example, trichostatin A, sub
  • HDAC inhibitors include BML-210, M344, NVP-LAQ-824, CHR-3996, CHR-2845, SB939, AR-42, ITF2357, panobinostat (LBH589), mocetinostat (MGCD0103), romidepsin (FR901228), resminostat (4SC-201), and belinostat (PXD101).
  • the HDAC inhibitor is vorinostat, LBH589, TSA, or sulforaphane.
  • the HDAC inhibitor is an antisense compound.
  • Any type of antisense compound that specifically targets and regulates expression of HDAC is contemplated for use. Methods of designing, preparing and using HDAC antisense compounds are within the abilities of one of skill in the art, for example, utilizing publicly available HDAC sequences.
  • Antisense compounds specifically targeting HDAC can be prepared by designing compounds that are complementary to an HDAC nucleotide sequence, such as an HDAC mRNA sequence. Antisense compounds need not be 100% complementary to the target nucleic acid molecule to specifically hybridize and regulate expression the target gene.
  • the antisense compound, or antisense strand of the compound if a double-stranded compound can be at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% complementary to the selected HDAC nucleic acid sequence, such as about 20-25 contiguous nucleotides of an HDAC nucleic acid.
  • HDAC nucleic acid sequences are provided above.
  • HDAC antisense compounds are commercially available (for example, from Santa Cruz Biotechnologies (Santa Cruz, CA); or Thermo Scientific
  • HDAC inhibitors for use in the present disclosure also include novel HDAC inhibitors developed in the future.
  • the disclosed methods include treating a subject with cancer (such as prostate cancer, breast cancer, or ovarian cancer) with an inhibitor of LSD1 or HDAC and a DNA damaging agent or an inhibitor of PARP.
  • DNA damaging agents are known to one of skill in the art, and include mitomycin C (MMC), diepoxybutane (DEB), platinum compounds (such as carboplatin, cisplatin, oxaliplatin, and bbr3464), cyclophosphamide, psoralen, adriamycin, 5-fluorouracil (5FU), etoposide (VP- 16), camptothecin, actinomycin-D, doxorubicin, bleomycin, or radiation (such as UVA radiation or gamma radiation).
  • PARP inhibitors are also known to one of skill in the art and are discussed in detail below.
  • the subject is treated with an inhibitor of LSD1 or HDAC and a PARP inhibitor.
  • Inhibitors of PARP are known to, or can be identified by, one of skill in the art.
  • a PARP inhibitor specifically inhibits PARP activity (such as poly(ADP ribosyl)ation activity).
  • a PARP inhibitor specifically inhibits PARP expression (such as PARP mRNA expression or longevity and/or PARP protein expression or longevity).
  • the PARP inhibitor is a previously identified small molecule PARP inhibitor.
  • a PARP inhibitor includes a benzamide analog, which binds competitively with the natural substrate NAD in the catalytic site of PARP.
  • a PARP inhibitor includes a quinolone, isoquinolone, benzopyrone, methyl 3,5-diiodo-4-(4'-methoxyphenoxy)benzoate, methyl-3,5-diiodo-4-(4'-methoxy-3',5'-diiodo-phenoxy)benzoate, benzimidazole, or indole.
  • the PARP inhibitor includes olaparib (AZD- 2281), BSI 201, veliparib (ABT-888), AG014699, CEP 9722, MK4827, LT-673, E7016, PF-01367338, and 3-aminobenzamide.
  • olaparib AZD- 2281
  • BSI 201 BSI 201
  • ABT-888 veliparib
  • CEP 9722 MK4827
  • LT-673 LT-673
  • E7016 PF-01367338
  • 3-aminobenzamide 3-aminobenzamide.
  • the PARP inhibitor is olaparib. In another particular example, the PARP inhibitor is ABT-888.
  • the PARP inhibitor is an antisense compound. Any type of antisense compound that specifically targets and regulates expression of PARP is contemplated for use. Methods of designing, preparing and using PARP antisense compounds are within the abilities of one of skill in the art, for example, utilizing publicly available PARP sequences. Antisense compounds specifically targeting PARP can be prepared by designing compounds that are complementary to a PARP nucleotide sequence, such as a PARP mRNA sequence. Antisense compounds need not be 100% complementary to the target nucleic acid molecule to specifically hybridize and regulate expression the target gene.
  • the antisense compound, or antisense strand of the compound if a double-stranded compound can be at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 99%, or 100% complementary to the selected PARP nucleic acid sequence, such as about 20-25 contiguous nucleotides of a PARP nucleic acid.
