WO2018185516A1 - Méthodes et compositions pharmaceutiques destinées à traiter une toxicité cardiovasculaire induite par une thérapie anticancéreuse - Google Patents

Méthodes et compositions pharmaceutiques destinées à traiter une toxicité cardiovasculaire induite par une thérapie anticancéreuse Download PDF

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WO2018185516A1
WO2018185516A1 PCT/IB2017/000566 IB2017000566W WO2018185516A1 WO 2018185516 A1 WO2018185516 A1 WO 2018185516A1 IB 2017000566 W IB2017000566 W IB 2017000566W WO 2018185516 A1 WO2018185516 A1 WO 2018185516A1
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sunitinib
cancer
compound
endothelin
treatment
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PCT/IB2017/000566
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English (en)
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Bertrand Tavitian
Neeraj DHAUN
Joevin SOURDON
Pierre-Louis Tharaux
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INSERM (Institut National de la Santé et de la Recherche Médicale)
Université Paris Descartes
Assistance Publique - Hôpitaux De Paris
The University Court Of The University Of Edinburgh
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Priority to PCT/IB2017/000566 priority Critical patent/WO2018185516A1/fr
Publication of WO2018185516A1 publication Critical patent/WO2018185516A1/fr

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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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • 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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention relates to methods and pharmaceutical compositions for treating cardiovascular toxicity induced by an anti-cancer and an anti-angiogenic compound.
  • anticancer drugs The major factor limiting therapeutic administration of anticancer drugs is their toxic side effect on off-target organs. It is well known that classical anticancer drugs, e.g. anthracyclines, antimetabolites, alkylating agents, taxanes, induce serious cardiovascular toxicity (1,2). Newer anticancer agents such as interferon and tyrosine kinase receptor (TKR) inhibitors also have cardiovascular side-effects (3) that, although often less severe than those observed with anthracyclines, are frequent and may be life-threatening (4). The clinical importance of cardiotoxicity associated with cancer therapy has led to the emergence of cardio- oncology, an interdisciplinary field that aims to better understand and limit the cardiotoxicity of cancer therapy (5).
  • classical anticancer drugs e.g. anthracyclines, antimetabolites, alkylating agents, taxanes
  • TTR tyrosine kinase receptor
  • VEGFRs Vascular Endothelial Growth Factor Receptors
  • Sunitinib (Sutent; Pfizer, USA) is an anti-angiogenic TKR inhibitor of VEGFRs, platelet-derived growth factor receptors (PDGF-Rs), and c-kit (13), approved in 2006 by the FDA for the treatment of renal cell carcinoma (14), imatinib-resistant gastrointestinal stromal tumor (15) and neuroendocrine tumors (16).
  • PDGF-Rs platelet-derived growth factor receptors
  • c-kit 13
  • sunitinib leads to mitochondrial dysfunction; in mice, to increased apoptosis of cardiomyocytes (8).
  • a poor coronary flow response to bradykinin was reported in sunitinib-treated hearts, supporting microvascular dysfunction as a direct cardiac side effect of the drug (21).
  • sunitinib inhibits AMPK (22) and induces mitochondrial damage (8) opens up the possibility that some or all of its side effects could result from a direct deregulation of cardiac metabolism.
  • ET receptor blockers can reduce blood pressure (BP) and renal injury in animals and patients treated with sunitinib (21,23-25).
  • BP blood pressure
  • ET receptor antagonism in treating or preventing the cardiotoxic effects of sunitinib have not been studied.
  • the inventors explored cardiac metabolism after sunitinib treatment in mice using PET-FDG.
  • the inventors aimed to (i) better clarify the cardiac metabolic pathways deregulated during the early stages of sunitinib treatment, (ii) determine if the cardiac side effects are mediated by the endothelin pathway (iii) test the blockade of the endothelin system to prevent the cardiac side effects of sunitinib, and (iv) confirm that PET- FDG can be useful to monitor cardiac metabolic remodeling.
  • the present invention relates to methods and pharmaceutical compositions for treating cardiovascular toxicity induced by an anti-cancer and an anti-angiogenic compound.
  • the growing field of cardio-oncology addresses the side effects of cancer treatment on the cardiovascular system.
  • sunitinib explored the cardiotoxicity induced by the antiangiogenic therapy, sunitinib, in the mouse heart from a diagnostic and therapeutic perspective.
  • the inventors showed that sunitinib induces an anaerobic switch of cellular metabolism within the myocardium which is associated with the development of myocardial fibrosis as demonstrated by echocardiography.
  • the capacity of positron emission tomography with [ 18 F]fluorodeoxyglucose to detect the changes in cardiac metabolism caused by sunitinib was dependent on fasting status and duration of treatment.
  • Pan proteomic analysis in the myocardium showed that sunitinib induced (i) an early metabolic switch with enhanced glycolysis and reduced oxidative phosphorylation, and (ii) a metabolic failure to use glucose as energy substrate, similar to the insulin resistance found in type 2 diabetes.
  • Co-administration of macitentan, the endothelin receptor antagonist, to sunitinib-treated animals prevented both metabolic defects, restored glucose uptake and cardiac function, and prevented myocardial fibrosis.
  • These results support the endothelin system in mediating the cardiotoxic effects of sunitinib and endothelin receptor antagonism as a potential therapeutic approach to prevent cardiotoxicity.
  • metabolic and functional imaging can monitor the cardiotoxic effects and the benefits of endothelin antagonism in a theranostics approach.
  • the present invention relates to a compound selected from the group consisting of endothelin receptor antagonist and inhibitor of endothelin receptor expression for use in the treatment of cardiovascular toxicity induced by anti-cancer compound in a subject in need thereof.
  • the present invention relates to a compound selected from the group consisting of endothelin receptor antagonist and inhibitor of endothelin receptor expression for use in the treatment of cardiovascular toxicity induced by anti-angiogenic compound in a subject in need thereof.
  • the term "subject” denotes a mammal. Typically, a subject according to the invention refers to any subject (preferably human) receiving anti-cancer therapy. Typically, a subject according to the invention refers to any subject (preferably human) receiving anti- angiogenic therapy. In a particular embodiment, the term “subject” refers to a subject afflicted or at risk to be afflicted with cardiovascular toxicity induced by anti-cancer therapy or anti- angiogenic therapy. In a particular embodiment, the term “subject” refers to a subject afflicted with cancer. In a particular embodiment, the term “subject” refers to a subject afflicted with angiogenesis-related diseases.
  • the term “subject” refers to a subject afflicted with cancer or angiogenesis-related diseases receiving anti-cancer therapy or anti- angiogenic therapy.
  • the term “subject” refers to a subject afflicted with cancer or angiogenesis-related diseases, and afflicted or at risk to be afflicted with cardiovascular toxicity induced by anti-cancer therapy or anti-angiogenic therapy.
  • treatment refers to both prophylactic or preventive treatment as well as curative or disease modifying treatment, including treatment of subjects at risk of contracting the disease or suspected to have contracted the disease as well as subjects who are ill or have been diagnosed as suffering from a disease or medical condition, and includes suppression of clinical relapse.
  • the treatment may be administered to a subject having a medical disorder or who ultimately may acquire the disorder, in order to prevent, cure, delay the onset of, reduce the severity of, or ameliorate one or more symptoms of a disorder or recurring disorder, or in order to prolong the survival of a subject beyond that expected in the absence of such treatment.
  • therapeutic regimen is meant the pattern of treatment of an illness, e.g., the pattern of dosing used during therapy.
  • a therapeutic regimen may include an induction regimen and a maintenance regimen.
  • the phrase “induction regimen” or “induction period” refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the initial treatment of a disease.
  • the general goal of an induction regimen is to provide a high level of drug to a subject during the initial period of a treatment regimen.
  • An induction regimen may employ (in part or in whole) a "loading regimen", which may include administering a greater dose of the drug than a physician would employ during a maintenance regimen, administering a drug more frequently than a physician would administer the drug during a maintenance regimen, or both.
  • maintenance regimen refers to a therapeutic regimen (or the portion of a therapeutic regimen) that is used for the maintenance of a subject during treatment of an illness, e.g., to keep the subject in remission for long periods of time (months or years).
  • a maintenance regimen may employ continuous therapy (e.g., administering a drug at a regular intervals, e.g., weekly, monthly, yearly, etc.) or intermittent therapy (e.g., interrupted treatment, intermittent treatment, treatment at relapse, or treatment upon achievement of a particular predetermined criteria [e.g., disease manifestation, etc.]).
  • cardiovascular toxicity has its general meaning in the art and refers to cardiotoxicity induced by anti-cancer therapy.
  • cardiac toxicity also refers to cardiotoxicity induced by anti-angiogenic therapy.
  • cardiovascular toxicity also refers to cardiovascular side-effects of anti-cancer therapy and anti-angiogenic therapy.
  • cardiac toxicity also refers to metabolic defects, increase myocardial fibrosis, reduction of myocardial glucose uptake, cardiac dysfunction, cardiac ischemia and switch toward anaerobic metabolism.
  • cardiovascular toxicity also refers to anaerobic switch of cellular metabolism within the myocardium which is associated with the development of myocardial fibrosis, early metabolic switch with enhanced glycolysis and reduced oxidative phosphorylation, and a metabolic failure to use glucose as energy substrate, similar to the insulin resistance found in type 2 diabetes.
  • the compound of the invention is used in the treatment of vascular toxicity induced by anti-cancer therapy and anti-angiogenic therapy.
  • vascular toxicity refers to microvascular dysfunction and damage in the heart, kidney, retina, brain and other target organs such as renal, retinal and cerebrovascular circulation dysfunction induced by anti-cancer therapy and anti-angiogenic therapy.
  • cancer has its general meaning in the art and includes, but is not limited to, solid tumors and blood borne tumors.
  • the term cancer includes diseases of the skin, tissues, organs, bone, cartilage, blood and vessels.
  • the term “cancer” further encompasses both primary and metastatic cancers. Examples of cancers include, but are not limited to, cancer cells from the adrenal, bladder, blood, bone, bone marrow, brain, breast, colon, esophagus, gastrointestine, gum, head, kidney, liver, lung, nasopharynx, neck, ovary, prostate, skin, stomach, sympathic and parasympathic ganglia, testis, tongue, or uterus.
