WO2020234454A1 - Traitement combiné contre le cancer ciblant le métabolisme énergétique et le ph intracellulaire - Google Patents

Traitement combiné contre le cancer ciblant le métabolisme énergétique et le ph intracellulaire Download PDF

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WO2020234454A1
WO2020234454A1 PCT/EP2020/064281 EP2020064281W WO2020234454A1 WO 2020234454 A1 WO2020234454 A1 WO 2020234454A1 EP 2020064281 W EP2020064281 W EP 2020064281W WO 2020234454 A1 WO2020234454 A1 WO 2020234454A1
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cancer
intracellular
decrease
inhibitor
compound causing
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PCT/EP2020/064281
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Svitlana MELNIK
Karin MÜLLER-DECKER
Christof Niehrs
Andrey Glinka
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Deutsches Krebsforschungszentrum
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    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to a compound causing a decrease of intracellular pH for use in treatment of cancer with an inhibitor of mitochondrial respiration and a proton ionophore; to a proton ionophore for use in treatment of cancer with an inhibitor of mitochondrial respiration and a compound causing a decrease of intracellular pH; and to an inhibitor of mitochondrial respiration for use in treatment of cancer with a proton ionophore and a compound causing a decrease of intracellular pH.
  • the present invention also relates to a combined preparation for simultaneous, separate or sequential use comprising (i) a compound causing a decrease of intracellular pH, (ii) an inhibitor of mitochondrial respiration, and (iii) a proton ionophore, and to a method for determining whether a subject suffering from cancer is susceptible to a combined treatment comprising administration of a compound causing a decrease of intracellular pH, an inhibitor of mitochondrial respiration, and a proton ionophore related thereto.
  • Cancer constitutes the fourth leading cause of death in Western countries. As the average age in the Western population steadily rises, so do cancer-related deaths indicating that cancer will be one of the most common causes of death in the 21st century.
  • the aggressive cancer cell phenotype is the result of a variety of genetic and epigenetic alterations leading to deregulation of intracellular signaling pathways. Cancer cells commonly fail to undergo so-called “programmed cell death” or "apoptosis", a signaling process that plays a key role in preventing cell tissues from abnormal growth.
  • Radiotherapy uses ionizing radiation, typically g-radiation, to destroy the tumor.
  • Radiation therapy is based on the principle that tumor cells with their high metabolic rates are especially susceptible to radiation induced cell damage.
  • the anti-tumor effect of radiation therapy has to be weighted against the damage to the surrounding healthy tissue.
  • possible tissue damage can rule out this option in some cases due to the damage to healthy tissues to be feared.
  • radiation therapy is limited to cases where the primary tumor has not yet spread or where only few metastases are present.
  • Chemotherapeutic agents are cytotoxic for all rapidly dividing cells. As cancer cells usually divide more rapidly than other cells in the body, they are preferably killed by these agents. Common groups of chemotherapeutic agents are substances that inhibit cell division by interfering with the formation of the mitotic spindle or agents which damage the DNA, e.g. by alkylating the bases. Because all rapidly dividing cells are targeted by chemotherapeutic agents, their side effects are usually severe. Depending on the substance used, they include organ toxicity (e.g.
  • chemotherapeutic agents e.g. alkylating agents
  • dosages have sometimes to be reduced or chemotherapy has to be discontinued completely.
  • side effects of chemotherapy often prohibit the treatment of patients in a bad general condition. Adding to all these problems is the often limited efficacy of chemotherapy.
  • chemotherapy fails from the very beginning.
  • tumor cells become resistant during the course of treatment.
  • combinations of different compounds with different modes of action are used. Nevertheless, the success of chemotherapy has been limited, especially in the treatment of solid tumors.
  • Imatinib is used for the specific treatment of chronic myelogenous leukemia. This compound specifically inhibits an abnormal tyrosine kinase which is the product of a fusion gene of her and abl. Because this kinase does not occur in non-malignant cells, treatment with Imatinib has only mild side effects.
  • Imatinib is not used for the treatment of hematological cancers other than myelogenous leukemia.
  • Rituximab is a monoclonal antibody directed against the cluster of differentiation 20 (CD20), which is widely expressed on B-cells. It is used for the treatment of B cell lymphomas in combination with conventional chemotherapy.
  • Immunotherapy aims at improving the immune response of a patient to cancer cells, and virotherapy uses oncolytic viruses for lysis of cancer cells.
  • Warburg effect confers selective advantages to cancer cells (reviewed e.g. in Liberti & Locasale (2016), Trends Biochem Sci 41(3):211).
  • Metformin is the first-line oral drug used for treatment of millions of diabetes Type II patients worldwide. Epidemiological studies established a link between intake of Metformin and a lower risk of cancer incidence for many types of malignancies (Wu et al. (2015), Scientific reports 5: 10147). Despite of numerous investigations, anticancer mechanism of Metformin remains elusive. Previous studies had suggested that AMPK activation mediates anticancer action of Metformin (Li et al. (2015), Oncotarget 6:7365; Song et al. (2012), Scientific reports 2:362). This notion, however, is contradicted by an increasing number of reports showing the AMPK- independent anticancer (Vincent et al.
  • the present invention relates to a compound causing a decrease of intracellular pH for use in treatment of cancer with an inhibitor of mitochondrial respiration and a proton ionophore.
  • the terms “have”, “comprise” or “include” or any arbitrary grammatical variations thereof are used in a non-exclusive way. Thus, these terms may both refer to a situation in which, besides the feature introduced by these terms, no further features are present in the entity described in this context and to a situation in which one or more further features are present.
  • the expressions“A has B”,“A comprises B” and“A includes B” may both refer to a situation in which, besides B, no other element is present in A (i.e. a situation in which A solely and exclusively consists of B) and to a situation in which, besides B, one or more further elements are present in entity A, such as element C, elements C and D or even further elements.
  • standard conditions if not otherwise noted, relates to IUPAC standard ambient temperature and pressure (SATP) conditions, i.e. preferably, a temperature of 25°C and an absolute pressure of 100 kPa; also preferably, standard conditions include a pH of 7.
  • SATP standard ambient temperature and pressure
  • the term “about” relates to the indicated value with the commonly accepted technical precision in the relevant field, preferably relates to the indicated value ⁇ 20%, more preferably ⁇ 10%, most preferably ⁇ 5%.
  • the term “essentially” indicates that deviations having influence on the indicated result or use are absent, i.e. potential deviations do not cause the indicated result to deviate by more than ⁇ 20%, more preferably ⁇ 10%, most preferably ⁇ 5%.
  • “consisting essentially of’ means including the components specified but excluding other components except for materials present as impurities, unavoidable materials present as a result of processes used to provide the components, and components added for a purpose other than achieving the technical effect of the invention.
  • a composition defined using the phrase“consisting essentially of’ encompasses any known acceptable additive, excipient, diluent, carrier, and the like.
  • a composition consisting essentially of a set of components will comprise less than 5% by weight, more preferably less than 3% by weight, even more preferably less than 1%, most preferably less than 0.1% by weight of non-specified component(s).
  • the term "essentially identical” indicates a %identity value of at least 80%, preferably at least 90%, more preferably at least 98%, most preferably at least 99%. As will be understood, the term essentially identical includes 100% identity. The aforesaid applies to the term "essentially complementary” mutatis mutandis.
  • intracellular pH is cytoplasmic and/or mitochondrial luminal pH, more preferably is cytoplasmic pH.
  • Methods for detecting modulations of intracellular pH are known in the art and are e.g. described herein in the Examples.
  • detecting a modulation, preferably a decrease, of intracellular pH comprises introducing into a host cell a chemical agent changing at least one measurable property in dependence of the pH it is exposed to. More preferably, said chemical agent changing at least one measurable property in dependence on pH is a pH sensitive variant of a fluorescent protein, more preferably as described herein in the Examples.
  • the compound causing a decrease of intracellular pH is a macromolecule, preferably a an inhibitory polypeptide inhibiting a transport protein of a host cell.