  • PARP antisense compounds are commercially available (for example, from Santa Cruz Biotechnologies (Santa Cruz, CA); or Thermo Scientific
  • PARP inhibitors for use in the present disclosure also include novel PARP inhibitors developed in the future.
  • the disclosed methods include administering a therapeutically effective amount of an LSD1 inhibitor to a subject with cancer (such as prostate cancer, breast cancer, or ovarian cancer). In other embodiments, the disclosed methods include administering a therapeutically effective amount of an LSD1 inhibitor and a PARP inhibitor to a subject with cancer. In further embodiments, the disclosed methods include administering a therapeutically effective amount of an LSD1 inhibitor and a PARP inhibitor to a subject with cancer.
  • the disclosed methods include administering a therapeutically effective amount of an HDAC inhibitor and a PARP inhibitor to a subject with cancer.
  • Inhibitors of LSD1, HDAC, and PARP are known to one of skill in the art, such as those discussed above (Section V).
  • the method includes selecting a subject with CRPC and administering a therapeutically effective amount of an LSD1 inhibitor (such as a polyamine analog) to the subject.
  • the method includes selecting a subject with small cell prostate carcinoma and administering a therapeutically effective amount of an LSD1 inhibitor (such as a polyamine analog) to the subject.
  • CRPC is generally defined as prostate cancer with disease progression despite androgen deprivation therapy and castrate serum levels of testosterone.
  • CRPC may present as a rise in serum levels of pro state- specific antigen (with or without symptoms), progression of pre-existing disease, appearance of new metastases, or a combination thereof (see, e.g., Hotte and Saad, Curr. Oncol. 17:S72-S79, 2010). Prognosis of CRPC is generally poor.
  • small cell prostate carcinoma can be diagnosed by histological examination of a prostate tumor biopsy (such as a fine-needle aspirate or core biopsy).
  • small cell prostate carcinoma can include histological features such as sheets of small round blue cells with a high nuclear-to-cytoplasmic ratio, necrosis, coarse (slat and pepper_ chromatin, and nuclear molding.
  • Small cell prostate carcinoma can also stain positive for neuron- specific enolase,
  • the subject may have a prostate tumor including both small cell carcinoma cells and adenocarcinoma cells.
  • Therapeutic agents can be administered to a subject in need of treatment using any suitable means known in the art.
  • Methods of administration include, but are not limited to, intradermal, transdermal, intramuscular, intraperitoneal, parenteral, intravenous, subcutaneous, intratumoral, vaginal, rectal, intranasal, inhalation, oral, or by gene gun.
  • the therapeutic agent is administered
  • the therapeutic agent is administered orally. If two or more agents are administered to a subject (such as an LSD1 inhibitor and a PARP inhibitor or an HDAC inhibitor and a PARP inhibitor), the agents may be administered by the same route or by different routes.
  • Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution of suspension in liquid prior to injection, or as emulsions. Injection solutions and suspensions can be prepared from sterile powders, granules, and tablets. Administration can be systemic or local.
  • Therapeutic agents can be administered in any suitable manner, preferably with pharmaceutically acceptable carriers.
  • Pharmaceutically acceptable carriers are determined in part by the particular composition being administered, as well as by the particular method used to administer the composition. Accordingly, there is a wide variety of suitable formulations of pharmaceutical compositions of the present disclosure.
  • the pharmaceutically acceptable carriers (vehicles) useful in this disclosure are conventional. Remington: The Science and Practice of Pharmacy, The University of the Sciences in Philadelphia, Editor, Lippincott, Williams, & Wilkins, Philadelphia, PA, 21 st Edition (2005) describes compositions and formulations suitable for pharmaceutical delivery of one or more therapeutic agents Preparations for parenteral administration include sterile aqueous or nonaqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents examples include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer's dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti- oxidants, chelating agents, and inert gases and the like.
  • compositions for oral administration include powders or granules, suspensions or solutions in water or non-aqueous media, capsules, sachets, or tablets. Thickeners, flavorings, diluents, emulsifiers, dispersing aids or binders may be desirable.
  • Appropriate dosages for treatment with one or more of LSD1 inhibitors, HDAC inhibitors, and PARP inhibitors can be determined by one of skill in the art.
  • an effective amount of a therapeutic agent that includes one or more of LSD1 inhibitors, HDAC inhibitors, and PARP inhibitors administered to a subject will vary depending upon a number of factors associated with that subject, for example the overall health of the subject, the condition to be treated, or the severity of the condition.