  • the cancer may specifically be of the following histological type, though it is not limited to these: neoplasm, malignant; carcinoma; carcinoma, undifferentiated; giant and spindle cell carcinoma; small cell carcinoma; papillary carcinoma; squamous cell carcinoma; lymphoepithelial carcinoma; basal cell carcinoma; pilomatrix carcinoma; transitional cell carcinoma; papillary transitional cell carcinoma; adenocarcinoma; gastrinoma, malignant; cholangiocarcinoma; hepatocellular carcinoma; combined hepatocellular carcinoma and cholangiocarcinoma; trabecular adenocarcinoma; adenoid cystic carcinoma; adenocarcinoma in adenomatous polyp; adenocarcinoma, familial polyposis coli; solid carcinoma; carcinoid tumor, malignant; branchiolo-alveolar adenocarcinoma; papillary adenocarcinoma; chromophobe carcinoma; acid
  • the subject suffers from a cancer selected from the group consisting of breast cancer, triple negative breast cancer, colon cancer, lung cancer, prostate cancer, testicular cancer, brain cancer, skin cancer, rectal cancer, gastric cancer, esophageal cancer, sarcomas, adrenal cancer, sympathic and parasympathic ganglia cancer, tracheal cancer, head and neck cancer, pancreatic cancer, liver cancer, ovarian cancer, lymphoid cancer, cervical cancer, vulvar cancer, melanoma, mesothelioma, renal cancer, bladder cancer, thyroid cancer, bone cancers, carcinomas, sarcomas, and soft tissue cancers.
  • a cancer selected from the group consisting of breast cancer, triple negative breast cancer, colon cancer, lung cancer, prostate cancer, testicular cancer, brain cancer, skin cancer, rectal cancer, gastric cancer, esophageal cancer, sarcomas, adrenal cancer, sympathic and parasympathic ganglia cancer, tracheal cancer
  • angiogenesis-related diseases has its general meaning in the art and refers to diseases associated with or supported by pathological angiogenesis (i.e., inappropriate, excessive or undesired formation of blood vessels), which may be induced by various angiogenic factors.
  • pathological angiogenesis i.e., inappropriate, excessive or undesired formation of blood vessels
  • angiogenesis-related diseases also relates to angiogenic diseases associated with abnormal neovascularisation.
  • Angiogenesis-related diseases include but are not limited to cancer, tumor angiogenesis, primary and metastatic solid tumors, including carcinomas of breast, colon, rectum, lung, oropharynx, hypopharynx, esophagus, stomach, pancreas, liver, gallbladder and bile ducts, small intestine, kidney, bladder, urothelium, female genital tract, (including cervix, uterus, and ovaries as well as choriocarcinoma and gestational trophoblastic disease), male genital tract (including prostate, seminal vesicles, testes and germ cell tumors), endocrine glands (including the thyroid, adrenal, and pituitary glands), and skin, as well as hemangiomas, melanomas, sarcomas (including those arising from bone and soft tissues as well as Kaposi's sarcoma) and tumors of the brain, nerves, eyes, such as astrocytomas,
  • Angiogenesis-related diseases also relate to tumors arising from hematopoietic malignancies such as leukemias as well both Hodgkin's and non-Hodgkin's lymphomas.
  • Angiogenesis-related diseases also relate to various ocular diseases such as diabetic retinopathy, retinopathy of prematurity, corneal graft rejection, retrolental fibroplasia, neovascular glaucoma, rubeosis, retinal neovascularization due to macular degeneration, hypoxia, angiogenesis in the eye associated with infection or surgical intervention, and other abnormal neovascularization conditions of the eye.
  • Angiogenesis- related diseases also relate to rheumatoid, immune and degenerative arthritis.
  • Angiogenesis-related diseases also relate to skin diseases such as psoriasis; blood vessel diseases such as hemagiomas, and capillary proliferation within atherosclerotic plaques; Osier-Webber Syndrome; myocardial angiogenesis; plaque neovascularization; telangiectasia; haemophiliac joints; angiofibroma; and wound granulation.
  • Angiogenesis-related diseases also relate to diseases characterized by excessive or abnormal stimulation of endothelial cells, including but not limited to intestinal adhesions, Crohn's disease, atherosclerosis, scleroderma, and hypertrophic scars, i.e. keloids., diseases that have angiogenesis as a pathologic consequence such as cat scratch disease (Rochele ninalia quintosa) and ulcers (Helicobacter pylori).
  • anti-cancer compound has its general meaning in the art and refers to compounds used in anti-cancer therapy such as anti-angiogenic compound, tyrosine kinase inhibitors, tyrosine kinase receptor (TKR) inhibitors, Vascular Endothelial Growth Factor Receptors (VEGFRs) pathway inhibitors, interferon therapy, anti-HER2 compounds, anti- EGFR compounds, alkylating agents, anti-metabolites, immunotherapeutic agents, Interferons (IFNs), Interleukins, and chemotherapeutic agents such as described below.
  • anti-angiogenic compound has its general meaning in the art and refers to compounds used in anti-angiogenic therapy such as tyrosine kinase inhibitors, anti-angiogenic tyrosine kinase receptor (TKR) inhibitors, anti-angiogenics targeting the Vascular Endothelial Growth Factor Receptors (VEGFRs) pathway, interferon therapy and anti-HER2 compounds such as Trastuzumab (herceptin) and pertuzumab.
  • anti- angiogenic compound refers to Sunitinib (Sutent), an anti-angiogenic TKR inhibitor of VEGFRs, platelet-derived growth factor receptors (PDGF-Rs), and c-kit.
  • tyrosine kinase inhibitor refers to any of a variety of therapeutic agents or drugs that act as selective or non-selective inhibitors of receptor and/or non-receptor tyrosine kinases. Tyrosine kinase inhibitors and related compounds are well known in the art and described in U.S Patent Publication 2007/0254295, which is incorporated by reference herein in its entirety.
  • a compound related to a tyrosine kinase inhibitor will recapitulate the effect of the tyrosine kinase inhibitor, e.g., the related compound will act on a different member of the tyrosine kinase signaling pathway to produce the same effect as would a tyrosine kinase inhibitor of that tyrosine kinase.
  • tyrosine kinase inhibitors and related compounds suitable for use in methods of embodiments of the present invention include, but are not limited to, sunitinib (Sutent; SU11248), dasatinib (BMS-354825), PP2, BEZ235, saracatinib, gefitinib (Iressa), erlotinib (Tarceva; OSI-1774), lapatinib (GW572016; GW2016), canertinib (CI 1033), semaxinib (SU5416), vatalanib (PTK787/ZK222584), sorafenib (BAY 43-9006), imatinib (Gleevec; STI571), leflunomide (SU101), vandetanib (Zactima; ZD6474), MK-2206 (8-[4-aminocyclobutyl)phenyl]-9-phenyl- l,2,4-triazolo[3,4
  • the tyrosine kinase inhibitor is a small molecule kinase inhibitor that has been orally administered and that has been the subject of at least one Phase I clinical trial, more preferably at least one Phase II clinical, even more preferably at least one Phase III clinical trial, and most preferably approved by the FDA for at least one hematological or oncological indication.
  • inhibitors include, but are not limited to, Gefitinib, Erlotinib, Lapatinib, Canertinib, BMS-599626 (AC-480), Neratinib, KR -633, CEP-11981, Imatinib, Nilotinib, Dasatinib, AZM-475271, CP-724714, TAK-165, Sunitinib, Vatalanib, CP- 547632, Vandetanib, Bosutinib, Lestaurtinib, Tandutinib, Midostaurin, Enzastaurin, AEE-788, Pazopanib, Axitinib, Motasenib, OSI-930, Cediranib, KR -951, Dovitinib, Seliciclib, SNS- 032, PD-0332991, MKC-I (Ro-317453; R-440), Sorafenib, ABT
  • anti-angiogenic compound refers to compounds targeting the vascular endothelial growth factor (VEGF) pathway such anti-VEGF antibody bevacizumab (Avastin) and VEGF receptor tyrosine kinase inhibitor (TKI) compounds such as sunitinib (Sutent), vandetanib (Zactima), pazopanib (Votrient), sorafenib (Nexavar) and cediranib.
  • VEGF vascular endothelial growth factor
  • TKI VEGF receptor tyrosine kinase inhibitor
  • endothelin has its general meaning in the art and refers to the vaso constricting peptide endothelin- 1 (ET-1) produced primarily in the endothelium and acting on its both receptors ETA and ETB .
  • the endothelin (ET- 1 ) can be from any source, but typically is a mammalian (e.g., human and non-human primate) endothelin, particularly a human endothelin.
  • An exemplary native endothelin- 1 amino acid sequence is provided in UniProt database under accession number P05305 and an exemplary native nucleotide sequence encoding for endothelin- 1 is provided in GenBank database under accession number NM_001955.
  • endothelin receptor has its general meaning in the art and refers to G-protein- coupled receptors ETA and ETB.
  • ETA has its general meaning in the art and refers to the endothelin receptor type A.
  • ETA can be from any source, but typically is a mammalian (e.g., human and non-human primate) ETA, particularly a human ETA.
  • An exemplary native ETA amino acid sequence is provided in UniProt database under accession number P25101 and an exemplary native nucleotide sequence encoding for ETA is provided in GenBank database under accession number NM_001957.
  • ETB has its general meaning in the art and refers to the endothelin receptor type B.
  • ETB can be from any source, but typically is a mammalian (e.g., human and non-human primate) ETB, particularly a human ETB.
  • An exemplary native ETB amino acid sequence is provided in UniProt database under accession number P24530 and an exemplary native nucleotide sequence encoding for ETB is provided in GenBank database under accession number NM 000115.
  • endothelin receptor antagonist refers to a compound that selectively blocks or inactivates endothelin receptor.
  • selectively blocks or inactivates refers to a compound that preferentially binds to and blocks or inactivates endothelin receptor with a greater affinity and potency, respectively, than its interaction with the other sub-types or isoforms of G protein-coupled receptors family.