  • the compound causing a decrease of intracellular pH may e.g. be an antibody inhibiting a cellular carboxylic acid export protein.
  • the compound causing a decrease of intracellular pH is a small molecule compound, i.e.
  • the compound causing a decrease of intracellular pH is a carboxylic acid export inhibitor or a biguanide compound.
  • the carboxylic acid export inhibitor is a monocarboxylic acid export inhibitor, more preferably is a lactate export inhibitor.
  • the carboxylic acid export inhibitor in particular the lactate export inhibitor, is an inhibitor of monocarboxyl ate transporter 4 (MCT4) or a homologue thereof.
  • MCT4 is known to the skilled person, and its amino acid sequence is available e.g. from Genbank Acc No. XP 024306791.1.
  • the carboxylic acid export inhibitor comprises at least one statin, a-cyano-4-hydroxycinnamate, syrosingopine, and/or at least one pyrazole compound, preferably a pyrazole compound as described in WO 2016/201426 Al .
  • the carboxylic acid export inhibitor comprises, preferably is, a statin, preferably selected from the list consisting of Simvastatin, Fluvastatin, Atorvastatin, Lovastatin, Pitavastatin, Pravastatin, and Rosuvastatin, preferably of Simvastatin, Fluvastatin, Atorvastatin, and Lovastatin.
  • the compound causing a decrease of intracellular pH is a biguanide, more preferably is Metformin or Phenformin, most preferably is Metformin.
  • the compound causing a decrease of intracellular pH is Drotaverine (CAS Number 985-12-6).
  • mitochondrial respiration relates to the biochemical reactions regenerating energy equivalents, preferably nucleotide triphosphates (NTPs), more preferably adenosine-triphosphate (ATP), in a mitochondrion of an animal cell.
  • NTPs nucleotide triphosphates
  • ATP adenosine-triphosphate
  • mitochondrial respiration is mitochondrial oxidative phosphorylation, i.e. oxidation of redox equivalents to H2O catalyzed by membrane-bound enzymes complexes of a mitochondrion, generating a proton gradient over the inner mitochondrial membrane usable by ATP synthase for regenerating ATP.
  • the term "inhibitor of mitochondrial respiration”, as used herein, relates to a chemical compound inhibiting mitochondrial respiration as specified herein above.
  • the inhibitor of mitochondrial respiration is an inhibitor of mitochondrial complex I (NADH-coenzyme Q oxidoreductase), of mitochondrial complex III (Q-cytochrome c oxidoreductase), of mitochondrial complex V (ATP synthase).
  • mitochondrial complex I NADH-coenzyme Q oxidoreductase
  • mitochondrial complex III Q-cytochrome c oxidoreductase
  • V ATP synthase
  • Respective inhibitors of mitochondrial complexes are known in the art, e.g. rotenone as inhibitor of complex I (cf, e.g.
  • the inhibitor of mitochondrial respiration is an inhibitor of mitochondrial complex I; even more preferably, the inhibitor of mitochondrial respiration is selected from the list consisting of (i) Papaverine (CAS Number: 61-25-6), (ii) Rotenone (CAS Number: 83-79-4), (iii) Annonacin (CAS NumberT 11035-65-5), (iv) 1-methyl 4-phenyl 1,2, 3, 6 tetrahydropyridine (CAS Number 23007-85-4), (v) 3-nitropropionic acid (CAS Number: 504-88-1), (vi) Piericidin A (CAS Number 2738-64-9), (vii) Bullatacin A (CAS Number 123123-32-0), (viii) Rolliniastatin-1 ((2S)-4-[(2R, 13R)-2,13
  • the inhibitor of mitochondrial respiration is selected from the list consisting of (i) Papaverine, (ii) Fenofibrate, (iii) Celastrol, (iv) Metformin, (v) a derivative of any one of (i) to (iv), (vi) a pharmaceutically acceptable salt of any one of (i) to (iv), and (vii) a prodrug of any of any one of (i) to (iv).
  • NT1014 is known to the skilled person from Zhang et al. (Journal of Hematology & Oncology (2016) 9:91).
  • ionophore is used herein in its conventional meaning known to the skilled person and, preferably, relates to a chemical compound transporting ions over a biological membrane, preferably at least over the plasma membrane and/or the inner mitochondrial membrane, of an animal cell. More preferably, said chemical compound reversibly binds to and transports ions over a biological membrane. Accordingly, the term “proton ionophore”, as used herein, is also used in its conventional meaning known to the skilled person and, preferably, relates to a chemical compound reversibly binding to and transporting protons over a biological membrane, preferably at least over the plasma membrane and/or the inner mitochondrial membrane, of an animal cell.
  • the proton ionophore is a specific proton ionophore, i.e. it is not required that the proton ionophore exclusively binds and transports protons over a biological membrane.
  • the proton ionophore is a compound further binding and transporting ions different from protons, preferably alkali metal ions, as well.
  • the proton ionophore is a K + /H + ionophore, like e.g. nigericin; or is a Na + /H + ionophore, like e.g. monensin.
  • the proton ionophore is (I) Nigericin,
  • the proton ionophore is selected from the list consisting of (I) Monensin, (II) Maduramycin, (III) Salinomycin, (IV) a derivative of any one of (I) to (III), (V) a prodrug of any of any one of (I) to (III), and (VI) a pharmaceutically acceptable salt of any one of (I) to
  • a derivative relates to a compound similar in structure to the compound it is derived from.
  • a derivative is a compound obtainable from a compound of interest by at most three, preferably at most two, more preferably by one derivatization step(s) known to the skilled person.
  • prodrug is understood by the skilled person to relate to a compound not having or having only to a reduced extent the relevant activity as specified and being converted in the body of a subject to the actual active compound.
  • a prodrug is a derivative as specified herein above which is cleaved, preferably hydrolyzed, in the body of a subject to a compound as specified above.
  • the prodrug is an ether or preferably an ester of the iron chelator. More preferably, the prodrug is an ether, an ester, a glycosylate, a phosphate, a sulphate, or a macromolecule-conjugated, e.g. polyethyleneglycol (PEG) conjugated, derivative of the compound as indicated above.
  • PEG polyethyleneglycol
  • the term "subject" relates to a vertebrate.
  • the subject is a mammal, more preferably, a mouse, rat, cat, dog, hamster, guinea pig, sheep, goat, pig, cattle, or horse.
  • the subject is a primate.
  • the subject is a human.
  • the subject is afflicted with a disease caused or aggravated by an inappropriate activity of cells showing a Warburg effect as specified elsewhere herein, more preferably, the subject is afflicted with cancer.
  • the term "host cell” relates to a vertebrate cell.
  • the host cell is a mammalian cell, more preferably, a mouse, rat, cat, dog, hamster, guinea pig, sheep, goat, pig, cattle, or horse cell. Still more preferably, the host cell is a primate cell. Most preferably, the host cell is a human cell.
  • the host cell is a cell showing inappropriate activity as specified elsewhere herein, more preferably, is a cell showing a Warburg effect.
  • the host cell is a cancer cell, more preferably a cancer cell showing a Warburg effect.
  • cancer in the context of this invention refers to a disease of an animal, including man, characterized by uncontrolled growth by a group of body cells (“cancer cells”). This uncontrolled growth may be accompanied by intrusion into and destruction of surrounding tissue and possibly spread of cancer cells to other locations in the body (“metastasis”). Moreover, cancer may entail recurrence of cancer cells after an initial treatment apparently removing cancer cells from a subject ("relapse"). Preferably, cancer cells are cancer stem cells.