  • An effective amount of an LSD1 inhibitor, HDAC inhibitor, or PARP inhibitor can be determined by varying the dosage of the compound and measuring the resulting therapeutic response, such as an increase in survival (such as overall survival, progression-free survival, or metastasis-free survival) or a decrease in the size, volume or number of tumors.
  • the LSD1, HDAC, and/or PARP inhibitors can be administered in a single dose, or in several doses, as needed to obtain the desired response.
  • the effective amount can be dependent on the source applied, the subject being treated, the severity and type of the condition being treated, and the manner of
  • the LSD1 inhibitor is administered intravenously, intraperitoneally, or orally.
  • the dose of an LSD1 inhibitor administered to a subject may be about 0.1 mg/kg to about 1000 mg/kg.
  • the dose may be about 0.5 mg/kg to about 100 mg/kg, such as about 1 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 40 mg/kg, 50 mg/kg, 75 mg/kg, or 100 mg/kg.
  • the dose may be about 10 to 800 mg, for example, about 50 mg to 800 mg, or about 100 mg to 600 mg of an LSD1 inhibitor (such as PG11047, PG11144, or XB 154).
  • PG11047 is administered to the subject intravenously once per week.
  • PG11047 is administered as one or more courses of treatment, where a course of treatment is one dose (such as 600 mg) weekly for three weeks followed by one week off.
  • the HDAC inhibitor is administered intravenously, orally, or intraperitoneally.
  • the dose of an HDAC inhibitor administered to a subject may be about 0.1 mg/kg to about 1000 mg/kg.
  • the dose may be about 1 mg/kg to about 100 mg/kg, such as about 1 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 40 mg/kg, 50 mg/kg, 75 mg/kg, or 100 mg/kg.
  • the dose may be about 10 to 800 mg, for example, about 50 mg to 800 mg, or about 100 mg to 600 mg of an HDAC inhibitor.
  • the PARP inhibitor is administered intravenously, orally, or intravenously. In particular examples, the PARP inhibitor is administered orally.
  • the dose of a PARP inhibitor administered to a subject may be about 0.1 mg/kg to about 1000 mg/kg. In particular examples, the dose may be about 1 mg/kg to about 100 mg/kg, such as about 1 mg/kg, 5 mg/kg, 10 mg/kg, 20 mg/kg, 40 mg/kg, 50 mg/kg, 75 mg/kg, or 100 mg/kg. In other examples, the dose may be about 10 to 800 mg, for example, about 50 mg to 800 mg, or about 100 mg to 600 mg of a PARP inhibitor.
  • the combined administration of an LSD1 inhibitor or HDAC inhibitor and a PARP inhibitor includes administering the LSD1 or HDAC inhibitor either sequentially with the PARP inhibitor (e.g., the treatment with one agent first and then the second agent) or administering both agents at substantially the same time (e.g., an overlap in performing the administration).
  • sequential administration a subject is exposed to the agents at different times so long as some amount of the first agent remains in the subject (or has a therapeutic effect) when the other agent is administered.
  • the treatment with both agents at the same time can be in the same dose, for example, physically mixed, or in separate doses administered at the same time.
  • a therapeutically effective dose of an LSD1 inhibitor or HDAC inhibitor includes daily, weekly, bi-weekly, or monthly use for at least about 2 weeks, such as at least about one month, two months, three months, six months, one year, two years, three years, four years, five years, or more.
  • the disclosed methods include an LSD1 inhibitor or an HDAC inhibitor, which can be administered alone, in the presence of a pharmaceutically acceptable carrier, in the presence of other therapeutic agents (for example other anti-cancer therapeutic agents), or both.
  • other therapeutic agents for example other anti-cancer therapeutic agents
  • chemotherapeutic drugs include, but are not limited to, chemotherapeutic drug treatment, radiation, gene therapy, hormonal manipulation, immunotherapy and antisense oligonucleotide therapy.
  • useful chemotherapeutic drugs include, but are not limited to, microtubule binding agents (such as paclitaxel, docetaxel, vinblastine, vindesine, vinorelbine, epothilones, colchicine, dolastatin 15, nocodazole, podophyllotoxin, rhizoxin, and derivatives or analogs thereof), DNA intercalators or cross-linkers (such as cisplatin, carboplatin, oxaliplatin, mitomycins such as mitomycin C, bleomycin, chlorambucil, cyclophosphamide, and derivatives or analogs thereof), DNA synthesis inhibitors (such as methotrexate, 5-fluoro-5'- deoxyuridine, 5'fluorouracil, gemcitabine, and analogs thereof
  • an LSDl inhibitor is administered in combination with one or more of cisplatin, docetaxel, gemcitabine, 5-fluorouracil, bevacizumab, erlotinib, or sunitinib.