  • Compounds that prefer endothelin receptor, but that may also block or inactivate other G protein-coupled receptors sub-types, as partial or full antagonists, are contemplated.
  • endothelin receptor antagonist refers to any compound that can directly or indirectly block the signal transduction cascade related to the endothelin receptor.
  • endothelin receptor antagonist should be understood broadly and encompasses compounds acting directly (by binding) on endothelin, ETA or ETB proteins and able to prevent the interaction or binding between endothelin and its receptor(s).
  • endothelin receptor antagonist also refers to dual ETA and ETB receptor antagonist (ETA/ETB antagonist), selective ETA receptor antagonist or selective ETB receptor antagonist.
  • the "endothelin receptor antagonist” may also consist in compounds that inhibit the binding of the endothelin to endothelin receptor.
  • endothelin receptor antagonist also refers to inhibition of endothelin downstream signalling, phospholipase C, protein kinase C and MAPK1;ERK2.
  • endothelin receptor antagonist also refers to endothelin inhibitor such as compound able to prevent the action of endothelin (ET-1) on its receptors ETA and ETB, inhibitor of endothelin formation and inhibitor of endothelin expression.
  • an endothelin receptor antagonist is a small organic molecule, an oligonucleotide, a polypeptide, an aptamer, an antibody or an intra-antibody.
  • Tests and assays for determining whether a compound is an endothelin receptor antagonist are well known by the skilled person in the art such as described in Aubert and Juillerat-Jeanneret, 2017; Okada M. et al, 2002; US5,292,740 and US5,883,254.
  • the endothelin receptor antagonists are well-known in the art as illustrated by Aubert and Juillerat-Jeanneret, 2017; Okada M. et al, 2002; US5,292,740 and US5,883,254.
  • the endothelin receptor antagonist is selected from the group consisting of macitentan, bosentan, darusentan, sitaxsentan, tezosentan, ambrisentan, atrasentan, avosentan, clazosentan, zibotentan, edonentan, enrasentan, danusentan, A- 182086, A- 192621, ABT-627, BMS193884, BQ-123, BQ-788, CI 1020, FR-139317, S-0139, CPU0213, J- 104132, SB-209670, TA-0201, TAK-044, TBC3711, YM-598, ZD-1611, ZD-4054 and compounds described in Aubert
  • the endothelin receptor antagonist is an ETA/ETB antagonist such as macitentan, bosentan (US5,292,740 and US5, 883,254), A-182086, CPU0213, J-104132 and SB209670.
  • ETA/ETB antagonist such as macitentan, bosentan (US5,292,740 and US5, 883,254), A-182086, CPU0213, J-104132 and SB209670.
  • the endothelin receptor antagonist is a selective ETB receptor antagonist such as BQ-788 (Okada M. et al, 2002) and A- 192621.
  • a selective ETB receptor antagonist exhibits an affinity (as expressed by dissociation constant Ki) for ETB less than about ⁇ and a selectivity for ETB over ETA (as expressed by the ratio KiETB/KiETA) is at least about 50.
  • KiETB is less than 5 nM, more particularly less than 2 nM and even more particularly less than 1 Nm.
  • the ratio KiETB/KiETA is at least about 100, more particularly about 500 and even more particularly about 1000.
  • the endothelin receptor antagonist is an endothelin inhibitor such as a molecule that decreases or prevents endothelin formation.
  • ECE inhibitor Endothelin-Converting Enzyme inhibitor
  • FR901533 also called WS79089B, Tsurumi Y, et al, 1994 and Tsurumi Y, et al, 1995
  • CGS 26303 De Lombaert S et al, 1994
  • EAE Endothelin-Converting Enzyme
  • the endothelin receptor antagonist of the invention is an aptamer.
  • Aptamers are a class of molecule that represents an alternative to antibodies in term of molecular recognition.
  • Aptamers are oligonucleotide sequences with the capacity to recognize virtually any class of target molecules with high affinity and specificity.
  • Such ligands may be isolated through Systematic Evolution of Ligands by Exponential enrichment (SELEX) of a random sequence library, as described in Tuerk C. and Gold L., 1990.
  • the random sequence library is obtainable by combinatorial chemical synthesis of DNA. In this library, each member is a linear oligomer, eventually chemically modified, of a unique sequence.
  • Peptide aptamers consists of a conformationally constrained antibody variable region displayed by a platform protein, such as E. coli Thioredoxin A that are selected from combinatorial libraries by two hybrid methods (Colas et al, 1996). Then after raising aptamers directed against endothelin receptor of the invention as above described, the skilled man in the art can easily select those inhibiting endothelin receptor.
  • the endothelin receptor antagonist of the invention is an antibody (the term including "antibody portion") directed against endothelin receptors ETA and/or ETB or endothelin.
  • the antibody is a monoclonal antibody. In one embodiment of the antibodies or portions thereof described herein, the antibody is a polyclonal antibody. In one embodiment of the antibodies or portions thereof described herein, the antibody is a humanized antibody. In one embodiment of the antibodies or portions thereof described herein, the antibody is a chimeric antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a light chain of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a heavy chain of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a Fab portion of the antibody.
  • the portion of the antibody comprises a F(ab')2 portion of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a Fc portion of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a Fv portion of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises a variable domain of the antibody. In one embodiment of the antibodies or portions thereof described herein, the portion of the antibody comprises one or more CDR domains of the antibody.
  • antibody includes both naturally occurring and non-naturally occurring antibodies. Specifically, “antibody” includes polyclonal and monoclonal antibodies, and monovalent and divalent fragments thereof. Furthermore, “antibody” includes chimeric antibodies, wholly synthetic antibodies, single chain antibodies, and fragments thereof. The antibody may be a human or nonhuman antibody. A nonhuman antibody may be humanized by recombinant methods to reduce its immunogenicity in man.
  • Antibodies are prepared according to conventional methodology. Monoclonal antibodies may be generated using the method of Kohler and Milstein (Nature, 256:495, 1975). To prepare monoclonal antibodies useful in the invention, a mouse or other appropriate host animal is immunized at suitable intervals (e.g., twice-weekly, weekly, twice-monthly or monthly) with antigenic forms of endothelin receptors ETA and/or ETB or endothelin. The animal may be administered a final "boost" of antigen within one week of sacrifice. It is often desirable to use an immunologic adjuvant during immunization.
  • Suitable immunologic adjuvants include Freund's complete adjuvant, Freund's incomplete adjuvant, alum, Ribi adjuvant, Hunter's Titermax, saponin adjuvants such as QS21 or Quil A, or CpG-containing immunostimulatory oligonucleotides.
  • Other suitable adjuvants are well-known in the field.
  • the animals may be immunized by subcutaneous, intraperitoneal, intramuscular, intravenous, intranasal or other routes. A given animal may be immunized with multiple forms of the antigen by multiple routes.
  • the antigen may be provided as synthetic peptides corresponding to antigenic regions of interest in endothelin receptors ETA and/or ETB or endothelin.
  • lymphocytes are isolated from the spleen, lymph node or other organ of the animal and fused with a suitable myeloma cell line using an agent such as polyethylene glycol to form a hydridoma.
  • cells are placed in media permissive for growth of hybridomas but not the fusion partners using standard methods, as described (Coding, Monoclonal Antibodies: Principles and Practice: Production and Application of Monoclonal Antibodies in Cell Biology, Biochemistry and Immunology, 3rd edition, Academic Press, New York, 1996).
  • cell supernatants are analyzed for the presence of antibodies of the desired specificity, i.e., that selectively bind the antigen.
  • Suitable analytical techniques include ELISA, flow cytometry, immunoprecipitation, and western blotting. Other screening techniques are well-known in the field. Preferred techniques are those that confirm binding of antibodies to conformationally intact, natively folded antigen, such as non-denaturing ELISA, flow cytometry, and immunoprecipitation.
  • an antibody from which the pFc' region has been enzymatically cleaved, or which has been produced without the pFc' region designated an F(ab')2 fragment, retains both of the antigen binding sites of an intact antibody.
  • an antibody from which the Fc region has been enzymatically cleaved, or which has been produced without the Fc region designated an Fab fragment, retains one of the antigen binding sites of an intact antibody molecule.
  • Fab fragments consist of a covalently bound antibody light chain and a portion of the antibody heavy chain denoted Fd.
  • the Fd fragments are the major determinant of antibody specificity (a single Fd fragment may be associated with up to ten different light chains without altering antibody specificity) and Fd fragments retain epitope-binding ability in isolation.
  • CDRs complementarity determining regions
  • FRs framework regions
  • CDR1 through CDRS complementarity determining regions
  • compositions and methods that include humanized forms of antibodies.
  • humanized describes antibodies wherein some, most or all of the amino acids outside the CDR regions are replaced with corresponding amino acids derived from human immunoglobulin molecules.
  • Methods of humanization include, but are not limited to, those described in U.S. Pat. Nos. 4,816,567, 5,225,539, 5,585,089, 5,693,761, 5,693,762 and 5,859,205, which are hereby incorporated by reference.
  • the above U.S. Pat. Nos. 5,585,089 and 5,693,761, and WO 90/07861 also propose four possible criteria which may used in designing the humanized antibodies.
  • the first proposal was that for an acceptor, use a framework from a particular human immunoglobulin that is unusually homologous to the donor immunoglobulin to be humanized, or use a consensus framework from many human antibodies.
  • the second proposal was that if an amino acid in the framework of the human immunoglobulin is unusual and the donor amino acid at that position is typical for human sequences, then the donor amino acid rather than the acceptor may be selected.
  • the third proposal was that in the positions immediately adjacent to the 3 CDRs in the humanized immunoglobulin chain, the donor amino acid rather than the acceptor amino acid may be selected.
  • the fourth proposal was to use the donor amino acid reside at the framework positions at which the amino acid is predicted to have a side chain atom within 3 A of the CDRs in a three dimensional model of the antibody and is predicted to be capable of interacting with the CDRs.
  • the above methods are merely illustrative of some of the methods that one skilled in the art could employ to make humanized antibodies.
  • One of ordinary skill in the art will be familiar with other methods for antibody humanization.