  • the cancer is selected from the list consisting of acute lymphoblastic leukemia, acute myeloid leukemia, adrenocortical carcinoma, aids-related lymphoma, anal cancer, appendix cancer, astrocytoma, atypical teratoid, basal cell carcinoma, bile duct cancer, bladder cancer, brain stem glioma, breast cancer, burkitt lymphoma, carcinoid tumor, cerebellar astrocytoma, cervical cancer, chordoma, chronic lymphocytic leukemia, chronic myelogenous leukemia, colon cancer, colorectal cancer, craniopharyngioma, endometrial cancer, ependymoblastoma, ependymoma, esophageal cancer, extracranial germ cell tumor, extragonadal germ cell tumor, extrahepatic bile duct cancer, gallbladder cancer, gastric cancer, gastrointestinal stromal tumor, gestational
  • the cancer is a tumor-forming cancer, i.e. is a solid cancer. Still more preferably, the cancer is pancreas cancer; colorectal cancer, preferably colon carcinoma; lung cancer, preferably non-small cell lung cancer; liver cancer; breast cancer; skin cancer, preferably melanoma; or Head and Neck cancer. Most preferably, the cancer is pancreas cancer.
  • the cancer is a cancer sensitive to triple treatment with a compound causing a decrease of intracellular pH, an inhibitor of mitochondrial respiration, and a proton ionophore.
  • the term "cancer sensitive to triple treatment with a compound causing a decrease of intracellular pH, an inhibitor of mitochondrial respiration, and a proton ionophore”, as used herein, relates to a cancer, wherein the cells of said cancer show a significant decrease in viability upon treatment with an inhibitor of mitochondrial respiration and a proton ionophore, measured with a conventional viability assay (e.g. one of the assays reviewed in book "Assay Guidance Manual", G.S.
  • the cancer is a Wnt signaling-dependent cancer.
  • the cancer sensitive to triple treatment with a compound causing a decrease of intracellular pH, an inhibitor of mitochondrial respiration, and a proton ionophore is a Wnt signaling-dependent cancer.
  • the term "Wnt signaling-dependent cancer”, as used herein, relates to a cancer, wherein the cells generate in nuclei and/or cytoplasm abnormally high amount of b-catenin.
  • a Wnt signaling-dependent cancer is identified by biopsy analysis, more preferably according to Gomez-Millan et al. 2014, BMC Cancer 14: 192.
  • the cancer is a TGFbeta signaling-dependent cancer.
  • TGFbeta signaling-dependent cancer is known to the skilled person.
  • the cancer is a cancer wherein cancer cells show an unfolded protein response upon administration of a compound causing a decrease of intracellular pH, an inhibitor of mitochondrial respiration, and a proton ionophore.
  • the cancer sensitive to the aforesaid combined treatment is a cancer wherein cancer cells show an unfolded protein response upon administration of compound causing a decrease of intracellular pH, an inhibitor of mitochondrial respiration, and a proton ionophore.
  • Determining whether cells, in particular cancer cells, show an unfolded protein response preferably, comprises contacting said cells with a compound causing a decrease of intracellular pH, an inhibitor of mitochondrial respiration, and a proton ionophore and determining at least one marker of unfolded protein response.
  • the marker of unfolded protein response is a gene product, e.g., preferably, an mRNA or a polypeptide, of a gene encoding a CHOP, preferably CHOP 10; DDIT3; Gaddl53; and/or CEBPZ polypeptide, more preferably is a gene product of the human gene encoding the CHOP polypeptide, most preferably is the human CHOP mRNA as disclosed in Genbank Acc No: AAH03637.1 GI: 13177718.
  • treating and “treatment” refer to ameliorating the diseases or disorders referred to herein or the symptoms accompanied therewith to a significant extent. Said treating as used herein also includes an entire restoration of the health with respect to the diseases or disorders referred to herein. It is to be understood that treating as used in accordance with the present invention may not be effective in all subjects to be treated. However, the term shall require that, preferably, a statistically significant portion of subjects suffering from a disease or disorder referred to herein can be successfully treated.
  • Whether a portion is statistically significant can be determined without further ado by the person skilled in the art using various well known statistic evaluation tools, e.g., determination of confidence intervals, p-value determination, Student ' s t-test, Mann- Whitney test etc. Details are found in Dowdy and Wearden, Statistics for Research, John Wiley & Sons, New York 1983.
  • Preferred confidence intervals are at least 90%, at least 95%, at least 97%, at least 98% or at least 99 %.
  • the p-values are, preferably, 0.1, 0.05, 0.01, 0.005, or 0.0001.
  • the probability envisaged by the present invention allows that the diagnosis will be correct for at least 60%, at least 70%, at least 80%, or at least 90% of the subjects of a given cohort or population.
  • treating is inhibition of growth of a tumor and/or metastases; more preferably, treating is causing a tumor and/or metastases to shrink.
  • metastasis prevention i.e., preferably, is preventing cancer cells from establishing metastasis in locations of the body non-identical to the location of the primary tumor.
  • treating is inducing cancer cell and/or tumor necrosis.
  • treatment comprises preventing embryonic pathway signaling, preferably Wnt and/or TGFbeta signaling.
  • treatment comprises inducing differentiation of cancer cells, preferably comprises induction of loss of stem cell properties of cancer cells.
  • the treatment preferably, comprises administration of at least one compound from each group of compounds indicated, i.e. at least one compound causing a decrease of intracellular pH, at least one inhibitor of mitochondrial respiration, and at least one proton ionophore.
  • the treatment comprises administration of at least three non-identical compounds as specified.
  • the inhibitor of mitochondrial respiration is not a biguanide compound; also preferably, in case the inhibitor of mitochondrial respiration is a biguanide compound, the compound causing a decrease of intracellular pH is a carboxylic acid export inhibitor.
  • the treatment comprises further administration of at least one further cancer therapy known in the art, preferably selected from the list consisting of radiotherapy, chemotherapy, anti-hormone therapy, targeted therapy, immunotherapy, and virotherapy, preferably being radiotherapy and/or chemotherapy.
  • chemotherapy relates to treatment of a subject with an antineoplastic drug.
  • chemotherapy is a treatment including alkylating agents (e.g. cyclophosphamide), platinum (e.g. carboplatin), antimetabolites (e.g. 5-Fluorouracil), anthracyclines (e.g.
  • doxorubicin doxorubicin, epirubicin, idarubicin, or daunorubicin
  • topoisomerase II inhibitors e.g. etoposide, irinotecan, topotecan, camptothecin, or VP 16
  • anaplastic lymphoma kinase (ALK)-inhibitors e.g. Crizotinib or AP26130
  • aurora kinase inhibitors e.g.
  • chemotherapy preferably, relates to a complete cycle of treatment, i.e. a series of several (e.g. four, six, or eight) doses of antineoplastic drug or drugs applied to a subject, which may be separated by several days or weeks without such application.
  • chemotherapy is nanoparticle- delivered chemotherapy.
  • radiation therapy and “radiotherapy” are known to the skilled artisan.
  • the term relates to the use of ionizing radiation to treat or control cancer.
  • targeted therapy relates to application to a patient a chemical substance known to block growth of cancer cells by interfering with specific molecules known to be necessary for tumorigenesis or cancer or cancer cell growth.
  • Examples known to the skilled artisan are small molecules like, e.g. PARP-inhibitors (e.g. Iniparib), antiangiogenic agents (e.g. Bevacizumab, Ramucirumab, Ziv-aflibercept), signalling inhibitors (e.g. cetuximab or panitumumab), or kinase inhibitors (e.g. Regorafenib).
  • PARP-inhibitors e.g. Iniparib
  • antiangiogenic agents e.g. Bevacizumab, Ramucirumab, Ziv-aflibercept
  • signalling inhibitors e.g. cetuximab or panitumumab
  • kinase inhibitors e.g. Regorafenib
  • immunotherapy as used herein relates to the treatment of cancer by modulation of the immune response of a subject. Said modulation may be inducing, enhancing, or suppressing said immune response, e.g. by administration of at least one cytokine, and/or of at least one antibody specifically recognizing cancer cells.
  • cell based immunotherapy relates to a cancer therapy comprising application of immune cells, e.g. T-cells, preferably tumor-specific NK cells, to a subject.
