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WO2018138510A1 - Mébendazole utilisé dans le traitement du cancer - Google Patents

Mébendazole utilisé dans le traitement du cancer Download PDF

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Publication number
WO2018138510A1
WO2018138510A1 PCT/GB2018/050222 GB2018050222W WO2018138510A1 WO 2018138510 A1 WO2018138510 A1 WO 2018138510A1 GB 2018050222 W GB2018050222 W GB 2018050222W WO 2018138510 A1 WO2018138510 A1 WO 2018138510A1
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ran
cancer
mebendazole
inhibitor
tyrosine kinase
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PCT/GB2018/050222
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Mohamed EL-TANANI
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University Of Bradford
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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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • 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
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to mebendazole or a pharmaceutically acceptable form thereof for use as an inhibitor of RAN, for example for use in the treatment of a cancer that overexpresses RAN or its protein product Ran.
  • Overexpression of RAN may be characteristic of the cancer type or may be stimulated by prior cancer therapy.
  • Neoplasm can be benign or malignant (cancerous) and are often referred to as tumours.
  • tumour is used to refer to malignant (cancerous) neoplasms.
  • tumours and the treatment of cancer have the same meaning herein, while reference to breast cancer or breast tumour, and treatment thereof, refers to a cancer or tumour that originates in the breast, or treatment thereof, rather than a tumour that originates in another organ and that has spread to the breast through the process of metastasis.
  • Tumours or cancers that originate in other organs or sites are referred to in a similar manner.
  • Tumours that are derived from the process of metastasis are referred to as metastases or secondary tumours.
  • cancer cells stimulate their own growth; (ii) cancer cells resist inhibitory signals that might otherwise stop their growth; (iii) cancer cells resist their programmed ceil death (they evade apoptosis); (iv) cancer ceils can multiply indefinitely; (v) cancer ceils stimulate the growth of blood vessels to supply nutrients to tumours (angiogenesis); and (vi) cancer ceils invade local tissue and spread to distant sites (metastasis).
  • cancer ceils Whether or not the full set of hallmarks, that have subsequently been supplemented ("Hallmarks of Cancer; The Next Generation" Cell 44 (5): 646-674), are exhibited by all cancers, it is apparent that targeting one or more of these hallmarks affords an opportunity to exert a selective killing effect on cancer cells.
  • Cancer cells are addicted to oncogenes or oncogenic pathways (Weinstein, Science 2002;297:83-4), which are usually uniquely present or hyperactivated, and are essential for tumour ceil growth and survival.
  • the two most frequently dysreguiated signaling pathways in cancers are the phosphoinositide 3-kinase (PI3K)/Akt/mTQRC1 and Ras/ EK/ERK [mitogen- activated protein/extracellular signal-regulated kinase (ERK; EK)] pathways (Grant, J Clin invest 2008; 1 13:3003-8).
  • Tumours or cancers are commonly referred to by the primary site of their occurrence, i.e. where the tumour first develops, and often also by reference to further characteristics, for example whether their growth is stimulated by hormones or whether they express certain receptors.
  • primary tumours located in the breast are referred to breast cancers while tumours whose growth is stimulated by hormones such as estrogen, progesterone and testosterone are referred to as hormone dependent cancers.
  • breast cancers whose growth is stimulated by the presence of estrogen are known as estrogen receptor positive (ER+ve) breast cancers.
  • ER+ve estrogen receptor positive
  • progesterone receptor positive (PR+ve) breast cancers breast cancers that express progesterone receptors and whose growth is sensitive to the presence of progesterone are referred to as progesterone receptor positive (PR+ve) breast cancers whilst those whose growth is independent of the expression of progesterone receptor are progesterone receptor negative (PR-ve) breast cancers.
  • HER2-positive breast cancer a subset of breast cancers that overexpress human epidermal growth factor 2.
  • HER2 targeted therapies examples include the anti-HER2 antibodies trastuzumab and pertuzumab and the antibody-drug-conjugate trastuzumab emtansine.
  • triple negative breast cancers those tumour types whose growth is independent of ER, PR or HER2 status, are commonly referred to as triple negative breast cancers. Patients suffering from triple negative breast cancers presently have the worst overall and disease-free survival rates. Treatment options for patients with triple negative breast tumours are relatively limited (Ontilo et al, Clin Med Res. 2009 Jun; 7(1-2): 4-13) with the present treatment paradigms usually involving a combination of surgery and radiation as appropriate with cytotoxic chemotherapy with agents such as anthracyclines, taxanes or platinum chemotherapeutic agents, such as carboplatin, unless the patient has a tumour with a BRCA1 mutation.
  • cytotoxic chemotherapy with agents such as anthracyclines, taxanes or platinum chemotherapeutic agents, such as carboplatin, unless the patient has a tumour with a BRCA1 mutation.