  • humanized forms of the antibodies some, most or all of the amino acids outside the CDR regions have been replaced with amino acids from human immunoglobulin molecules but where some, most or all amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they would not abrogate the ability of the antibody to bind a given antigen.
  • Suitable human immunoglobulin molecules would include IgGl, IgG2, IgG3, IgG4, IgA and IgM molecules.
  • a "humanized" antibody retains a similar antigenic specificity as the original antibody.
  • the affinity and/or specificity of binding of the antibody may be increased using methods of "directed evolution", as described by Wu et al, /. Mol. Biol. 294: 151, 1999, the contents of which are incorporated herein by reference.
  • Fully human monoclonal antibodies also can be prepared by immunizing mice transgenic for large portions of human immunoglobulin heavy and light chain loci. See, e.g., U.S. Pat. Nos. 5,591,669, 5,598,369, 5,545,806, 5,545,807, 6,150,584, and references cited therein, the contents of which are incorporated herein by reference. These animals have been genetically modified such that there is a functional deletion in the production of endogenous (e.g., murine) antibodies. The animals are further modified to contain all or a portion of the human germ-line immunoglobulin gene locus such that immunization of these animals will result in the production of fully human antibodies to the antigen of interest.
  • monoclonal antibodies can be prepared according to standard hybridoma technology. These monoclonal antibodies will have human immunoglobulin amino acid sequences and therefore will not provoke human anti-mouse antibody (KAMA) responses when administered to humans.
  • KAMA human anti-mouse antibody
  • the present invention also provides for F(ab') 2 Fab, Fv and Fd fragments; chimeric antibodies in which the Fc and/or FR and/or CDR1 and/or CDR2 and/or light chain CDR3 regions have been replaced by homologous human or non-human sequences; chimeric F(ab')2 fragment antibodies in which the FR and/or CDR1 and/or CDR2 and/or light chain CDR3 regions have been replaced by homologous human or non-human sequences; chimeric Fab fragment antibodies in which the FR and/or CDR1 and/or CDR2 and/or light chain CDR3 regions have been replaced by homologous human or non-human sequences; and chimeric Fd fragment antibodies in which the FR and/or CDR1 and/or CDR2 regions have been replaced by homologous human or non-human sequences.
  • the present invention also includes so-called single chain antibodies.
  • the various antibody molecules and fragments may derive from any of the commonly known immunoglobulin classes, including but not limited to IgA, secretory IgA, IgE, IgG and IgM.
  • IgG subclasses are also well known to those in the art and include but are not limited to human IgGl, IgG2, IgG3 and IgG4.
  • the endothelin receptor antagonist of the invention is a Human IgG4.
  • the antibody according to the invention is a single domain antibody.
  • the term “single domain antibody” (sdAb) or “VHH” refers to the single heavy chain variable domain of antibodies of the type that can be found in Camelid mammals which are naturally devoid of light chains. Such VHH are also called “nanobody®”. According to the invention, sdAb can particularly be llama sdAb.
  • VHH refers to the single heavy chain having 3 complementarity determining regions (CDRs): CDR1, CDR2 and CDR3.
  • CDRs complementarity determining region
  • CDR complementarity determining region
  • VHH according to the invention can readily be prepared by an ordinarily skilled artisan using routine experimentation.
  • VHH variants and modified form thereof may be produced under any known technique in the art such as in- vitro maturation.
  • VHHs or sdAbs are usually generated by PCR cloning of the V-domain repertoire from blood, lymph node, or spleen cDNA obtained from immunized animals into a phage display vector, such as pHEN2.
  • Antigen- specific VHHs are commonly selected by panning phage libraries on immobilized antigen, e.g., antigen coated onto the plastic surface of a test tube, biotinylated antigens immobilized on streptavidin beads, or membrane proteins expressed on the surface of cells.
  • immobilized antigen e.g., antigen coated onto the plastic surface of a test tube, biotinylated antigens immobilized on streptavidin beads, or membrane proteins expressed on the surface of cells.
  • VHHs often show lower affinities for their antigen than VHHs derived from animals that have received several immunizations.
  • VHHs from immune libraries are attributed to the natural selection of variant VHHs during clonal expansion of B-cells in the lymphoid organs of immunized animals.
  • the affinity of VHHs from non-immune libraries can often be improved by mimicking this strategy in vitro, i.e., by site directed mutagenesis of the CDR regions and further rounds of panning on immobilized antigen under conditions of increased stringency (higher temperature, high or low salt concentration, high or low pH, and low antigen concentrations).
  • VHHs derived from camelid are readily expressed in and purified from the E. coli periplasm at much higher levels than the corresponding domains of conventional antibodies.
  • VHHs generally display high solubility and stability and can also be readily produced in yeast, plant, and mammalian cells.
  • the "Hamers patents” describe methods and techniques for generating VHH against any desired target (see for example US 5,800,988; US 5,874, 541 and US 6,015,695).
  • the "Hamers patents” more particularly describe production of VHHs in bacterial hosts such as E. coli (see for example US 6,765,087) and in lower eukaryotic hosts such as moulds (for example Aspergillus or Trichoderma) or in yeast (for example Saccharomyces, Kluyveromyces, Hansenula or Pichia) (see for example US 6,838,254).
  • the compound of the invention is an inhibitor of endothelin receptor expression or inhibitor of endothelin expression.
  • a gene product can be the direct transcriptional product of a gene (e.g., mRNA, tRNA, rRNA, antisense RNA, ribozyme, structural RNA or any other type of RNA) or a protein produced by translation of a mRNA.
  • Gene products also include messenger RNAs, which are modified, by processes such as capping, polyadenylation, methylation, and editing, and proteins (e.g., endothelin receptor ETA, endothelin receptor ETB and endothelin) modified by, for example, methylation, acetylation, phosphorylation, ubiquitination, SUMOylation, ADP-ribosylation, myristilation, and glycosylation.
  • proteins e.g., endothelin receptor ETA, endothelin receptor ETB and endothelin
  • an “inhibitor of expression” refers to a natural or synthetic compound that has a biological effect to inhibit the expression of a gene.
  • Inhibitors of expression for use in the present invention may be based on antisense oligonucleotide constructs.
  • Anti-sense oligonucleotides including anti-sense RNA molecules and anti-sense DNA molecules, would act to directly block the translation of mRNA by binding thereto and thus preventing protein translation or increasing mRNA degradation, thus decreasing the level of proteins, and thus activity, in a cell.
  • antisense oligonucleotides of at least about 15 bases and complementary to unique regions of the mRNA transcript sequence encoding endothelin receptor ETA, endothelin receptor ETB and endothelin can be synthesized, e.g., by conventional phosphodiester techniques and administered by e.g., intravenous injection or infusion.
  • Methods for using antisense techniques for specifically alleviating gene expression of genes whose sequence is known are well known in the art (e.g. see U.S. Pat. Nos. 6,566,135; 6,566,131; 6,365,354; 6,410,323; 6,107,091; 6,046,321; and 5,981,732).
  • Small inhibitory RNAs can also function as inhibitors of expression for use in the present invention.
  • Gene expression can be reduced by contacting the subject or cell with a small double stranded RNA (dsRNA), or a vector or construct causing the production of a small double stranded RNA, such that endothelin receptor ETA, endothelin receptor ETB and endothelin expression is specifically inhibited (i.e. RNA interference or RNAi).
  • dsRNA small double stranded RNA
  • RNAi RNA interference
  • Methods for selecting an appropriate dsRNA or dsRNA-encoding vector are well known in the art for genes whose sequence is known (e.g. see Tuschl, T. et al. (1999); Elbashir, S. M. et al.
  • Ribozymes can also function as inhibitors of expression for use in the present invention.
  • Ribozymes are enzymatic RNA molecules capable of catalysing the specific cleavage of RNA.
  • the mechanism of ribozyme action involves sequence specific hybridization of the ribozyme molecule to complementary target RNA, followed by endonucleo lytic cleavage.
  • Engineered hairpin or hammerhead motif ribozyme molecules that specifically and efficiently catalyze endonucleo lytic cleavage of mRNA sequences are thereby useful within the scope of the present invention.
  • ribozyme cleavage sites within any potential RNA target are initially identified by scanning the target molecule for ribozyme cleavage sites, which typically include the following sequences, GUA, GUU, and GUC. Once identified, short RNA sequences of between about 15 and 20 ribonucleotides corresponding to the region of the target gene containing the cleavage site can be evaluated for predicted structural features, such as secondary structure, that can render the oligonucleotide sequence unsuitable. The suitability of candidate targets can also be evaluated by testing their accessibility to hybridization with complementary oligonucleotides, using, e.g., ribonuclease protection assays.
  • antisense oligonucleotides and ribozymes useful as inhibitors of expression can be prepared by known methods. These include techniques for chemical synthesis such as, e.g., by solid phase phosphoramadite chemical synthesis. Alternatively, anti-sense RNA molecules can be generated by in vitro or in vivo transcription of DNA sequences encoding the RNA molecule. Such DNA sequences can be incorporated into a wide variety of vectors that incorporate suitable R A polymerase promoters such as the T7 or SP6 polymerase promoters. Various modifications to the oligonucleotides of the invention can be introduced as a means of increasing intracellular stability and half-life.
  • Possible modifications include but are not limited to the addition of flanking sequences of ribonucleotides or deoxyribonucleotides to the 5' and/or 3' ends of the molecule, or the use of phosphorothioate or 2'-0-methyl rather than phosphodiesterase linkages within the oligonucleotide backbone.
  • Antisense oligonucleotides siRNAs and ribozymes of the invention may be delivered in vivo alone or in association with a vector.
  • a "vector" is any vehicle capable of facilitating the transfer of the antisense oligonucleotide siRNA or ribozyme nucleic acid to the cells and preferably cells expressing endothelin receptor ETA, endothelin receptor ETB and endothelin.
  • the vector transports the nucleic acid to cells with reduced degradation relative to the extent of degradation that would result in the absence of the vector.