  • the LSDl inhibitor PG11047 is administered in combination with cisplatin.
  • the LSDl inhibitor is administered in combination with a PARP inhibitor.
  • the LSDl inhibitor is administered to the subject for a period of time (such as at least one day) prior to administration of the PARP inhibitor.
  • the LSDl inhibitor and PARP inhibitor are administered to the subject at least once per day (such as at least two, three, four, or more times a day) for at least two weeks (such as at least three weeks, four weeks, two months, three months, or more).
  • the HDAC inhibitor is administered to the subject for a period of time (such as at least one day) prior to administration of the PARP inhibitor.
  • the HDAC inhibitor and PARP inhibitor are administered to the subject at least once per day (such as at least two, three, four, or more times a day) for at least two weeks (such as at least three weeks, four weeks, two months, three months, or more).
  • This example describes the effect of inhibition of LSDl on gene expression profiles in prostate cell lines.
  • RWPE-1 were cultured in RPMI1640 medium with 10% fetal bovine serum.
  • Cells were transfected with 50 nM LSDl siRNA (siLSDl; target sequence C AC A AGG A A AGCU AG A AG AUU ; SEQ ID NO: 1) or control siRNA (siLuc; target sequence CGUACGCGGAAUACUUCGATT; SEQ ID NO: 2) with 50 nM LSDl siRNA (siLSDl; target sequence C AC A AGG A A AGCU AG A AG AUU ; SEQ ID NO: 1) or control siRNA (siLuc; target sequence CGUACGCGGAAUACUUCGATT; SEQ ID NO: 2) with 50 nM LSDl siRNA (siLSDl; target sequence C AC A AGG A A AGCU AG A AG AUU ; SEQ ID NO: 1) or control siRNA (siLuc; target sequence CGUACGCGGAAUACUUCGATT; SEQ ID NO: 2) with 50 nM LSDl siRNA
  • Stable transfectants were selected in the presence of 1 ⁇ g/ml puromycin (In vitro gen, Carlsbad, CA). Cells were treated with polyamine analogs for 48 hours at the indicated concentrations.
  • Microarray hybridization All samples were processed simultaneously with labeling and hybridization to Affymetrix U133 2.0 Plus assays. Each biological replicate was labeled and hybridized to its own array without pooling.
  • Hybridized arrays were evaluated for consistency and quality using the Affy package in the R statistical computing environment (R Development Core Team, R Foundation for Statistical Computing, 2008 (R-project.org); Gautier et al,
  • Immunoblotting Whole cell protein extracts were prepared and separated by SDS-PAGE and transferred to an Immobilon® membrane (Millipore, Billerica, MA). Blots were probed with mouse anti-FANCD2 (Santa Cruz Biotechnologies, Santa Cruz, CA), rabbit anti-LSD 1 (Cell Signaling, Beverly, MA), or mouse anti- actin (Sigma- Aldrich), followed by horseradish peroxidase-conjugated goat anti- mouse or goat anti-rabbit IgG. Detection was performed with ECL Western Reagents (Pierce, Rockford, IL).
  • LNCaP prostate cancer cells were treated with the LSDl inhibitor XB154
  • LSDl siRNA also known as 2d or LSDl siRNA. This resulted in global increases in the active di-methyl lysine 4 (2MK4) and repressive di-methyl lysine 9 (2MK9) marks on histone H3, which are removed by LSDl (FIG. 1A and B). This demonstrated XB154 and LSDl siRNA both inhibited LSDl demethylase activity.
  • Gene expression profiling was performed using LNCaP cells treated with polyamine analogs XB154 (10 ⁇ ) or LSDl siRNA for 96 hours. This treatment resulted in >2-fold increase in expression of over 61 common genes and >2-fold decrease in expression of 293 common genes. Notably, many of these genes were not AR target genes.
  • the Fanconi anemia (FA) DNA damage repair pathway was the top pathway whose gene members changed in expression in both polyamine analog- and LSDl siRNA-treated cells. Many of these genes had >1.5-fold decrease in expression in cells treated with XB154, PG11144, PG11047, or LSDl siRNA (FIG. 2).
  • FANCD2 mRNA levels versus vector-transfected cells FIG. 3
  • XB154 treatment reduced FANCD2 mRNA levels in LNCaP cells treated for 48 hours (FIG. 4A).