  • Tyrosine kinases are enzymes responsible for the activation, via phosphorylation, of many proteins by signal transduction cascades. Inhibition of tyrosine kinases has proven to be a successful therapeutic approach from the treatment of a number of cancer types and drugs that selectively inhibit specific tyrosine kinases have been developed.
  • the Bcr- Abl tyrosine kinases inhibitor nilotinib is used to treat chronic myelogenous leukaemia
  • the epidermal growth factor receptor tyrosine kinase (EGFR/ ErbB-1) inhibitor gefitinib is used for the treatment of certain breast and lung cancers, especially for patient with EGFR mutations.
  • RAN a member of the RAS Oncogene family
  • RAS Oncogene is a gene that encodes the GTP-binding nuclear protein Ran.
  • Overexpression of RAN gene is observed in a number of cancers and this overexpression has been linked to poor patient prognosis.
  • RAN overexpression has been shown to correlate with increased aggressiveness of cancer cells in vitro and in vivo (Kurisetty et al, Oncogene 2008, 27, 7139-49), i.e. RAN overexpressing cancer cells are seen to grow rapidly and exhibit high metastatic potential.
  • silencing RAN by siRNA or shRNA reduced cell adhesion, migration and invasion in vitro and metastasis in vivo.
  • RAN silencing the RAN gene with siRNA or shRNA induces a greater degree of apoptosis in cancer cells relative to that induced in normal cells and in activated KRas-mutant cells relative to their isogenic KRas wild-type counterparts. Cancer cells are observed to be more sensitive to changes in RAN status than their normal counterparts. RAN silencing has also been observed to promote apoptosis in cancer cells with mutations that correlate with activation of the PI3K/Akt/mTORC1 and Ras/MEK/ERK signalling pathways (Yuen et al, Clin Cancer Res 201 1 ; 18(2); 1-12). As a result, RAN has been suggested as a potential therapeutic target for cancer phenotypes in which the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways are activated.
  • Ran Ras-related nuclear protein, a 25-kDa protein product encoded by RAN gene, is a G- protein GTPase that cycles between a GDP-bound (RanGDP) and a GTP-bound (RanGTP) state that regulates nucleocytoplasmic transport, mitotic spindle fibre assembly and post- mitotic nuclear envelope dynamics.
  • Ran exists in a different conformation depending on whether it is bound to GTP or GDP. in its GTP bound state, Ran is capable of binding karyopherins (importins and exportins) a set of proteins that are involved in importing and exporting molecules between the nucleus and the cytoplasm of a eukaryotic ceil, importins release a molecular cargo upon binding to RanGTP in the nucleus, while exportins must bind RanGTP in the nucleus to form a ternary complex with their export cargo in order to transport the cargo to the cytoplasm.
  • karyopherins importins and exportins
  • the dominant nucleotide binding state of Ran depends on whether it is located in the nucleus (RanGTP) or the cytoplasm (RanGDP), with RanGTP being formed inside the nucleus through interaction of Ran with its specific guanine nucleotide exchange factor (GEF), regulator of chromosome condensation 1 referred to herein as RCC1 , which catalyses the exchange of GDP for GTP on the nucleotide binding pocket of Ran.
  • GEF guanine nucleotide exchange factor
  • RCC1 regulator of chromosome condensation 1
  • Hydrolysis of RanGTP to RanGDP in the cytoplasm by RanGAP and RanBPI releases energy and causes the ternary complex of Ran, exportin and cargo to dissociate thus releasing the cargo exported from the nucleus.
  • Cytoplasmic RanGDP is in turn imported into the nucleus by the small protein NTF2 (Nuclear Transport Factor 2), where RCC1 can then catalyse exchange of GDP for GTP on Ran and
  • the Ran cycle is involved in mitotic spindle assembly and nuclear envelope reassembly after the chromosomes have been separated.
  • the steep gradient in RanGTP-RanGDP ratio at the nuclear pores breaks down as the nuclear envelope becomes leaky and disassembles.
  • RanGTP concentration stays high around the chromosomes as RCC1 stays attached to chromatin as the nucleoporin RanBP2 (Nup358) and Ran GTPase activating protein (RanGAP) move to the kinetochores where they facilitate the attachment of spindle fibres to chromosomes.
  • RanGTP promotes spindle assembly by mechanisms similar to mechanisms of nuclear transport: the activity of spindle assembly factors such as NuMA and TPX2 is inhibited by the binding to importins. By releasing importins, RanGTP activates these factors and therefore promotes the assembly of the mitotic spindle.
  • RanGTP hydrolysis and nucleotide exchange are required for vesicle fusion at the reforming nuclear envelopes of the daughter nuclei.
  • Ran expression was independently associated with patient survival times in Cox-regression analyses.