  • the vectors useful in the invention include, but are not limited to, plasmids, phagemids, viruses, other vehicles derived from viral or bacterial sources that have been manipulated by the insertion or incorporation of the antisense oligonucleotide siRNA or ribozyme nucleic acid sequences.
  • Viral vectors are a preferred type of vector and include, but are not limited to nucleic acid sequences from the following viruses: retrovirus, such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus; adenovirus, adeno-associated virus; Simian Virus (SV)40-type viruses; polyomaviruses; Herpes viruses; papilloma viruses; vaccinia virus; poliovirus; and RNA virus such as a retrovirus.
  • retrovirus such as moloney murine leukemia virus, harvey murine sarcoma virus, murine mammary tumor virus, and rouse sarcoma virus
  • adenovirus adeno-associated virus
  • Simian Virus (SV)40-type viruses Simian Virus (SV)40-type viruses
  • polyomaviruses Herpes viruses
  • Non-cytopathic viruses include retroviruses (e.g., lentivirus), the life cycle of which involves reverse transcription of genomic viral RNA into DNA with subsequent pro-viral integration into host cellular DNA. Retroviruses have been approved for human gene therapy trials. Most useful are those retroviruses that are replication-deficient (i.e., capable of directing synthesis of the desired proteins, but incapable of manufacturing an infectious particle). Such genetically altered retroviral expression vectors have general utility for the high-efficiency transduction of genes in vivo.
  • viruses for certain applications are the adenoviruses and Adeno-Associated Viruses (AAV), which are double-stranded DNA viruses that have already been approved for human use in gene therapy.
  • AAV can be engineered to be replication deficient and is capable of infecting a wide range of cell types and species. It further has advantages such as, heat and lipid solvent stability; high transduction frequencies in cells of diverse lineages, including hematopoietic cells; and lack of super-infection inhibition thus allowing multiple series of transductions.
  • AAV can integrate into human cellular DNA in a site-specific manner, thereby minimizing the possibility of insertional mutagenesis and variability of inserted gene expression characteristic of retroviral infection.
  • wild-type AAV infections have been followed in tissue culture for greater than 100 passages in the absence of selective pressure, implying that AAV genomic integration is a relatively stable event.
  • AAV can also function in an extra-chromosomal fashion.
  • Plasmid vectors have been extensively described in the art and are well known to those of skill in the art. See e.g., SANBROOK et al, "Molecular Cloning: A Laboratory Manual," Second Edition, Cold Spring Harbor Laboratory Press, 1989. In the last few years, plasmid vectors have been used as DNA vaccines for delivering antigen- encoding genes to cells in vivo. They are particularly advantageous for this because they do not have the same safety concerns as with many of the viral vectors. These plasmids, however, having a promoter compatible with the host cell, can express a peptide from a gene operatively encoded within the plasmid.
  • Plasmids may be delivered by a variety of parenteral, mucosal and topical routes.
  • the DNA plasmid can be injected either by intramuscular, intradermal, subcutaneous, or other routes. It may also be administered by intranasal sprays or drops, rectal suppository and orally. It may also be administered into the epidermis or a mucosal surface using a gene-gun. Plasmids may be given in an aqueous solution, dried onto gold particles or in association with another DNA delivery system including but not limited to liposomes, dendrimers, cochleate and microencapsulation.
  • the compounds according to the invention as described above are administered to the subject in a therapeutically effective amount.
  • a “therapeutically effective amount” of the compound of the present invention as above described is meant a sufficient amount of the compound for treating cardiovascular toxicity induced by anti-angiogenic compound at a reasonable benefit/risk ratio applicable to any medical treatment. It will be understood, however, that the total daily usage of the compounds and compositions of the present invention will be decided by the attending physician within the scope of sound medical judgment.
  • the specific therapeutically effective dose level for any particular subject will depend upon a variety of factors including the disorder being treated and the severity of the disorder; activity of the specific compound employed; the specific composition employed, the age, body weight, general health, sex and diet of the subject; the time of administration, route of administration, and rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed; and like factors well known in the medical arts.
  • the daily dosage of the products may be varied over a wide range from 0.01 to 1,000 mg per adult per day.
  • the compositions contain 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 250 and 500 mg of the compound of the present invention for the symptomatic adjustment of the dosage to the subject to be treated.
  • a medicament typically contains from about 0.01 mg to about 500 mg of the compound of the present invention, preferably from 1 mg to about 100 mg of the compound of the present invention.
  • An effective amount of the drug is ordinarily supplied at a dosage level from 0.0002 mg/kg to about 20 mg/kg of body weight per day, especially from about 0.001 mg/kg to 7 mg/kg of body weight per day.
  • the compound according to the invention may be used in a concentration between 0.01 ⁇ and 20 ⁇ , particularly, the compound of the invention may be used in a concentration of 0.01, 0.05, 0.1, 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 20.0 ⁇ .
  • the present invention relates to the compound according to the invention in combination with one or more anti-cancer compound for use in the treatment of cardiovascular toxicity induced by anti-cancer compound in a subject in need thereof.
  • the present invention relates to the compound according to the invention in combination with one or more anti-angiogenic compound for use in the treatment of cardiovascular toxicity induced by anti-angiogenic compound in a subject in need thereof.
  • the compound of the invention is administered sequentially or concomitantly with one or more anti-cancer compound and anti-angiogenic compound.
  • the compound of the present invention is administered to the subject in the form of a pharmaceutical composition.
  • the compound of the present invention may be combined with pharmaceutically acceptable excipients, and optionally sustained-release matrices, such as biodegradable polymers, to form therapeutic compositions.
  • pharmaceutically acceptable excipients or “pharmaceutically acceptable” refer to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to a mammal, especially a human, as appropriate.
  • a pharmaceutically acceptable carrier or excipient refers to a non-toxic solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • the active principle in the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, transdermal, local or rectal administration, can be administered in a unit administration form, as a mixture with conventional pharmaceutical supports, to animals and human beings.
  • Suitable unit administration forms comprise oral-route forms such as tablets, gel capsules, powders, granules and oral suspensions or solutions, sublingual and buccal administration forms, aerosols, implants, subcutaneous, transdermal, topical, intraperitoneal, intramuscular, intravenous, subdermal, transdermal, intrathecal and intranasal administration forms and rectal administration forms.
  • the pharmaceutical compositions contain vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • vehicles which are pharmaceutically acceptable for a formulation capable of being injected.
  • These may be in particular isotonic, sterile, saline solutions (monosodium or disodium phosphate, sodium, potassium, calcium or magnesium chloride and the like or mixtures of such salts), or dry, especially freeze-dried compositions which upon addition, depending on the case, of sterilized water or physiological saline, permit the constitution of injectable solutions.
  • the pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions; formulations including sesame oil, peanut oil or aqueous propylene glycol; and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions.
  • the form In all cases, the form must be sterile and must be fluid to the extent that easy syringability exists. It must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi.
  • Solutions comprising compounds of the invention as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • the compound of the present invention can be formulated into a composition in a neutral or salt form.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like.
  • inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like.
  • Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine,
  • the carrier can also be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and vegetables oils.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • the prevention of the action of microorganisms can be brought about by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
  • isotonic agents for example, sugars or sodium chloride.
  • Prolonged absorption of the injectable compositions can be brought about by the use in the compositions of agents delaying absorption, for example, aluminium monostearate and gelatin.
  • Sterile injectable solutions are prepared by incorporating the active compounds in the required amount in the appropriate solvent with several of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized agent of the present inventions into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • sterile powders for the preparation of sterile injectable solutions the typical methods of preparation are vacuum-drying and freeze- drying techniques which yield a powder of the compound of the present invention plus any additional desired ingredient from a previously sterile- filtered solution thereof.
  • the preparation of more, or highly concentrated solutions for direct injection is also contemplated, where the use of DMSO as solvent is envisioned to result in extremely rapid penetration, delivering high concentrations of the active agents to a small tumor area.
  • solutions Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective.
  • the formulations are easily administered in a variety of dosage forms, such as the type of injectable solutions described above, but drug release capsules and the like can also be employed.
  • aqueous solutions For parenteral administration in an aqueous solution, for example, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic with sufficient saline or glucose.
  • aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration.
  • sterile aqueous media which can be employed will be known to those of skill in the art in light of the present disclosure. Some variation in dosage will necessarily occur depending on the condition of the subject being treated. The person responsible for administration will, in any event, determine the appropriate dose for the individual subject.
  • the compound of the present invention is administered sequentially or concomitantly with one or more therapeutic active agent such as chemotherapeutic or radiotherapeutic.
  • the compound of the present invention is administered with a chemotherapeutic agent.
  • chemotherapeutic agent refers to chemical compounds that are effective in inhibiting tumor growth.
  • examples of chemotherapeutic agents include alkylating agents such as thiotepa and cyclosphosphamide; alkyl sulfonates such as busulfan, improsulfan and piposulfan; aziridines such as benzodopa, carboquone, meturedopa, and uredopa; ethylenimines and methylamelamines including altretamine, triethylenemelamine, trietylenephosphoramide, triethylenethiophosphaorarnide and trimethylolomelamine; acetogenins (especially bullatacin and bullatacinone); a carnptothecin (including the synthetic analogue topotecan); bryostatin; callystatin; CC-1065 (including its adozeles).
  • calicheamicin especially calicheamicin (11 and calicheamicin 211, see, e.g., Agnew Chem Intl. Ed. Engl. 33: 183-186 (1994); dynemicin, including dynemicin A; an esperamicin; as well as neocarzinostatin chromophore and related chromoprotein enediyne antiobiotic chromomophores), aclacinomysins, actinomycin, authramycin, azaserine, bleomycins, cactinomycin, carabicin, canninomycin, carzinophilin, chromomycins, dactinomycin, daunorubicin, detorubicin, 6-diazo-5-oxo-L-norleucine, doxorubicin (including morpholino- doxorubicin, cyanomorpholino-doxorubicin, 2-pyrrol
  • paclitaxel (TAXOL®, Bristol-Myers Squibb Oncology, Princeton, N.].) and doxetaxel (TAXOTERE®, Rhone-Poulenc Rorer, Antony, France); chlorambucil; gemcitabine; 6- thioguanine; mercaptopurine; methotrexate; platinum analogs such as cisplatin and carboplatin; vinblastine; platinum; etoposide (VP- 16); ifosfamide; mitomycin C; mitoxantrone; vincristine; vinorelbine; navelbine; novantrone; teniposide; daunomycin; aminopterin; xeloda; ibandronate; CPT-1 1 ; topoisomerase inhibitor RFS 2000; difluoromethylornithine (DMFO); retinoic acid; capecitabine; and pharmaceutically acceptable salts, acids or derivatives of any of the above.