  • FANCD2 protein levels and levels of ubiquitinated FANCD2 (ub- FANCD2) were also reduced in LNCaP cells following 24-48 hours of treatment with XB154 or LSDl siRNA (FIG. 4B) and in LSDl stable knockdown cells (FIG. 4C). This result was also obtained in cells treated with the monoamine oxidase LSDl inhibitor pargyline (FIG. 4D).
  • Treatment with XB154 for 24 or 48 hours also reduced levels of BRCA1 mRNA in a concentration-dependent manner (FIG. 5).
  • LNCaP cells were also treated with HDAC inhibitors and analyzed by gene expression profiling. Similar to XB154 and LSDl siRNA treatment, inhibition of HDAC resulted in >1.5-fold decrease in expression of DNA damage repair enzyme expression (FIG. 6).
  • This example describes the effect of inhibition of LSDl on cell proliferation and viability.
  • LNCaP cells were plated in 12- well plates at 75,000 cells/well.
  • XB154 was added at 1 ⁇ or 5 ⁇ final concentration the next day.
  • Mitomycin C (MMC) was added 24 hours after XB154 treatment.
  • Cell counts were performed after 48 hours of MMC treatment with the Countess® Automated Cell Counter (Invitrogen).
  • shLSDl cells and shNTC cells (described in Example 1) were plated in 12 well plates at 50,000 cells/well.
  • Olaparib was added at 1 ⁇ or 5 ⁇ the next day, and again after 3 days. Cell counts were performed after 5 days with the Countess® Automated Cell Counter (Invitrogen).
  • LNCaP cells with a stable knockdown of LSDl expression had greatly reduced proliferation compared to control cells (FIG. 7). Similar results were obtained with cells treated with XB154 or pargyline and all other prostate cancer cell lines tested (DU145, VCaP, and LAPC4).
  • LNCaP cells treated with XB154 for 24 hours and subsequently co-treated with MMC for 48 hours showed greater sensitivity to MMC than cells treated with XB154 or MMC alone (FIG. 8).
  • Treatment of shLSDl cells with olaparib, a PARP inhibitor also resulted in enhanced cell death compared to control shNTC cells (FIG. 9).
  • This example describes analysis of gene expression in androgen-dependent and androgen-independent cells and the effect of inhibition of LSD1.
  • ADT Androgen deprivation therapy
  • Intratumoral androgens and canonical, androgen- dependent signaling persist in CRPC cells from patients (Mostahel et al., Cancer Res. 67:5033-5041, 2007; Mohler ei a/., Clin. Cancer Res. 10:440-448, 2004). This highlights the misnomer of only classifying prostate cancers that have not been treated with ADT or which are responding to ADT as androgen-dependent (non- CRPC may be a more accurate descriptor for these cancers).
  • CRPC cell lines (Abl or C42B), which are LNCaP derivatives grown chronically in the absence of androgens
  • the top upregulated pathways versus LNCaP cells are "cell cycle” or “mitotic cell cycle” (Wang et al., Cell 138:245-256, 2009).
  • This androgen- independent program promotes progression through the mitotic phase of the cell cycle, and RNA interference to AR in CRPC cells leads to reduced expression of these genes (which highlights their AR-dependency) and leads to G2-M cell cycle arrest (Wang et al., Cell 138:245-256, 2009).
  • Prostate cancer cell line LNCaP and PC3 were cultured in RPMI 1640 medium with 10% fetal bovine serum.
  • Cells were transfected with 50 nM AR siRNA (siAR, target sequence GACCUACCGAGGAGCUUUCUU: SEQ ID NO: 4), LSD1 siRNA, or control siRNA (described in Example 1) with 50 nM AR siRNA (siAR, target sequence GACCUACCGAGGAGCUUUCUU: SEQ ID NO: 4), LSD1 siRNA, or control siRNA (described in Example 1) with
  • DharmaFECT 3 siRNA transfection reagent (Thermo Scientific Dharmacon, Lafayette, CO). Cells were harvested 96 hours post-transfection. Stable LSD1 knockdown cells were described in Example 1.
  • XB154 treatment cells were treated with XB154 for 48 hours at the indicated concentrations.
  • PG11144 (Progen) treatment cells were treated with PG11144 for 96 hours at the indicated concentrations.
  • RT-PCR was performed as described in Example 1. Primers used for RT-PCR are provided in Table 1. Immunoblotting: Immunoblots were performed as described in Example 1. Antibodies used were rabbit anti-AR (Millipore), mouse anti-2MK9 (Abeam, Cambridge, MA), and mouse anti-GAPDH (Santa Cruz Biotechnologies).