  • viralotherapy as used herein, relates to treatment of cancer by administration of viruses, preferably oncolytic viruses. The method is known to the skilled person e.g. from Russel et al. (2012), Nat Biotechnol. 30(7): 658.
  • the present invention also relates to a proton ionophore for use in treatment of cancer with an inhibitor of mitochondrial respiration and a compound causing a decrease of intracellular pH; and to an inhibitor of mitochondrial respiration for use in treatment of cancer with a proton ionophore and a compound causing a decrease of intracellular pH.
  • the present invention relates to a combined preparation for simultaneous, separate or sequential use comprising (i) a compound causing a decrease of intracellular pH, (ii) an inhibitor of mitochondrial respiration, and (iii) a proton ionophore. Also, the present invention relates to the aforesaid combined preparation for use in medicine and for use in treatment of cancer and/or treatment of an inappropriate activity of cells showing a Warburg effect.
  • the term“combined preparation”, as referred to in this application, relates to a preparation comprising the pharmaceutically active compounds of the present invention in one preparation.
  • the combined preparation is comprised in a container, i.e. preferably, said container comprises all pharmaceutically active compounds of the present invention.
  • said container comprises the pharmaceutically active compounds of the present invention as separate formulations, i.e. preferably, one formulation of the compound causing a decrease of intracellular pH, one formulation of the inhibitor of mitochondrial respiration, and one formulation of the proton ionophore.
  • formulation relates to a, preferably pharmaceutically acceptable, mixture of compounds, comprising or consisting of at least one pharmaceutically active compound of the present invention.
  • the combined preparation comprises a compound causing a decrease of intracellular pH, a proton ionophore, and an inhibitor of mitochondrial respiration in a single solid pharmaceutical form, e.g. a tablet or infusion.
  • a compound causing a decrease of intracellular pH, a proton ionophore, and an inhibitor of mitochondrial respiration in a single solid pharmaceutical form, e.g. a tablet or infusion.
  • one or two compound(s) of the present invention is/are comprised in an immediate or fast release formulation, and the second and third or the third compound(s) of the present invention is/are comprised in a slow or retarded release formulation; more preferably, the compounds of the present invention are comprised in separate, preferably liquid, formulations; said separate liquid formulations, preferably are for injection, more preferably at different parts of the body of a subject.
  • the compound causing a decrease of intracellular pH, the inhibitor of mitochondrial respiration, and the proton ionophore are present in the subject simultaneously at an effective concentration for at least 3 hours per treatment cycle, preferably at least 12 hours per treatment cycle, more preferably at least 72 hours per treatment cycle, most preferably at least 7 days per treatment cycle.
  • the compound causing a decrease of intracellular pH, the inhibitor of mitochondrial respiration, and the proton ionophore are present in the subject simultaneously at an effective concentration for at least 25% of the time of a treatment cycle, preferably at least 50% of the time of a treatment cycle, more preferably at least 75% of the time of a treatment cycle, most preferably at least 85% of the time of a treatment cycle.
  • Preferred combined preparations comprise (1) Simvastatin, Metformin, and Monensin; (2) Fluvastatin, Metformin, and Monensin; (3) Atorvastatin, Metformin, and Salinomycin; (4) Simvastatin, Metformin, and Salinomycin; (5) Lovastatin, Celastrol, and Monensin; (6) Simvastatin, Celastrol, and Monensin; (7) Metformin, Celastrol, and Monensin; (8)Metformin, Fenofibrate, and Monensin; (9) Metformin, Papaverine, and Monensin; (10) Metformin, Papaverine, and Maduramycin; or (11) any combination of (1) to (10). As will be understood by the skilled person, these are also the preferred combinations to be administered in the treatments as specified elsewhere herein.
  • the combined preparation is for separate or for combined administration.
  • Separatate administration relates to an administration wherein at least two of the pharmaceutically active compounds of the present invention are administered via different routes and/or at different parts of the body of a subject. E.g. one compound may be administered by enteral administration (e.g. orally), whereas another compound is administered by parenteral administration (e.g. intravenously).
  • the combined preparation for separate administration comprises at least two, preferably three physically separated preparations for separate administration, wherein each preparation contains at least one pharmaceutically active compound; said alternative is preferred e.g. in cases where the pharmaceutically active compounds of the combined preparation have to be administered by different routes, e.g. parenterally and orally, due to their chemical or physiological properties.
  • combined administration relates to an administration wherein the pharmaceutically active compounds of the present invention are administered via the same route, e.g. orally or intravenously.
  • the combined preparation is for simultaneous or for sequential administration.
  • Simultaneous administration relates to an administration wherein the pharmaceutically active compounds of the present invention are administered at the same time, i.e., preferably, administration of the pharmaceutically active compounds starts within a time interval of less than 15 minutes, more preferably, within a time interval of less than 5 minutes. Most preferably, administration of the pharmaceutically active compounds starts at the same time, e.g. by swallowing a tablet comprising the pharmaceutically active compounds, or by applying an intravenous injection of a solution comprising one pharmaceutically active compound and injecting a second compound in different part of the body.
  • sequential administration relates to an administration causing plasma concentrations of the pharmaceutically active compounds in a subject enabling the synergistic effect of the present invention, but which, preferably, is not a simultaneous administration as specified herein above.
  • sequential administration is an administration wherein administration of the pharmaceutically active compounds, preferably all pharmaceutically active compounds, starts within a time interval of 1 or 2 days, more preferably within a time interval of 12 hours, still more preferably within a time interval of 4 hours, even more preferably within a time interval of one hour, most preferably within a time interval of 5 minutes.
  • the combined preparation is a pharmaceutically compatible combined preparation.
  • pharmaceutically compatible preparation and“pharmaceutical composition”, as used herein, relate to compositions comprising the compounds of the present invention and optionally one or more pharmaceutically acceptable carrier.
  • the compounds of the present invention can be formulated as pharmaceutically acceptable salts.
  • Preferred acceptable salts are acetate, HC1, sulfate, chloride and the like.
  • the pharmaceutical compositions are, preferably, administered topically or, more preferably, systemically. Suitable routes of administration conventionally used for drug administration are oral, intravenous, subcutaneous, or parenteral administration as well as inhalation. However, depending on the nature and mode of action of a compound, the pharmaceutical compositions may be administered by other routes as well.
  • the compounds can be administered in combination with other drugs either in a common pharmaceutical composition or as separated pharmaceutical compositions as specified elsewhere herein, wherein said separated pharmaceutical compositions may be provided in form of a kit of parts.
  • the combined preparation is an extended release preparation with regard to at leat one of the compounds, wherein the term "extended release”, preferably, relates to a compound encapsulated in microspheres based, preferably, on Medisorb or similar microsphere technology (Kim M.R. et al, (2010), Chem. Comm. (Camb) 46: 7433).
  • the compounds are, preferably, administered in conventional dosage forms prepared by combining the drugs with standard pharmaceutical carriers according to conventional procedures. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate for the desired preparation. It will be appreciated that the form and character of the pharmaceutically acceptable carrier or diluent is dictated by the amount of active ingredient with which it is to be combined, the route of administration and other well- known variables.
  • the carrier(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and being not deleterious to the recipient thereof.
  • the pharmaceutical carrier employed may be, for example, a solid, a gel or a liquid.
  • Exemplary of solid carriers are lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid, degradable polymers like PLGA (DeYoung at al. (2011), DIABETES TECHNOLOGY & THERAPEUTICS 13 : 1 145; Ramazani et al, (2016), Int J Pharm. 499(1-2): 358-367, and the like.
  • Exemplary liquid carriers are phosphate buffered saline solution, syrup, oil such as peanut oil and olive oil, water, emulsions, various types of wetting agents, sterile solutions and the like.
  • the carrier or diluent may include time delay material well known to the art, such as glyceryl mono-stearate or glyceryl distearate alone or with a wax.