  • anti-estrogens including for example tamoxifen, raloxifene, aromatase inhibiting 4(5)-imidazoles, 4-hydroxytamoxifen, trioxifene, keoxifene, LY117018, onapristone, and toremifene (Fareston); and anti-androgens such as flutamide, nilutamide, bicalutamide, leuprolide, and goserelin; and phannaceutically acceptable salts, acids or derivatives of any of the above.
  • the compound of the present invention is administered with a targeted cancer therapy.
  • Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules ("molecular targets") that are involved in the growth, progression, and spread of cancer.
  • Targeted cancer therapies are sometimes called “molecularly targeted drugs", “molecularly targeted therapies”, “precision medicines”, or similar names.
  • the targeted therapy consists of administering the subject with a tyrosine kinase inhibitor as defined above.
  • compound of the present invention is administered with an immunotherapeutic agent.
  • immunotherapeutic agent refers to a compound, composition or treatment that indirectly or directly enhances, stimulates or increases the body's immune response against cancer cells and/or that decreases the side effects of other anticancer therapies. Immunotherapy is thus a therapy that directly or indirectly stimulates or enhances the immune system's responses to cancer cells and/or lessens the side effects that may have been caused by other anti-cancer agents. Immunotherapy is also referred to in the art as immunologic therapy, biological therapy biological response modifier therapy and biotherapy.
  • immunotherapeutic agents examples include, but are not limited to, cytokines, cancer vaccines, monoclonal antibodies and non-cytokine adjuvants.
  • the immunotherapeutic treatment may consist of administering the subject with an amount of immune cells (T cells, NK, cells, dendritic cells, B cells).
  • Immunotherapeutic agents can be non-specific, i.e. boost the immune system generally so that the human body becomes more effective in fighting the growth and/or spread of cancer cells, or they can be specific, i.e. targeted to the cancer cells themselves immunotherapy regimens may combine the use of non-specific and specific immunotherapeutic agents.
  • Non-specific immunotherapeutic agents are substances that stimulate or indirectly improve the immune system.
  • Non-specific immunotherapeutic agents have been used alone as a main therapy for the treatment of cancer, as well as in addition to a main therapy, in which case the non-specific immunotherapeutic agent functions as an adjuvant to enhance the effectiveness of other therapies (e.g. cancer vaccines).
  • Non-specific immunotherapeutic agents can also function in this latter context to reduce the side effects of other therapies, for example, bone marrow suppression induced by certain chemotherapeutic agents.
  • Non-specific immunotherapeutic agents can act on key immune system cells and cause secondary responses, such as increased production of cytokines and immunoglobulins. Alternatively, the agents can themselves comprise cytokines.
  • Nonspecific immunotherapeutic agents are generally classified as cytokines or non-cytokine adjuvants.
  • cytokines have found application in the treatment of cancer either as general non-specific immunotherapies designed to boost the immune system, or as adjuvants provided with other therapies.
  • Suitable cytokines include, but are not limited to, interferons, interleukins and colony- stimulating factors.
  • Interferons (IFNs) contemplated by the present invention include the common types of IFNs, IFN-alpha (IFN-a), IFN-beta (IFN- ⁇ ) and IFN- gamma (IFN- ⁇ ).
  • IFNs can act directly on cancer cells, for example, by slowing their growth, promoting their development into cells with more normal behaviour and/or increasing their production of antigens thus making the cancer cells easier for the immune system to recognise and destroy.
  • IFNs can also act indirectly on cancer cells, for example, by slowing down angiogenesis, boosting the immune system and/or stimulating natural killer (NK) cells, T cells and macrophages.
  • Recombinant IFN-alpha is available commercially as Roferon (Roche Pharmaceuticals) and Intron A (Schering Corporation).
  • Interleukins contemplated by the present invention include IL-2, IL-4, IL-11 and IL-12. Examples of commercially available recombinant interleukins include Proleukin® (IL-2; Chiron Corporation) and Neumega® (IL- 12; Wyeth Pharmaceuticals). Zymogenetics, Inc.
  • Colony-stimulating factors contemplated by the present invention include granulocyte colony stimulating factor (G-CSF or filgrastim), granulocyte-macrophage colony stimulating factor (GM-CSF or sargramostim) and erythropoietin (epoetin alfa, darbepoietin). Treatment with one or more growth factors can help to stimulate the generation of new blood cells in subjects undergoing traditional chemotherapy.
  • CSFs can be helpful in decreasing the side effects associated with chemotherapy and can allow for higher doses of chemo therapeutic agents to be used.
  • Various-recombinant colony stimulating factors are available commercially, for example, Neupogen® (G-CSF; Amgen), Neulasta (pelfilgrastim; Amgen), Leukine (GM-CSF; Berlex), Procrit (erythropoietin; Ortho Biotech), Epogen (erythropoietin; Amgen), Arnesp (erytropoietin).
  • immunotherapeutic agents can be active, i.e. stimulate the body's own immune response, or they can be passive, i.e.
  • Passive specific immunotherapy typically involves the use of one or more monoclonal antibodies that are specific for a particular antigen found on the surface of a cancer cell or that are specific for a particular cell growth factor.
  • Monoclonal antibodies may be used in the treatment of cancer in a number of ways, for example, to enhance a subject's immune response to a specific type of cancer, to interfere with the growth of cancer cells by targeting specific cell growth factors, such as those involved in angiogenesis, or by enhancing the delivery of other anticancer agents to cancer cells when linked or conjugated to agents such as chemotherapeutic agents, radioactive particles or toxins.
  • Monoclonal antibodies currently used as cancer immunotherapeutic agents that are suitable for inclusion in the combinations of the present invention include, but are not limited to, rituximab (Rituxan®), trastuzumab (Herceptin®), ibritumomab tiuxetan (Zevalin®), tositumomab (Bexxar®), cetuximab (C-225, Erbitux®), bevacizumab (Avastin®), gemtuzumab ozogamicin (Mylotarg®), alemtuzumab (Campath®), and BL22.
  • Other examples include anti-CTLA4 antibodies (e.g.
  • antibodies include B cell depleting antibodies.
  • Typical B cell depleting antibodies include but are not limited to anti-CD20 monoclonal antibodies [e.g.
  • the immunotherapeutic treatment may consist of allografting, in particular, allograft with hematopoietic stem cell HSC.
  • the immunotherapeutic treatment may also consist in an adoptive immunotherapy as described by Nicholas P. Restifo, Mark E.
  • NK cells circulating lymphocytes
  • the activated lymphocytes or NK cells are most preferably be the subject's own cells that were earlier isolated from a blood or tumor sample and activated (or "expanded") in vitro.
  • the compound of the present invention is administered with a radio therapeutic agent.
  • radiotherapeutic agent as used herein, is intended to refer to any radiotherapeutic agent known to one of skill in the art to be effective to treat or ameliorate cancer, without limitation.
  • the radiotherapeutic agent can be an agent such as those administered in brachytherapy or radionuclide therapy.
  • Such methods can optionally further comprise the administration of one or more additional cancer therapies, such as, but not limited to, chemotherapies, and/or another radiotherapy.
  • said additional active compounds may be contained in the same composition or administrated separately.
  • the pharmaceutical composition of the invention relates to combined preparation for simultaneous, separate or sequential use in the treatment of cardiovascular toxicity induced by anti-cancer compound and anti-angiogenic compound in a subject in need thereof.
  • the present invention also relates to a method for treating cardiovascular toxicity induced by anti-cancer compound in a subject in need thereof, comprising the step of administering to said subject the compound of the invention.
  • the present invention also relates to a method for treating cardiovascular toxicity induced by anti-angiogenic compound in a subject in need thereof, comprising the step of administering to said subject the compound of the invention.
  • kits comprising the compound of the invention. Kits containing the compound of the invention find use in therapeutic methods.
  • the present invention relates to a method of screening a candidate compound for use as a drug for the treatment of cardiovascular toxicity induced by anti-cancer compound and anti-angiogenic compound in a subject in need thereof, wherein the method comprises the steps of:
  • a candidate compound such as small organic molecule, an oligonucleotide, a polypeptide, an aptamer, antibody or an intra-antibody, measuring the cardiovascular toxicity,
  • cardiovascular toxicity is measured such as described in the example.
  • measuring the cardiovascular toxicity involves determining a Ki on the endothelin receptor cloned and transfected in a stable manner into a CHO cell line, measuring the endothelin receptor downstream signalling phospho lipase C, protein kinase C and MAPK1;ERK2, measuring aerobic and anaerobic metabolism, measuring myocardial metabolism, measuring glucose uptake, measuring cardiac fibrosis, measuring diastolic dysfunction and myocardial flux dysfunction and performing nuclear imaging of the heart using Sicintigraphy, Single photon emiccion tomograpgy (SPECT) or PET with various radiopharmaceuticals and with or without kinetics analysis of dynamic scans of the heart for monitoring cardiac metabolic remodeling.
  • SPECT Single photon emiccion tomograpgy
  • the present invention relates to a method of monitoring cardiovascular toxicity induced by an anti-cancer compound and an anti-angiogenic compound by performing PET-FDG scan such as described in the example.
  • the present invention relates to a method of monitoring the efficacy of the compound of the invention in the treatment of cardiovascular toxicity induced by an anticancer compound and anti-angiogenic compound by performing PET-FDG scan such as described in the example.
  • FIGURES are a diagrammatic representation of FIGURES.