  • Chromatin Immunoprecipitation Cells were cross-linked with formaldehyde and reactions were stopped with glycine. Cross-linked cells were resuspended in IP buffer with SigmaFastTM protease inhibitor tablets (Sigma- Aldrich) and sonicated on ice by using a Branson Digital Sonifier® model 450. Immunoprecipitations were performed with rabbit anti-LSD 1 (Abeam), rabbit anti- AR (Santa Cruz), rabbit anti-AcH3 (Millipore) and normal rabbit IgG (Millipore) on Dynabeads® (Invitrogen). For real time PCR, 2 ⁇ of 50 ⁇ DNA extract was used.
  • RNA interference This allowed comparison of the effect of RNA interference to LSDl in LNCaP cells versus AR in LNCaP and Abl cells.
  • the gene expression profiles were compared to published gene expression profiles after the addition of dihydrotestosterone (DHT) to LNCaP or Abl cells grown in charcoal- stripped serum, which allowed determination of the effect of RNA interference to LSDl on androgen-dependent genes.
  • DHT dihydrotestosterone
  • RNA interference to LSDl in LNCaP cells or to AR in both LNCaP and Abl cells reduced gene expression of many AR-bound genes. Indeed, RNA interference to LSDl in LNCaP most closely resembled gene expression profiles after RNA interference to AR in Abl cells. None of the AR-bound genes that declined in expression with RNA interference to LSDl in LNCaP cells (RNA interference to LSDl was done in cells grown in the presence of androgens) increased in expression with the addition of androgens, which highlights their andro gen-independence (FIG. 10).
  • PGl 1144 inhibited LSDl function (increased 2MK9 levels) and attenuated androgen-independent (but not canonical androgen-dependent) "AR" signaling without affecting AR protein levels (FIG. 11).
  • This effect of RNA interference to LSDl or PGl 1144 treatment was recapitulated in non-CRPC cells such as VCaP and LAPC4 and CRPC C42B cells, which highlights the generalizability of these findings.
  • Chrin immunoprecipitation (ChIP) assays showed that these androgen-independent "AR" genes are direct targets of both AR and LSDl in
  • LNCaP cells grown in the absence of androgens. RNAi-mediated suppression of AR, LSDl, or both decreased expression of both UBE2C and CCNA2 (FIGS. 12A and B) in LNCaP cells.
  • a representative ChIP PCR for UBE2C and CCNA2 is shown in FIG. 12C.
  • RNA interference to AR or LSDl or treatment with PGl 1144 or XB154 recapitulated the effect of these manipulations in LNCaP cells, resulting in reduced androgen-independent "AR" target gene expression and reduced proliferation (FIG. 13). Furthermore, treatment of PC3 cells (AR negative) with siLDSl or XB154 caused decreases in proliferation gene expression (FIG. 14). Finally, treatment with PG11144 did not lower expression of classic androgen-dependent genes, such as Nkx3.1 in LNCaP cells (FIG. 15).
  • This example describes the effect of inhibition of LSDl on cell growth and proliferation and cell cycle progression.
  • LNCaP, Abl, or C42B cells were transfected with siAR, siLSDl or siLUC (described as in Examples 1 and 3), then plated in 12-well plates at 50,000 cells/well. Cell counts were performed the next day (set as start point) and 5 days after siRNA transfection with the Countess® Automated Cell Counter (Invitrogen). Growth in CSM was examined as above, except cells were cultured in RPMI1640 plus 10% FBS after siRNA transfection. Cell counts were performed the next day (set as start point) and 5 days after siRNA transfection with the Countess® Automated Cell Counter (Invitrogen).
  • Stable shLSDl (or shNTC) cells were plated in 12-well plates at 50,000 cells/well with 5 ⁇ g/ml puromycin. Cell counts were performed at indicated days with the Countess® Automated Cell Counter (Invitrogen).
  • RNA interference to LSDl prostate cancer cell growth was assessed.
  • LSDl knockdown inhibited growth of Abl and C42B cells (FIG. 16).
  • LSDl knockdown with siRNA also inhibited growth of LNCaP cells (non-CRPC cells) in the absence of androgens (FIG. 17).
  • RNA interference to LSD1 led to accumulation of cells in the G2-M phases of the cell cycle (FIG. 18).
  • Prostate cancer cell lines LNCaP, Abl, and PC3 were cultured in RPMI1640 medium with 10% fetal bovine serum. Cells at 30% confluency were treated with PG11144 or PG11047 in water at the indicated concentrations and harvested at the indicated times post-treatment. Cell viability was analyzed by trypan blue exclusion.