  • Stable transfection of non-invasive mammary cells with an expression vector for Ran (R37-Ran and MCF-1 OA-Ran) was found to induce an invasive/metastatic phenotype in vitro and the development of metastases in vivo (Kurisetty VV, El-Tanani MK et al. Oncogene. 2008,27(57) :7139-49).
  • Stable transfection of invasive cells MDA-MB-231 , R37-OPN and R37-RAN
  • siRNA directed at Ran specifically inhibits the invasive/metastatic phenotype in vitro and in vivo (Kurisetty VV, El-Tanani MK et al. Oncogene.
  • Ran silencing was found to induce a significant apoptotic response in GR5 c-Met amplified cells in the presence of gefitinib, but not in HCC827 parental cells (p ⁇ 0.01), suggesting that Ran silencing may be used as a modulator of chemosensitivity (Yuen HF, El-Tanani M, et al. J Natl Cancer Inst. 2013; 105(7):475-88).
  • TKI EGFR tyrosine kinase inhibitors
  • Osimertinib was developed to treat T790M mutation-positive NSCLCs. Exploration of novel approaches to further enhance the therapeutic efficacy of TKIs in such patient cohorts aimed at improving progression-free and overall survival times remains an important challenge.
  • Diseases overexpressing RAN include but are not limited to certain breast, lung, prostate, ovarian, blood, brain and renal cancers as well as certain cancers currently associated with poor patient prognosis such as triple negative breast cancer.
  • mebendazole or a pharmaceutically acceptable form thereof, for use as an inhibitor of RAN at a transcriptional level.
  • the mebendazole for use as an inhibitor of RAN at a transcriptional level is for use in the treatment of cancer, for example a cancer that overexpresses RAN or its protein product Ran.
  • the mebendazole for use as an inhibitor of RAN at a transcriptional level in the treatment of cancer is for use in patients identified as having a cancer that overexpresses RAN, for example a cancer that overexpresses Ran mRNA, or its protein product Ran.
  • the mebendazole for use is used in the treatment of breast, lung, prostate, ovarian, blood, brain and renal cancers including those cancers currently associated with poor patient prognosis such as triple negative breast cancer.
  • a cancer that overexpresses RAN may overexpress Ran mRNA and/or Ran protein and may be identified, for example, by establishing that elevated levels of Ran mRNA and/or Ran protein are present in the cancer cells. Note that not all cancers within a particular cancer type or sub-type will overexpress RAN.
  • the invention also provides a Ran inhibitor, i.e. a compound capable of inhibiting RAN, for example at a transcriptional level, or its protein product Ran, for example a small molecule inhibitor of RAN at a transcriptional level such as mebendazole or pimozide (as described in UK patent application No. GB1616880.9) or a protein inhibitor of the Ran / RCC-1 interaction (as described in UK patent application No. GB1607593.9), for use in combination with a tyrosine kinase inhibitor, such as a small molecule or an antibody tyrosine kinase inhibitor, for the treatment of cancer.
  • a tyrosine kinase inhibitor such as a small molecule or an antibody tyrosine kinase inhibitor
  • tyrosine kinase inhibitors that may be used in combination with a RAN inhibitor for the treatment of cancer include afatinib (GiotrifTM), axitinib (InlytaTM), bosutinib (BosulifTM), crizotinib (XalkoriTM), dasatinib (SprycelTM), erlotinib (Tarceva), gefitinib (IressaTM), osimertinib (TagrissoTM), imatinib (GlivecTM), lapatinib (TyverbTM), nilotinib (TasignaTM), pazopanib (VotrientTM), regorafenib (StivargaTM), sorafenib (NexavarTM), sunitinib (SutentTM) and ibrutinib (ImbruvicaTM).
  • afatinib GaotrifTM
  • the inhibitor of RAN for use with a tyrosine kinase inhibitor is an inhibitor of RAN at a transcriptional level such as mebendazole.
  • mebendazole is used as an inhibitor of RAN in combination with an inhibitor of an epidermal growth factor receptor (EGFR) tyrosine kinase such as the small molecules gefitinib, erlotinib, afatinib, brigatinib, icotinib, or osimertinib or the antibodies cetuximab, panitumumab, zalutumumab, nimotuzumab, or matuzumab.
  • EGFR epidermal growth factor receptor
  • EGFR inhibitors Molecules and antibodies that inhibit epidermal growth factor receptor (EGFR) tyrosine kinase are generally referred to herein as EGFR inhibitors.
  • the co-administration of mebendazole and an EGFR inhibitor may be simultaneous, sequential or separate. It has been demonstrated that the combination of mebendazole and an EGFR inhibitor has a synergistic effect against cancer cell proliferation. It has also been shown that mebendazole can restore sensitivity of gefitinib resistant cancer cells to gefitinib treatment therefore providing a new therapeutic approach for the treatment of patients who have progressed on EGFR inhibitor therapy and, potentially, a new mechanism to prevent development of EGFR inhibitor resistance.