  • FIG. 1 represents study design: (A) represents investigation for short-term cardiotoxic effects on immunodeficient tumor-bearing mice (nude). Sunitinib-treated mice were studied at baseline and week 1 using a cancer PET protocol compared to vehicle. (B) represents investigation for short-term cardiotoxic effects on immunocompetent mice (C57BL/6). Sunitinib-treated mice were studied at baseline and week 1 using a cancer PET protocol and echocardiography compared to vehicle. (C) represents study design for long-term treatment on immunocompetent mice (C57BL/6). Sunitinib-treated mice were followed at baseline, week 1, week 2 and week 3 using a cardiac PET protocol and echocardiography compared to vehicle and sunitinib+macitentan groups.
  • FDG 2'-deoxy-2'-[18F]fluoro-D-glucose.
  • FIG. 3 Sunitinib-induced increased FDG uptake in fasted mice is associated with increased fibrosis:
  • A Quantification of microvascular density normalized by cell number in nude and C57B1/6 mice treated with vehicle (open circles) or sunitinib (black circles).
  • B Quantification of fibrosis (normalized by tissue area) in nude and C57B1/6 mice treated with vehicle (open circles) or sunitinib (filled circles).
  • C Representative quantification for GLUT1, HK2 and PGCl (normalized by cyclophilin B) mice treated with vehicle (open circles) or sunitinib (filled circles). Data expressed as mean ⁇ SEM; $$p ⁇ 0.01 $$$p ⁇ 0.001 compared to vehicle.
  • HK2 Hexokinase 2
  • GLUT1 glucose transporter 1
  • PGCl Peroxisome proliferator- activated receptor gamma coactivator 1-alpha
  • S sunitinib
  • V vehicle.
  • FIG. 4 Macitentan prevents sunitinib-induced diastolic dysfunction.
  • C Difference treatment - baseline of left ventricular internal diameter at diastole for the three groups.
  • D Difference treatment - baseline of aortic velocity time integral for both groups.
  • AoVTI Aortic velocity tracking integral
  • CO cardiac output
  • LVID left ventricular internal diameter
  • SUV standard uptake value
  • MRGlu metabolic rate of glucose.
  • FIG. 7 Schematic representation of the mechanism of sunitinib-induced cardiac side effects:
  • Sunitinib upregulates glycolysis and downregulates oxidative metabolism in cardiac mitochondria.
  • Sunitinib induces resistance to insulin stimulation of cardiac glucose uptake.
  • the metabolic switch is an immediate early response to sunitinib while insulin resistance either appears later or is masked by the metabolic switch during the early stages of sunitinib treatment. Both mechanisms depend on signaling by the endothelin pathway, and lead to myocardial fibrosis and impaired cardiac function, and are reversed by the endothelin receptors antagonist macitentan. Red indicates upregulated proteins and pathways, blue indicates downregulated protein and pathways.
  • ATP Adenosine triphosphate
  • ET-1 endothelin 1
  • ETA endothelin receptor type A
  • FA fatty acid
  • GLUT glucose transporter protein
  • 02 oxygen
  • OXPHOS oxidative phosphorylation
  • TCA tricarboxylic acid.
  • mice from groups A and B were fasted overnight. Mice from panel C were not fasted and had free access to food and water. Mice were anesthetized (2 ⁇ 0.5% isoflurane in air), weighted and glycemia was measured in blood drawn from the caudal ventral artery using an Accu-Chek® Aviva Nano A (Accu-Chek, France). A catheter home-made from a 26G needle (Fischer Scientific, France) connected to a 5cm polyethylene tubing (Tygon Microbore Tubing, 0.010" x 0.030"OD; Fisher Scientific, France) was inserted in the caudal vein for radiotracer injection. Mice were then installed into the PET-CT dedicated bed and respiration and body temperature were registered.
  • CT was acquired in a PET- CT scanner (nanoScan PET-CT; Mediso, Hungary) using the following acquisition parameters: semi-circular mode, 39kV tension, 720 projections full scan, 300ms per projection, binning 1 :4. Then, PET acquisition was started and, 30 seconds later, lOMBq of 2'-deoxy-2'-[18F]fluoro-D- glucose (FDG; Advanced Applied Applications, France) in 0.2mL saline was injected via the catheter. The first scan was a dynamic acquisition of 30.5min and was followed by a gated cardiac scan of 30min duration.
  • FDG 2'-deoxy-2'-[18F]fluoro-D- glucose
  • PET data were collected in list mode and binned using a 5ns time window, with a 400-600keV energy window and a 1 :5 coincidence mode.
  • Data were reconstructed using the Tera-Tomo reconstruction engine (3D-OSEM based manufactured customized algorithm) with expectation maximization iterations, scatter and attenuation correction.
  • the first scan was reconstructed starting 10s before FDG injection with the following time sequence: 26 x 5s; 6 x 30s; 5 x 120s; 3 x 300s and 3 x 600s.
  • the second scan reconstructed in a single time frame from 45 to 60min post-injection.
  • FDG accumulation was quantified as mean Standard Uptake Value (SUV, ratio of the radioactivity concentration in myocardium on the whole body concentration of the injected radioactivity) between 45 and 60min post-injection in 3D volumes-of- interest (VOI) delineated semi-automatically by iso-contours at 45% threshold of maximal value in the myocardium on PET/CT fusion slices using the PMOD software package (PMOD Technologies Ltd, Zurich, Switzerland).
  • Metabolic flux was quantified using compartmental modeling tool of PMOD software using the same VOI as above and a VOI semi-automatically delineated on the vena cava for the arterial input function as previously described (65). Metabolic rate of glucose were calculated by the multiplication of the metabolic flux by [plasma glucose (mmol/l)/lumped constant (fixed at 0.69)].
  • LVID Left Ventricular Internal Diameter
  • LVPW Left Ventricular Posterior Wall thickness
  • CO Cardiac Output
  • FS fractional shortering
  • Ascending aorta diameter (Ao) and Left Atrium diameter (LA) were measured using M-mode in parasternal long axis.
  • Aortic velocity tracking integral (AoVTI) was measured using PW Doppler, in suprasternal view allowing measurement of mean aortic velocity and peak aortic velocity.
  • Cardiac microvessels were stained using Isolectine B4 Griffonia Simplicifolia-FITC (Sigma Aldrich). Nuclei were counter stained with DAPI. Microvessels and nuclei were counted in 4 fields at a magnification of x200 in 2 independent sections from each heart using Matlab® based software. Microvessel density was normalized to the number of nuclei.
  • Chemiluminescence detection was performed using the ECL kit (Clarity Western ECl substrate; BioRad). Quantitation of immunoblots was done on digitalized images using ImageJ software. The intensity of immunoreactive bands was normalized by the loading control (Cyclophilin B, 1 : 1000, abl6045, Abeam).
  • Tissue sample preparation Frozen mouse hearts were individually ground under liquid nitrogen to yield a fine powder using a pestle and mortar. The tissue powder was weighted and solubilized in lysis buffer (4% SDS, lOOmM Tris-HCl, pH 8.0). Protein extracts were clarified by centrifugation at 21,000 X G, 1 hour, 4°C. Protein concentration of the supernatant was determined using bicinchoninic acid assay (BCA, Pierce). Peptides were prepared by Filter Aided Separation method (FASP) essentially as described (66).
  • FASP Filter Aided Separation method
  • solubilization buffer 50 mM Tris/HCl, pH8.5, SDS 2%, 20mM TCEP, 50 mM chloroacetamide
  • extracts were diluted with 300 ⁇ Tris Urea buffer (Urea 8M, Tris/HCl 50mM (pH 8.5) and transferred onto 30kDa centrifuged filters and prepared for digestion as described (66). Proteins were digested during 14h at 37°C with ⁇ g trypsin (Promega) and peptides were desalted on C18 StageTips (67).
  • peptides were solubilized in 2% trifiuoroacetic acid (TFA) and fractionated by strong cationic exchange (SCX) StageTips, mainly as described (Kulak et al, 2014) except that fractions 1 and 2 were pooled in most experiments.
  • Mass spectrometry analysis Mass spectrometry analyses were performed on a Dionex U3000 RSLC nano-LC- system coupled to either a Q-Exactive or a LTQ Orbitrap- Velos mass spectrometer, all from Thermo Fisher Scientific. After drying, peptides from SCX StageTip fractions were solubilized in 10 ⁇ of 0.1% TFA containing 2% acetonitrile (ACN).
  • ACN acetonitrile
  • the mass spectrometer acquired data throughout the elution process and operated in a data-dependent scheme with full MS scans acquired with the Orbitrap, followed by up to 10 MS/MS HCD fragmentations in the Q-Exactive (Thermo Fisher) on the most abundant ions detected. Settings were essentially as in (68) with slight modifications: the recurrent loop of the 10 most intense nLC-eluting peptides were HCD- fragmented between each full scan (data dependent mode). Resolution was set to 70,000 for full scans at AGC target 1,10e6 within 60ms MIIT. The MS scans spanned from 350 to 1500m/z.
  • Precursor selection window was set at 2Th, and MS/MS scan resolution was set at 17,500 with AGC target 1,10e5 within 60ms MIIT. HCD Normalized Collision Energy (NCE) was set at 27%. Dynamic exclusion was set to 30s duration. Spectra were recorded in profile mode. The mass spectrometry data were analyzed using Maxquant version 1,5,2,8 (69). The database used was a concatenation of human sequences from the Uniprot-Swissprot database (Uniprot, release 2015-02) and a list of contaminant sequences from Maxquant. The enzyme specificity was trypsin. The precursor mass tolerance was set to 4.5ppm and the fragment mass tolerance to 20ppm for Q-Exactive data.
  • Protein copy numbers per cell were then calculated using the "Protein ruler” plugin of Perseus by standardization on total histone MS signal as described (70).
  • RNA extraction and qPCR R A from hearts and aorta was isolated using TRI Reagent Solution (Invitrogen). Any DNA present was degraded using RQ1 RNAse-Free DNase (Promega) according to the manufacturer's instructions.
  • cDNA was synthesized using a High Capacity cDNA Reverse Transcription kit with RNase inhibitor (Invitrogen).