  • Immunoblotting Whole cell protein extracts were prepared and separated by SDS-PAGE and transferred to an Immobilon® membrane (Millipore, Billerica, MA). Blots were probed with mouse anti-FANCD2 (Santa Cruz Biotechnologies, Santa Cruz, CA), rabbit anti-Histone H3 di-methyl lysine 4 (Millipore, Billerica, MA), mouse anti-Histone H3 di-methyl lysine 9 (Abeam, Cambridge, MA) or mouse anti-actin (Sigma- Aldrich), followed by infrared dye-labeled goat anti-mouse or goat anti-rabbit IgG. Detection was performed with an Odyssey® imager (LI- COR Biotechnology, Lincoln, Iowa).
  • suppression of LSDl expression with RNAi eliminated the effect of PGl 1047 treatment on histone methylation (FIG. 20C).
  • This example describes assessment of effectiveness and toxicity of treatment of cells in vitro with a combination of LSDl inhibitor and PARP inhibitor.
  • prostate cancer cell lines are treated with an LSDl inhibitor plus or minus a PARP inhibitor.
  • the prostate cancer cell lines include androgen-dependent cell lines (such as LNCaP, PC3, and DU145 cells) and androgen-independent prostate cancer cell lines (such as Abl and C42B cells).
  • the prostate cancer cells are transfected with LSDl siRNA or shRNA to decrease LSDl expression (LSDl knockdown cells).
  • LSDl knockdown cells are treated with varying amounts (such as 0.1 ⁇ to 100 ⁇ ) of a PARP inhibitor (such as olaparib) for 1-7 days.
  • unmodified prostate cancer cells are treated with varying amounts (such as 0.1 ⁇ to 100 ⁇ ) of an LSDl inhibitor (such as XB154, PGl 144, or pargyline) for one day.
  • LSDl inhibitor such as XB154, PGl 144, or pargyline
  • the cells are then co-treated with the LSDl inhibitor and with varying amounts (such as 0.1 ⁇ to 100 ⁇ ) of a PARP inhibitor (such as olaparib) for 1-7 days.
  • the number of cells is counted and compared to cells treated with vehicle alone or cells treated with the LSDl inhibitor alone.
  • a decrease (such as a statistically significant decrease) in the number of cells following treatment with an LSDl inhibitor and a PARP inhibitor indicates that the combination is effective at decreasing proliferation and/or killing prostate cancer cells.
  • the number of cells undergoing apoptosis may also be determined, for example, using a TUNEL assay, annexin V staining, or other methods known to one of skill in the art.
  • An increase (such as a statistically significant increase) in the number of cells undergoing apoptosis following treatment with an LSDl inhibitor and a PARP inhibitor indicates that the combination is effective at decreasing proliferation and/or killing prostate cancer cells.
  • H2AX foci are measured using
  • the effect of LSDl inhibitor plus PARP inhibitor is assessed in non-cancer cells in culture.
  • non-cancer cells in culture For example, primary cultures from normal bone marrow donors can be used. The cells are treated with an LSDl inhibitor (such as XB154, PG11047, PG11144, or pargyline) and a PARP inhibitor (such as olaparib) as described above. Cell number and apoptosis are assessed as discussed above. No change (for example, no statistically significant change) in cell number or the number of cells undergoing apoptosis as compared to cells treated with vehicle alone indicates that the treatment is not toxic to non-cancer cells.
  • LSDl inhibitor such as XB154, PG11047, PG11144, or pargyline
  • PARP inhibitor such as olaparib
  • This example describes methods for assessing the effectiveness of LSDl inhibitors against prostate cancer cells in an in vivo xenograft model.
  • LNCaP cells with a stable knockdown of LSDl (shLSDl cells) or control cells (such as shNTC cells) are inoculated in the dorsal flank of nude mice by subcutaneous injection (such as 3 x 10 6 cells in 100 of 50% RPMI 1640/BD Matrigel).
  • a two- sample t-test is performed to determine statistical differences in mean tumor volume between the two groups.
  • Unmodified LNCaP cells are inoculated by subcutaneous injection into the dorsal flank of nude mice (such as 3 x 10 6 cells in 100 ⁇ . of 50% RPMI 1640/BD Matrigel). After three weeks, mice are injected intraperitoneally once per day with water (control), pargyline (0.53 mg or 1.59 mg; 1 or 3 mM final concentration, assuming 70% bioavailability), or XB154 (4 or 20 ⁇ g; 1 or 5 ⁇ final concentration, assuming 70% bioavailability) or treated with PGl 1144 (5 mg/kg each week) or PGl 1047 (10 mg/kg each week) Treatment continues for three weeks, during which time mouse weight and tumor volume are measured as above.