  • Said suitable carriers comprise those mentioned above and others well known in the art, see, e.g., Remington ' s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.
  • the diluent(s) is/are selected so as not to affect the biological activity of the compound or compounds.
  • examples of such diluents are distilled water, physiological saline, Ringer's solutions, dextrose solution, and Hank's solution.
  • the pharmaceutical composition or formulation may also include other carriers, adjuvants, or nontoxic, nontherapeutic, nonimmunogenic stabilizers, reactive oxygen scavengers, and the like.
  • the pharmaceutical composition comprises an agent inducing the cAMP pathway of a host cell, preferably a mammalian cell.
  • Inducers of the cAMP pathway include in particular activators of adenylyl cyclase, preferably forskolin (CAS 66428-89-5), inhibitors of phosphodiesterase, e.g. caffeine, and cAMP analogues, preferably 8-(4-Chlorophenylthio)- adenosine-3',5'-cyclic monophosphate (8-CPT-cAMP, CAS 93882-12-3) or 8-Bromoadenosine 3', 5'-cyclic monophosphate (CAS 23583-48-4).
  • the agent inducing the cAMP pathway is forskolin or 8-CPT-cAMP.
  • a therapeutically effective dose refers to an amount of the compounds to be used in a pharmaceutical composition of the present invention which prevents, ameliorates or treats the symptoms accompanying a disease or condition referred to in this specification.
  • Therapeutic efficacy and toxicity of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., ED50 (the dose therapeutically effective in 50% of the population) and LD50 (the dose lethal to 50% of the population).
  • the dose ratio between therapeutic and toxic effects is the therapeutic index, and it can be expressed as the ratio, LD50/ED50.
  • the dosage regimen will be determined by the attending physician and other clinical factors; preferably in accordance with any one of the above described methods.
  • dosages for any one patient depends upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and other drugs being administered concurrently. Progress can be monitored by periodic assessment.
  • a typical dose can be, for example, in the range of 1 to 1000 pg; however, doses below or above this exemplary range are envisioned, especially considering the aforementioned factors.
  • the regimen as a regular administration of the pharmaceutical composition should be in the range of 1 pg to 10 mg units per day.
  • the regimen is a continuous infusion, it should also be in the range of 1 pg to 10 mg units per kilogram of body weight per minute, respectively.
  • extended release preparations of each drug are injected from once per 1 week to once per 2 months or even at longer intervals. Progress can be monitored by periodic assessment.
  • Preferred doses and concentrations of the compounds of the present invention are specified elsewhere herein.
  • a final concentration of Rotenone in tumor tissue preferably is not less than 1.25 nM.
  • the Rotenone concentration in blood is less than 1 mM.
  • Rotenone is administered in an extended release formulation, in particular from extended release microspheres in a monthly or bimonthly dose of from 5 pg/kg to 250 pg/kg, more preferably of from 14 pg/kg to 125 pg/kg.
  • Papaverine hydrochloride may be administered in a single oral dose of Papaverine of from 50 mg to 150 mg, preferably 80 mg. The same dose may also be administered as intravenous injection for 5 min.
  • a further preferred dosage of Papaverine is 1 to 25 mg/kg, more preferably 2.2 - 20 mg/kg.
  • preferred concentrations of Salinomycin, Monensin and Nigericin in tumor tissue are more than 1.25 nM.
  • Salinomycin preferably is administered for treatment in human subjects at doses of from 100 to 300 pg/kg, more preferably 200 pg/kg intravenously every 2nd day, most preferably in an extended release formulation.
  • Preferred doses of Nigericin are 2-3 times lower compared to Salinomycin.
  • a further preferred dosage of Nigericin, Monensin and Salinomycin is 14 pg- 125 pg/kg using subcutaneous delivery of extended release microspheres.
  • Monensin is administered orally.
  • the concentration of a statin in tumor tissue preferably, is of from 5 nM to 500 nM, more preferably of from 10 nM to 250 nM, still more preferably of from 15 nM to 100 nM, most preferably of from 20 nM to 50 nM.
  • Statins are preferably administered for treatment in human subjects at doses of from 10 mg/day to 200 mg/day, preferably of from 20 mg/day to 80 mg/day.
  • the concentration of biguanides in tumor tissue preferably, is of from 1 pM to 100 pM, preferably of from 2 pM to 25 pM, more preferably of from 2.5 pM to 10 pM. Biguanides are preferably administered for treatment in human subjects at doses of from 100 mg/day to 5000 mg/day, more preferably of from 250 mg/day to 2500 mg/day, still more preferably of from 500 mg/day to 1500 mg/day.
  • compositions and formulations referred to herein are, preferably, administered at least once, e.g. in case of extended release formulations, in order to treat or ameliorate or prevent a disease or condition recited in this specification.
  • the said pharmaceutical compositions may be administered more than one time, for example from one to four times daily up to a non-limited number of days.
  • compounds with a short clearance time may be applied as infusion in blood stream to provide effective dose in whole body during long treatment time.
  • Specific pharmaceutical compositions are prepared in a manner well known in the pharmaceutical art and comprise at least one active compound referred to herein above in admixture or otherwise associated with a pharmaceutically acceptable carrier or diluent.
  • the active compound(s) will usually be mixed with a carrier or the diluent, or enclosed or encapsulated in a capsule, sachet, cachet, paper or other suitable containers or vehicles.
  • the resulting formulations are to be adopted to the mode of administration, i.e. in the forms of tablets, capsules, suppositories, solutions, suspensions or the like.
  • Dosage recommendations shall be indicated in the prescribers or users instructions in order to anticipate dose adjustments depending on the considered recipient.
  • the term "inappropriate activity” relates to any activity of cells of a subject which is not appropriate to the physiological state of said subject and/or to the tissue context of said cells.
  • the inappropriate activity is tumor-protective activity of reprogrammed bystander cells in tumor chemo- and/or radiotherapy; thus, in such case, the host cells showing a Warburg effect are said reprogrammed bystander cells.
  • the inappropriate activity is inappropriate cell proliferation.
  • the term "inappropriate cell proliferation” relates to any proliferation of cells of a subject which is not appropriate to the physiological state of said subject and/or to the tissue context of said cells.
  • inappropriate cell proliferation is caused or aggravated by an inhibition or insufficient activation of the immune system.
  • inappropriate cell proliferation is cancer, preferably as specified herein above.
  • treatment of an inappropriate proliferation of cells showing a Warburg effect relates to an inappropriate proliferation of cells performing fermentative energy metabolism even in the presence of oxygen as specified above.
  • said inappropriately proliferating cells showing a Warburg effect are cells infected by a virus, preferably a papillomavirus, preferably a human papillomavirus (HPV), a cytomegalovirus, preferably human cytomegalovirus (HCMV); Kaposi's sarcoma herpesvirus (KSHV), or hepatitis C virus (HCV).
  • the inappropriate cellular proliferation preferably, is a HPV-related lesion, or a HCMV-, HSHV- or HCV-related proliferation.
  • the present invention further relates to a medicament comprising (i) a compound causing a decrease of intracellular pH, (ii) an inhibitor of mitochondrial respiration, and (iii) a proton ionophore.
  • said medicament is for use in treatment of cancer and/or treatment of an inappropriate activity of cells showing a Warburg effect.
  • the term "medicament” is understood by the skilled person.
  • the definitions given herein above for the term "combined preparation” preferably, apply to the term medicament of the present invention mutatis mutandis.
  • the present invention also relates to a kit comprising (i) a compound causing a decrease of intracellular pH, (ii) an inhibitor of mitochondrial respiration, and (iil) a proton ionophore, preferably comprised in a housing.
  • kit refers to a collection of the aforementioned components.
  • said components are combined with additional components, preferably within an outer container.
  • the outer container also preferably, comprises instructions for carrying out a method of the present invention. Examples for such the components of the kit as well as methods for their use have been given in this specification.
  • the kit preferably, contains the aforementioned components in a ready-to-use formulation.