  • qRT-PCR was performed using Fast SYBR Green Master Mix (Applied Biosystems) on the ABI7900 System (Applied Biosystems). Primers for 18s, prepro-ET-1, ETA and ETB receptors were generated. The amplification reaction mixture was heated at 95°C for 20s, then subject to 40 cycles of 95°C for Is then 60°C for 20s. Values obtained for experimental gene measurements were normalized against expression of 18s.
  • Sunitinib downregulates oxidative energy metabolism pathways
  • Ingenuity® analysis highlighted that sunitinib treatment induced mitochondrial dysfunction and a clear switch towards anaerobic glycolytic metabolism, similar to the one seen during cardiac hypertrophy (31).
  • proteins of the fatty acid degradation pathway such as acyl-CoA dehydrogenase (Acad8), phospholipases, and fatty acid transferases, those controlling glycogen breakdown (Pgaml, Me3) and the synthesis of the cofactor flavine adenine dinucleotide (FAD) were reduced in sunitinib-treated hearts.
  • Endothelin receptor antagonism prevents sunitinib-induced diastolic dysfunction and myocardial flux dysfunction
  • Macitentan reduces cardiac fibrosis and downregulates myocardial ETA receptors
  • Macitentan reverses the sunitinib-induced aerobic to anaerobic switch
  • Protein clusters involved in myocardial infarction, endothelial cell dysfunction and apoptosis, atherosclerosis, thrombosis, inflammation and hypertension were targeted by sunitinib. Comparing protein expression in the sunitinib-treated group with that in the vehicle and sunitinib plus macitentan groups highlighted once again the protective effects of macitentan, notably on the following clusters: myocardial infarction, endothelial cell dysfunction and apoptosis (data not shown), glycogen metabolism, TCA cycle, acetyl CoA biosynthesis.
  • the level of expression of the pyruvate dehydrogenase (PDH) components were maintained at control levels by macitentan in the oxidative phosphorylation deficient myocardium induced by sunitinib (data not shown).
  • the levels of expression of some proteins involved in glycolysis were augmented by 3 weeks of sunitinib treatment (e.g. glucose-6-phosphate isomerase and phosphoglycerate mutase), while those of others were reduced, e.g. muscle-type phosphofructokinase and glyceraldehyde-3 -phosphate dehydrogenase.
  • Sunitinib-treated hearts showed higher lactate dehydrogenase (LDH) that is released during tissue hypoxia and damage.
  • LDH lactate dehydrogenase
  • sunitinib induced a dramatic (8-fold) increase in the expression of GLUT4 (SLC2a4), the insulin-regulated transporter of glucose at the plasma membrane.
  • GLUT4 SLC2a4
  • RablO a small ras-family GTPase required for translocation of GLUT4
  • Macitentan only partially reverted the effects of sunitinib on the level of GLUT4 and RablO, but significantly increased the level of expression of the pleiotropic regulatory protein sirtuin 2, in line with the role of this protein in energetic metabolism preservation.
  • Sunitinib treatment is limited by its cardiovascular side effects.
  • a recent study reported that sunitinib induces an early switch of cardiac metabolism to anaerobic glycolysis and impairs heart function (30).
  • myocardial remodeling by sunitinib also induces a reduced glucose uptake resembling the one found during insulin resistance, and show that sunitinib cardiotoxicity is a combination of several complex mechanisms occurring over a sequential time course.
  • sunitinib-induced cardiac injury and dysfunction are prevented through inhibition of endothelin signaling, strongly supporting a role for this pathway in sunitinib 's cardio toxic effects (Figure 7).
  • FDG uptake is higher in non-fasting than in fasting conditions (37) and in oncology studies FDG PET imaging is acquired under fasting conditions in order to minimize muscular and myocardial uptake and improve tumor detection.
  • cardiac PET-FDG often utilizes an euglycemic clamp (glucose load with additional insulin administration after overnight fasting) in order to maximize heart uptake (37,38).
  • ischemic territories appear as hot spots with higher FDG uptake than the intact myocardium after fasting (39) while they may not differentiate from intact tissue in non-fasted conditions after a glucose load (40-42).
  • sunitinib Systemic administration of sunitinib rapidly induces a metabolic switch towards glycolysis with reduced expressions of key enzymes of the TCA cycle and key proteins for mitochondrial oxidative phosphorylation (OXPHOS) and for the beta-oxidation of fatty acids.
  • OXPHOS mitochondrial oxidative phosphorylation
  • OXPHOS mitochondrial oxidative phosphorylation
  • sunitinib-treated hearts presented anaerobic metabolism and it is known that PDH inhibition leads to a slow recovery of glucose uptake and uncoupling of glycolysis (49), and that lactate accumulation decreases glucose uptake (43).
  • patterns of protein expression in the 3-week sunitinib-treated heart resembled the one seen in diabetic patients in which the FDG metabolic flux is reduced (50), as well as the pattern in diabetic rats where myocardial glucose uptake is reduced under ischemic conditions (51).
  • ischitinib-treated hearts we observed a dramatic increase of GLUT4 activated in high glycaemia-high insulinemia conditions (36).
  • Macitentan is a mixed ETA/ETB antagonist approved for the treatment of pulmonary arterial hypertension and has no known direct or indirect interaction with sunitinib of other TKI (FDA). Furthermore, non-selective ET receptors antagonism prevents hypertension and renal injury (24) induced by sunitinib. In the future, it will be interesting to test if the use of a selective ETA receptor antagonism produces comparable cardioprotection since ET-1 is known to exert a pro-fibrotic action (62) and hypertrophy (34) via the ETA receptor.
  • TCA cycle Isobutyryl-CoA dehydrogenase, mitochondrial Acad8 ⁇ -1.30
  • TCA cycle Isocitrate dehydrogenase [NAD] subunit Idh3g 0.03 -1.24 gamma 1, mitochondrial
  • Mitochondria Mitochondrial import receptor subunit TOM70 Tomm70 0.06 -1.27 a
  • AMPK 5' AMP-activated protein kinase
  • cdp cytidine diphospho
  • ERR estrogen-related receptor
  • NAD nicotinamide adenine dinucleotide
  • NADP nicotinamide adenine dinucleotide phosphate
  • PGC-1 peroxisome proliferator- activated receptor gamma coactivator 1 -alpha
  • TCA tricarboxylic acid. sunitinib sunitinib sunitinib + versus vehicle versus macitentan sunitinib + versus macitentan vehicle
  • Glucogenolysis RAB10, member RAS Ra 0,071 -1,30 0,405 1,07 0,030
  • Glucogenolysis Phosphoglycerate mutase 1 Pga 0,011 1,48 0,141 1,18 0,057 1,26 ml
  • TCA cycle Isobutyryl-CoA Aca 0,026 -1,21 0,002 -1,20 0,932
  • Mitochondria 3-hydroxyisobutyryl-CoA Hib 0,403 -1,06 0,018 -1,18 0,020 1,12 FA hydrolase, mitochondrial ch Mitochondria 3-hydroxyisobutyrate Hib 0,738 1,04 0,036 -1,26 0,005 1,30 dehydrogenase, adh
  • Mitochondria Mitochondrial-processing Pm 0,049 -1,17 0,011 -1,36 0,142 1,16 peptidase subunit beta pcb
  • Mitochondria Mitochondrial import To 0,299 1,16 0,006 -1,46 0,001 1,70 receptor subunit TOM22 mm
  • Mitochondria Mitochondrial Rho Rh 0,008 3,11 0,862 1,01 0,010 3,08
  • Mitochondria Mitochondrial import Ti 0,474 1,08 0,418 -1,08 0,010 1,17 membrane translocase mm
  • Mitochondria Mitochondrial import To 0,024 1,23 0,923 1,01 0,022 1,22 receptor subunit TOM40 mm
  • Mitochondria Mitochondrial Mte 0,045 -2,39 0,005 -2,27 0,821
  • Mitochondria A-kinase anchor protein 1, Ak 0,185 -1,19 0,057 -1,31 0,471 1,10 mitochondrial apl
  • Atherosclerosis Apolipoprotein A-IV Ap 0,013 1,62 0,212 1,24 0,106 1,31 oa4
  • ATP Adenosine triphosphate
  • CD36 cluster of differentiation 36
  • FA fatty acid
  • GTP Guanosine- 5 '-triphosphate
  • IR insulin resitance
  • K+ potassium
  • Na+ sodium
  • NAD nicotinamide adenine dinucleotide
  • RAB Ras-related protein
  • RNA Ribonucleic acid
  • TCA tricarboxylic acid.

Abstract

L'invention concerne des méthodes de traitement de la toxicité cardiovasculaire induite par un composé anti-cancéreux et anti-angiogénique. Les inventeurs ont exploré la cardiotoxicité induite par le sunitinib, thérapie antiangiogénique, dans le cœur de la souris. Les inventeurs ont montré que le sunitinib induit une commutation anaérobie du métabolisme cellulaire dans le myocarde qui est associée au développement d'une fibrose myocardique comme démontré par échocardiographie. La capacité de la tomographie par émission de positrons à détecter les changements du métabolisme cardiaque provoqué par le sunitinib était dépendante de l'état de jeûne et de la durée du traitement. Une analyse pan-protéomique dans le myocarde a montré que le sunitinib induit (i) une commutation métabolique précoce avec une glycolyse accrue et une phosphorylation oxydative réduite, et (ii) une insuffisance métabolique à utiliser le glucose comme substrat d'énergie, similaire à la résistance à l'insuline trouvée dans le diabète de type 2. La co-administration de macitentan, l'antagoniste du récepteur de l'endothéline, à des animaux traités au sunitinib permettait de prévenir les deux défauts métaboliques, de rétablir l'absorption de glucose et la fonction cardiaque, et de prévenir la fibrose myocardique. Ainsi, l'invention concerne un composé choisi dans le groupe constitué par un antagoniste du récepteur de l'endothéline et un inhibiteur de l'expression du récepteur de l'endothéline destiné à être utilisé dans le traitement de la toxicité cardiovasculaire induite par un composé anti-cancéreux et anti-angiogénique.
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WO2022232586A1 (fr) * 2021-04-30 2022-11-03 Perfuse Therapeutics, Inc. Traitement de maladies oculaires à l'aide d'antagonistes du récepteur de l'endothéline
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