  • shLSDl LNCaP cells or control cells are injected in nude mice as above. After three weeks, mice are treated with 2.6 ⁇ g mitomycin C (predicted final concentration of 1 ⁇ assuming 40% bioavailability), olaparib (for example, about 0.5 mg/kg to 25 mg/kg), or vehicle intraperitoneally once per day for three weeks. In other examples, unmodified LNCaP cells are injected in nude mice as above.
  • mice are treated with pargyline, XB154, PGl 1047, PGl 1144, or vehicle as above, plus MMC or olaparib. Treatment continues for three weeks, during which time mouse weight and tumor volume are measured as above.
  • a decrease in tumor volume compared to control in mice injected with shLSDl cells indicates that LSDl inhibition decreases tumor growth in vivo.
  • mice injected with LNCaP cells and treated with XB154, PGl 1144, or PGl 1047 indicates that LSDl inhibition decreases tumor growth in vivo.
  • a decrease in tumor volume in mice injected with LNCaP cells and treated with XB154, PGl 1144, or PGl 1047 plus olaparib as compared to mice treated with XB154, PGl 1144, or PGl 1047 alone indicates that inhibition of LSDl plus inhibition of PARP decreases tumor growth in vivo.
  • the harvested xenograft tissue is examined for evidence of LSDl inhibition. This is assessed with Western blots to examine global levels of the 2MK4 and 2MK9 histone marks, expression of FA/BRCA genes, FANCD2 ubiquitination, and LSDl protein levels in the cases of the shRNA cells. A decrease in one or more of these parameters indicates the effective inhibition of LSD 1. Additionally, effects on DNA damage repair are assessed with staining for H2AX foci.
  • This example describes an exemplary prospective clinical trial for treating prostate cancer with polyamine analogs PG11144 or PG11047.
  • methods that deviate from these specific methods can also be used in a clinical trial.
  • Patients identified as having a prostate tumor are selected for treatment. Patients with small cell prostate carcinoma diagnosed by histology on biopsy are selected and followed as a subset of patients. Patients with CRPC are also selected and followed as a subset of patients.
  • Patients are administered PG11047 or PG1144 intravenously (50 mg-750 mg) on days 1, 8, and 15 of a 28 day cycle for at least 2 cycles.
  • PG11047 or PG1144 intravenously (50 mg-750 mg) on days 1, 8, and 15 of a 28 day cycle for at least 2 cycles.
  • PG11047 patients are administered 610 mg PG11047 on days 1, 8, and 15 of a 28 day cycle for at least 2 cycles. Patients are monitored for signs of unacceptable toxicity. Disease progression is monitored periodically (such as weekly, bi-weekly, monthly). Outcome measures include time to progression (for example as measured by Response Evaluation Criteria in Solid Tumors (RECIST) v2.0), overall survival, and quality of life.
  • RECIST Response Evaluation Criteria in Solid Tumors

Abstract

La présente invention concerne des méthodes de traitement du cancer utilisant un inhibiteur de la déméthylase 1 spécifique de la lysine (LSD1), un inhibiteur de LSD1 en combinaison à un agent endommageant l'ADN ou un inhibiteur de poly(ADP-ribose) polymérase (PARP) ou un inhibiteur de l'histone désacétylase (HDAC) en combinaison à un agent endommageant l'ADN ou à un inhibiteur de PARP. Dans un mode de réalisation, les méthodes incluent l'administration d'une quantité thérapeutiquement efficace d'un inhibiteur de LSD1 à un sujet présentant un cancer (tel qu'un cancer de la prostate résistant à la castration). Dans d'autres modes de réalisation, les méthodes comprennent l'administration d'une quantité thérapeutiquement efficace d'un inhibiteur de LSD1 et d'une quantité thérapeutiquement efficace d'un inhibiteur de PARP à un sujet présentant un cancer (tel qu'un cancer de la prostate, un cancer du sein ou un cancer de l'ovaire). Dans d'autres modes de réalisation, les méthodes de l'invention comprennent l'administration d'une quantité thérapeutiquement efficace d'un inhibiteur de HDAC et d'une quantité thérapeutiquement efficace d'un inhibiteur de PARP à un sujet présentant un cancer (tel qu'un cancer de la prostate, un cancer du sein ou un cancer de l'ovaire).
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