  • the kit additionally comprises instructions, e.g., a user’s manual for applying the inhibitor of mitochondrial respiration and the proton ionophore with respect to the applications provided by the methods of the present invention. Details are to be found elsewhere in this specification. Additionally, such user’s manual may provide instructions about correctly using the components of the kit.
  • a user’s manual may be provided in paper or electronic form, e.g., stored on CD or CD ROM.
  • the present invention also relates to the use of said kit in any of the methods according to the present invention.
  • the kit may also be used in a cell viability assay using cancer cells obtained from a patient.
  • the present invention relates to a method of treating cancer in a subject comprising administering to said subject
  • the method of treating of the present invention preferably, is an in vivo method. Moreover, it may comprise steps in addition to those explicitly mentioned above. For example, further steps may relate, e.g., to diagnosing cancer for step a), or administering further treatments, e.g. surgery, radiotherapy, and/or administration of cancer therapeutic agents before, simultaneously to, or after administering one or both of steps a) and b). Moreover, one or more of said steps may be performed by automated equipment.
  • the subject according to the present invention is a subject suffering from cancer as specified herein above. Also preferably, the subject is a subject not suffering from diabetes type II.
  • cancer therapeutic agent relates to an agent used to treat cancer.
  • the term cancer therapeutic agent is not used for a compound causing a decrease of intracellular pH, not for an inhibitor of mitochondrial respiration and not for a proton ionophore, although these groups of compounds are suitable in cancer therapy.
  • the term cancer therapeutic agent preferably, relates to a chemical substance known to inhibit growth of cancer cells, to kill cancer cells, or to cause the body of a patient to inhibit the growth of or to kill cancer cells in the treatment of cancer by application of said chemical substance to a patient in need thereof. More preferably, the cancer therapeutic agent is a chemotherapeutic agent, an agent for targeted therapy, an agent for immunotherapy, a virotherapeutic agent, or any combination thereof.
  • the present invention further relates to a method for determining whether a subject suffering from cancer is susceptible to a combined treatment comprising administration of a compound causing a decrease of intracellular pH, an inhibitor of mitochondrial respiration, and a proton ionophore, comprising
  • step a) detecting in a sample of cancer cells of said subject whether said cancer cells (i) are Wnt signaling-dependent cancer cells, (ii) are TGFbeta signaling-dependent cancer cells, and/or (iii) show a decrease in viability upon administration of compound causing a decrease of intracellular pH, an inhibitor of mitochondrial respiration, and a proton ionophore, and b) based on the result of the detection of step a), determining whether said subject suffering from cancer is susceptible to a combined treatment comprising administration of compound causing a decrease of intracellular pH, an inhibitor of mitochondrial respiration, and a proton ionophore.
  • the method for determining whether a subject is susceptible to a combined treatment preferably, is an in vitro method. Moreover, it may comprises further steps in addition to those explicitly mentioned above. For example, further steps may relate, e.g., to obtaining cancer cells from a sample before step a), or providing a recommendation for or administering at least one cancer therapy to the subject examined.
  • the method for determining whether a subject is susceptible to a combined treatment is a method for providing information useful in deciding in further therapy of a subject.
  • the method for determining whether a subject is susceptible to a combined treatment preferably, is a method for providing relevant information to the medical practitioner, however, more preferably, does not provide a diagnosis and/or decision on therapy.
  • Means and methods for determining whether cells, in particular cancer cells, are sensitive to combined treatment as specified have been described herein above and include, preferably, comparing viability measured as ATP level of said cells in the presence and absence of an effective concentration of said inhibitor of mitochondrial respiration and proton ionophore.
  • viability measured as ATP level of said cells in the presence and absence of an effective concentration of said inhibitor of mitochondrial respiration and proton ionophore.
  • said cells are determined to be susceptible to the combined treatment as related to herein.
  • Means and methods for determining whether a cancer is a Wnt signaling-dependent cancer have been described herein above and in the Examples.
  • said cells are determined to be Wnt-signaling dependent and, preferably, are determined to be susceptible to the combined treatment as related to herein.
  • said determination of increased b-catenin expression is performed as described by Gomez-Millan (2014), BMC Cancer. 14: 192. Analogous methods may be used to determine whether cancer cells are TGFbeta signaling-dependent cancer cells.
  • cells in particular cancer cells, show an unfolded protein response or decrease in Sox4 expression upon administration of an inhibitor of mitochondrial respiration and a proton ionophore have been described herein above and in the Examples.
  • cells are determined comprise an increased amount of said marker of unfolded protein response upon administration of an inhibitor of mitochondrial respiration and a proton ionophore as compared to a control without administration of an inhibitor of mitochondrial respiration and a proton ionophore, said cells are determined to be susceptible to the combined treatment as related to herein.
  • the present invention also relates to a compound causing a decrease of intracellular pH for use in treatment of cancer with an inhibitor of mitochondrial respiration; and relates to an inhibitor of mitochondrial respiration for use in treatment of cancer with a compound causing a decrease of intracellular pH.
  • the present invention further relates to a combined preparation for simultaneous, separate or sequential use comprising (i) a compound causing a decrease of intracellular pH and (ii) an inhibitor of mitochondrial respiration; and relates to a medicament comprising (i) a compound causing a decrease of intracellular pH and (ii) an inhibitor of mitochondrial respiration.
  • the present invention also relates to a method of treating cancer in a subject comprising administering to said subject a) (i) a compound causing a decrease of intracellular pH and (ii) an inhibitor of mitochondrial respiration; b) a combined preparation comprising said compounds; and/or c) a medicament comprising said compounds; and thereby treating cancer in said subject.
  • carboxylic acid export inhibitor comprises at least one statin, a-cyano-4- hydroxycinnamate, syrosingopine, and/or at least one pyrazole compound.
  • carboxylic acid export inhibitor comprises, preferably is, Simvastatin, Fluvastatin, Atorvastatin, Lovastatin, Pitavastatin, Pravastatin, or Rosuvastatin, preferably Simvastatin, Fluvastatin, Atorvastatin, or Lovastatin.
  • the compound causing a decrease of intracellular pH for use of any one of embodiments 1 to 8, with the provisio that if the inhibitor of mitochondrial respiration is a biguanide compound, the compound causing a decrease of intracellular pH is a carboxylic acid export inhibitor.
  • inhibitor of mitochondrial respiration is selected from the list consisting of (i) Papaverine, (ii) Fenofibrate, (iii) Celastrol, (iv) Metformin, (v) a derivative of any one of (i) to (iv), (vi) a pharmaceutically acceptable salt of any one of (i) to (iv), and (vii) a prodrug of any of any one of (i) to (iv).
  • a combined preparation for simultaneous, separate or sequential use comprising (i) a compound causing a decrease of intracellular pH, (ii) an inhibitor of mitochondrial respiration, and (iii) a proton ionophore.
  • a medicament comprising (i) a compound causing a decrease of intracellular pH, (ii) an inhibitor of mitochondrial respiration, and (iii) a proton ionophore.
  • the medicament according to embodiment 29 for use in treatment of cancer and/or treatment of an inappropriate activity of cells showing a Warburg effect.
  • kits comprising (i) a compound causing a decrease of intracellular pH, (ii) an inhibitor of mitochondrial respiration, and, optionally, (iii) a proton ionophore, preferably comprised in a housing. 34.
  • the kit of embodiment 33 with the features as specified in any one of embodiments 2 to 20.
  • a method of treating cancer in a subject comprising administering to said subject
  • a method for determining whether a subject suffering from cancer is susceptible to a combined treatment comprising administration of a compound causing a decrease of intracellular pH, an inhibitor of mitochondrial respiration, and a proton ionophore comprising a) detecting in a sample of cancer cells of said subject whether said cancer cells (i) are Wnt signaling-dependent cancer cells, (ii) are TGFbeta signaling-dependent cancer cells, and/or (iii) show a decrease in viability upon administration of compound causing a decrease of intracellular pH, an inhibitor of mitochondrial respiration, and a proton ionophore, and b) based on the result of the detection of step a), determining whether said subject suffering from cancer is susceptible to a combined treatment comprising administration of compound causing a decrease of intracellular pH, an inhibitor of mitochondrial respiration, and a proton ionophore.
  • a compound causing a decrease of intracellular pH for use in treatment of cancer with an inhibitor of mitochondrial respiration 41.
  • the compound causing a decrease of intracellular pH for use of embodiment 40 or the inhibitor of mitochondrial respiration for use of embodiment 41, wherein said compound causing a decrease of intracellular pH is a compound according to any one of embodiments 2 to 7.
  • the compound causing a decrease of intracellular pH for use of embodiment 40 or any one of embodiments 42 to 44 or the inhibitor of mitochondrial respiration for use of any one of embodiments 41 to 44, wherein said compound causing a decrease of intracellular pH is Simvastatin.
  • a combined preparation for simultaneous, separate or sequential use comprising (i) a compound causing a decrease of intracellular pH and (ii) an inhibitor of mitochondrial respiration.
  • a medicament comprising (i) a compound causing a decrease of intracellular pH and (ii) an inhibitor of mitochondrial respiration.
  • a method of treating cancer in a subject comprising administering to said subject
  • the cancer is pancreas cancer; colorectal cancer, preferably colon carcinoma; lung cancer, preferably non-small cell lung cancer; liver cancer; breast cancer; skin cancer, preferably melanoma; or Head and Neck cancer.
  • any one of embodiments 40 to 55 wherein said cancer is acute myeloid leukemia, acute lymphocytic leukemia, pancreatic cancer, chronic myelogenous leukemia, and non-Hodgkin's lymphoma, preferably is acute myeloid leukemia or pancreatic cancer, more preferably is acute myeloid leukemia.
  • Fig. 1 Western blots of cell extracts from cells of example 2 with antibodies against Sox4, beta- catenin (b-cat) and, as a control, tubulin (tub), in the presence (+) or absence (-) of Wnt3a.
  • Fig. 2 Effect of compounds of the present invention on the intracellular pH of cells; x-axis: treatment time in h, y-axis: intracellular pH (pHi).
  • Fig. 3 Effect of triple combined treatment on colony formation efficiency; A) DLD1 cancer cells, and B) MRC5 non-cancer cells were treated as indicated for 3 d. After treatment, 10 5 cells, respectively, were plated and assayed for colony formation for 7 (DLD1 cells) or 10 (MRC5 cells) days.
  • Fig. 4 Colon cancer DLD1 cells expressing pH-sensitive variant of GFP (EC-GFP) along with pH non-sensitive protein mCherry were used for live imaging to detect intracellular pH (pHi). Fluorometric measurement started 10 min after drug addition to the cells and was performed at indicated time points. Extracellular pH (pHe) was calorimetrically detected using Phenol Red. A) solvent control; B) Simvastatin 10 mM and Papaverine 8 mM.
  • Fig. 5 Effect of Drotaverine on the intracellular pH of cells; x-axis: treatment time in h, y-axis: intracellular pH (pHi) and extracellular pH (pHe), respectively..
  • Cancer cell viability was evaluated in cell culture experiments. Examples of treatment using various cancer cell lines and combinations of compounds shows a synergistic (cooperative) effect of the triple combinations in killing cancer cells (Tables 1, 3, 5-9, and 12-26), but not in non-cancer cells (Tables 2, 4, 10, and 11) under conditions of tumor microenvironment
  • indicated cells were treated with indicated drug combinations for 48 h or as indicated in conditions imitating tumor environment - RPMI supplemented with 10% FCS and 20 mM PIPES, adjusted to pH 6.5. After treatment, cells were analyzed for cell viability using CellTiter-Glo® Cell Viability Assay, Promega according manufacturer recommendations. For each treatment the fraction (%) of viable cells are indicated. Untreated viable cells were set to 100%. Each measurement represents the mean value of 4 biological replicates for each condition. Tablel : Synergistic killing of DLD1 cells.
  • Table 2 Minimal effect on survival in non-cancer 293T cells.
  • Table 8 Synergistic killing of MIA PaCa-2 cells. (Fenofibrate was used at 10 mM)
  • Example 2 Wnt signaling is inhibited by triple combination.
  • Lung cancer H1299 cells were treated with Wnt3a to induce wnt signaling. Induction was manifested by SOX4 protein appearance and b-catenin accumulation. Treatment with Monensin (5 nM), Metformin (1.5 mM), Fenofibrate (10 mM), or combination of all three drugs was done for 72 h, cell extracts were analyzed by Western blot (Fig. 1).
  • Example 3 Triple combination induces intracellular acidification.
  • Colon cancer DLD1 cells expressing pH-sensitive variant of GFP (EC-GFP) along with pH not sensitive protein mCherry were used for live imaging to detect intracellular pH. Fluorometric measurement started 1 h after drugs addition to the cells and performed at indicated time points. Monensin (5 nM), Metformin (1.5 mM), Fenofibrate (10 pM) (Fig. 2).
  • Example 4 Triple combination blocks colony formation of cancer cells but has minor effect on non-cancer cells.
  • Colon cancer DLD1 cells or non-cancer cells MRC5 were treated with indicated drugs for 3 days either alone or in combination with standard care drug Doxorubicin (10 nM, 24 h). Metformin 1.5 mM, Monensin 5 nM, Fenofibrate 10 pM. After 3 days treatment cells were harvested and total 40 000 cells per well were plated in triplicates. Cell colonies were quantitated 7 days after (DLD1 cells) of 10 days after (MRC5 cells) (Fig. 3), a quantitation of the results is provided in Table 27.
  • Example 5 Triple combination much better as double prevents tumors growth in vivo in colon cancer xenograft model.
  • Nude mice were xenografted with human colon cancer DLD1 cells. Once tumor size reached about 3 mm in longest dimension (palpable tumors), mice started receiving Metformin in drinking water (200 pg/ml) and a diet supplemented with Fenofibrate (1.25g/kg of diet) and Monensin (50mg/kg of diet). Monensin and Metformin were given in suboptimal dose to allow evaluation of cooperation with the third component (Fenofibrate) (Table 28). Tumor growth rate was calculated from multiple measurement of tumor size during 21 days of drugs treatment.
  • Table 29 Simvastatin and Papaverine cooperation in THP-1 cells.
  • Table 35 Low dose of Simvastatin and Papaverine combination enhance effect of standard care drug for AML - Cytarabine in colony forming assay
  • Drotaverine induces intracellular acidification.
  • Colon cancer DLD1 cells expressing pH-sensitive variant of GFP (EC-GFP) along with pH not sensitive protein mCherry were used for live imaging to detect intracellular pH as it was done in Example 3.
  • extracellular pH pHe, medium around cells
  • Phenol Red dye was measured in indicated time points by addition of Phenol Red dye to the same way prepared additional samples, using absorption ratio A414/A566.
  • Phenol Red dye was measured in indicated time points by addition of Phenol Red dye to the same way prepared additional samples, using absorption ratio A414/A566.
  • Phenol Red dye a distinct drop of pHi compared to the control.
  • Effects of Drotaverine in combination treatments on cancer and non-cancer cells To evaluate the effect of Drotaverine in combination with further compounds, cell viability was assayed in the presence of Drotaverine or combinations thereof essentially as described in Example 1. Results are shown in Tables 37 to 39.
  • Table 38 Minimal effect on viability of non-cancer primary human adult fibroblasts.

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Abstract

La présente invention concerne un composé provoquant une diminution du pH intracellulaire, destiné à une utilisation dans le traitement du cancer en association avec un inhibiteur de la respiration mitochondriale et un ionophore à protons ; un ionophore à protons destiné à être utilisé dans le traitement du cancer en association avec un inhibiteur de la respiration mitochondriale et un composé provoquant une diminution du pH intracellulaire ; et un inhibiteur de la respiration mitochondriale destiné à être utilisé dans le traitement du cancer en association avec un ionophore à protons et un composé provoquant une diminution du pH intracellulaire. La présente invention concerne également une préparation combinée pour une utilisation simultanée, séparée ou séquentielle comprenant (i) un composé provoquant une diminution du pH intracellulaire, (ii) un inhibiteur de la respiration mitochondriale, et (iii) un ionophore à protons, et une méthode permettant de déterminer si un patient atteint d'un cancer sera sensible à un traitement combiné comprenant l'administration d'un composé provoquant une diminution du pH intracellulaire, d'un inhibiteur de la respiration mitochondriale, et d'un ionophore à protons en lien avec ce cancer.
PCT/EP2020/064281 2019-05-23 2020-05-22 Traitement combiné contre le cancer ciblant le métabolisme énergétique et le ph intracellulaire WO2020234454A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113855690A (zh) * 2021-10-20 2021-12-31 南京农业大学 马度米星铵在制备抗乳腺癌药物中的应用
CN114903892A (zh) * 2021-02-09 2022-08-16 中国海洋大学 海洋Piericidin F及其衍生物在治疗宫颈癌中的应用
CN115414485A (zh) * 2022-09-30 2022-12-02 北京大学第一医院 uN2CpolyG蛋白抑制剂的用途

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101352444A (zh) * 2008-09-11 2009-01-28 中国科学院广州生物医药与健康研究院 雷公藤红素在制药中的新应用
WO2016201426A1 (fr) 2015-06-12 2016-12-15 Vettore, LLC Inhibiteurs de mct4 pour le traitement de maladies
EP3111931A1 (fr) * 2014-02-27 2017-01-04 National Cancer Center Composition pharmaceutique pour le traitement du cancer contenant du gossypol et de la phénformine en tant que principes actifs
WO2017216257A1 (fr) * 2016-06-15 2017-12-21 Deutsches Krebsforschungszentrum Traitement du cancer par ciblage simultané du métabolisme énergétique et du ph intracellulaire
WO2018044369A2 (fr) * 2016-05-19 2018-03-08 The Regents Of The University Of California Combinaison de trois médicaments (metformine, simvastatine, digoxine) pour le traitement ciblé du cancer du pancréas
US20180169242A1 (en) * 2016-12-19 2018-06-21 Shiner Pharm Corp. Pharmaceutical combination for cancer treatment and the therapeutic use thereof

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101352444A (zh) * 2008-09-11 2009-01-28 中国科学院广州生物医药与健康研究院 雷公藤红素在制药中的新应用
EP3111931A1 (fr) * 2014-02-27 2017-01-04 National Cancer Center Composition pharmaceutique pour le traitement du cancer contenant du gossypol et de la phénformine en tant que principes actifs
WO2016201426A1 (fr) 2015-06-12 2016-12-15 Vettore, LLC Inhibiteurs de mct4 pour le traitement de maladies
WO2018044369A2 (fr) * 2016-05-19 2018-03-08 The Regents Of The University Of California Combinaison de trois médicaments (metformine, simvastatine, digoxine) pour le traitement ciblé du cancer du pancréas
WO2017216257A1 (fr) * 2016-06-15 2017-12-21 Deutsches Krebsforschungszentrum Traitement du cancer par ciblage simultané du métabolisme énergétique et du ph intracellulaire
US20180169242A1 (en) * 2016-12-19 2018-06-21 Shiner Pharm Corp. Pharmaceutical combination for cancer treatment and the therapeutic use thereof

Non-Patent Citations (27)

* Cited by examiner, † Cited by third party
Title
"Remington's Pharmaceutical Sciences (book", MACK PUBLISHING COMPANY
CHEMICAL ABSTRACTS, Columbus, Ohio, US; abstract no. 1227158-85-1
DAMAGHI ET AL., FRONTIERS IN PHYSIOLOGY, vol. 4, 2013, pages 370
DEGLI ESPOSTI, BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1364, 1998, pages 222
DEYOUNG, DIABETES TECHNOLOGY & THERAPEUTICS, vol. 13, 2011, pages 1145
DOWDYWEARDEN: "Statistics for Research (Book", 1983, JOHN WILEY & SONS
FORETZ ET AL., CELL METABOLISM, vol. 20, 2014, pages 953
G.S. SITTAMPALAM AT AL.: "Assay Guidance Manual (Book", 2016
GOMEZ-MILLAN ET AL., BMC CANCER, vol. 14, 2014, pages 192
HATHER ET AL., CANCER INFORM, vol. 13, no. 4, 2014, pages 65
IOANA Z. PAVEL ET AL: "Drotaverine - a Concealed Cytostatic! : Drotaverine", ARCHIV DER PHARMAZIE, vol. 350, no. 1, 1 January 2017 (2017-01-01), Weinheim, pages e1600289, XP055719234, ISSN: 0365-6233, DOI: 10.1002/ardp.201600289 *
JANZER A. ET AL., PNAS, vol. 111, no. 29, 2014, pages 10574 - 9
KIM M.R. ET AL., CHEM. COMM. (CAMB, vol. 46, 2010, pages 7433
LAGADIC-GOSSMANN ET AL., CELL DEATH AND DIFFERENTIATION, vol. 11, 2004, pages 953 - 961
LI ET AL., ONCOTARGET, vol. 6, 2015, pages 7365
LIBERTILOCASALE, TRENDS BIOCHEM SCI, vol. 41, no. 3, 2016, pages 211
LIU ET AL., ONCOLOGY REPORTS, vol. 28, 2012, pages 1406
MARSH ET AL., NUTR METAB (LOND, vol. 5, 2008, pages 33
RAMAZANI ET AL., INT J PHARM., vol. 499, no. 1-2, 2016, pages 358 - 367
RUSSEL ET AL., NAT BIOTECHNOL., vol. 30, no. 7, 2012, pages 658
SINGH ET AL., STRAHLENTHER ONKOL., vol. 181, no. 8, 2005, pages 507 - 14
SONG ET AL., SCIENTIFIC REPORTS, vol. 2, 2012, pages 362
UENO KAORI ET AL: "Different rate-limiting activities of intracellular pH regulators for HCO3-secretion stimulated by forskolin and carbachol in rat parotid intralobular ducts", JOURNAL OF PHYSIOLOGICAL SCIENCES, SPRINGER JAPAN KK, JP, vol. 66, no. 6, 11 March 2016 (2016-03-11), pages 477 - 490, XP036068137, ISSN: 1880-6546, [retrieved on 20160311], DOI: 10.1007/S12576-016-0443-6 *
VINCENT ET AL., ONCOGENE, vol. 34, no. 28, 2015, pages 3627 - 39
WU ET AL., SCIENTIFIC REPORTS, vol. 5, 2015, pages 10147
ZHANG ET AL., JOURNAL OF HEMATOLOGY & ONCOLOGY, vol. 9, 2016, pages 91
ZHIGUANG XIAO ET AL: "Metformin and salinomycin as the best combination for the eradication of NSCLC monolayer cells and their alveospheres (cancer stem cells) irrespective of EGFR, KRAS, EML4/ALK and LKB1 status", ONCOTARGET, vol. 5, no. 24, 30 December 2014 (2014-12-30), pages 12877 - 12890, XP055397598, DOI: 10.18632/oncotarget.2657 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114903892A (zh) * 2021-02-09 2022-08-16 中国海洋大学 海洋Piericidin F及其衍生物在治疗宫颈癌中的应用
CN113855690A (zh) * 2021-10-20 2021-12-31 南京农业大学 马度米星铵在制备抗乳腺癌药物中的应用
CN115414485A (zh) * 2022-09-30 2022-12-02 北京大学第一医院 uN2CpolyG蛋白抑制剂的用途
CN115414485B (zh) * 2022-09-30 2024-02-27 北京大学第一医院 uN2CpolyG蛋白抑制剂的用途

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