  • Identification of the patients indicated for mebendazole treatment i.e. those having a cancer that overexpresses RAN, its protein product Ran or its target pathways including c-myc, c- Met, osteopontin, PI3K/AKT/mTORC and KRas/MEK/ERK1/2 may be achieved by obtaining a sample from the candidate patient, for example a tumour biopsy or a blood sample, and analysing the sample for high expression of Ran mRNA or protein or a biomarker for Ran expression.
  • the patient identification may involve testing for c- Met amplification, PI3K/AKT/mTORC and KRas/MEK/ERK1/2 or mutation status of a tyrosine kinase such as EGFR.
  • a tumour biopsy sample can be stained with a stain comprising a RAN selective antibody linked to a visualising means such as an enzyme or fluorophore.
  • the stained tumour biopsy can then be categorised as a RAN overexpressing tumour or a non-RAN overexpressing tumour. This categorisation can be done by a visual or automated scoring.
  • Testing for tyrosine kinase mutation status can be by the methods available in the art, for example the commercially available testing kits produced by Genzyme, QIAGEN and Argenomics S.A.
  • Analysis of a patient blood sample to determine whether a patient has a RAN overexpressing tumour may be performed by isolating the serum exosome and then carrying out an ELISA (to assess Ran protein expression) or quantitative real time PCR (q RT-PCR, to detect RNA expression) analysis to provide the necessary tumour/patient classification.
  • the patient is a human patient.
  • the mebendazole for use is administered in a dosage of from 1 to 5000 mg/day.
  • the invention also relates to a method of treatment of a cancer that overexpresses RAN (or Ran mRNA) or its protein product Ran, comprising a step of administering to a patient in need thereof an effective amount of mebendazole or a pharmaceutically acceptable form thereof.
  • This method of treatment may further comprise a step of testing a sample obtained from said patient to determine whether said patient has a RAN overexpressing cancer prior to said administration step.
  • the invention also provides a method of treatment of a cancer that overexpresses RAN (or Ran mRNA), or its protein product Ran, comprising the step of administering to a patient who has been identified as having a cancer that overexpresses RAN, or its protein product Ran, an effective amount of mebendazole or a pharmaceutically acceptable form thereof.
  • This method of treatment may further comprise a step of testing a sample obtained from said patient to determine whether said patient has a RAN overexpressing cancer prior to said administration step.
  • the invention also provides a method of treatment of a cancer that overexpresses RAN, (or Ran mRNA) or its protein product Ran, comprising the steps of selecting a patient who has a cancer that overexpresses RAN or its protein product Ran, and administering an effective amount of mebendazole or a pharmaceutically acceptable form thereof to that patient.
  • This method of treatment may further comprise a step of testing a sample obtained from said patient to determine whether said patient has a RAN overexpressing cancer prior to said administration step.
  • the invention also provides a method of treatment for cancer in a patient diagnosed as having a cancer characterised by an overexpression of RAN or its protein product Ran involving administration to a patient in need thereof an effective amount of mebendazole.
  • the cancer characterised by an overexpression of RAN may be triple negative breast cancer.
  • the cancer characterised by an overexpression of RAN may be lung cancer, and in particular lung cancers that have previously been treated with a tyrosine kinase inhibitor, for example wherein the previous treatment involved administration of an tyrosine kinase inhibitor such as an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor such as gefitinib, erlotinib, afatinib, brigatinib, icotinib or osimertinib to a lung cancer patient and wherein the disease no longer responds to the treatment with the EGFR inhibitor.
  • EGFR epidermal growth factor receptor
  • Such methods may involve co- administration of the previously used tyrosine kinase inhibitor with a Ran inhibitor, in particular wherein the Ran inhibitor is mebendazole.
  • the invention also provides a method of treatment for cancer in a patient diagnosed as having a cancer characterised by an overexpression of a tyrosine kinase, such as a mutated tyrosine kinase, such as epidermal growth factor receptor (EGFR) tyrosine kinase, involving administering mebendazole in combination with an inhibitor of the tyrosine kinase that is overexpressed, for example in a cancer with a mutation in the EGFR tyrosine kinase domain, an EGFR inhibitor may be used.
  • the administration of mebendazole and an EGFR inhibitor may be simultaneous, sequential or separate.
  • the combination of mebendazole and an EGFR inhibitor may prevent or substantially delay the emergence of resistance to the EGFR inhibitor associated with EGFR inhibitor monotherapy.
  • the combination of mebendazole and an EGFR inhibitor may resensitize a tumour to treatment with an EGFR inhibitor to which the patient no longer responds as a monotherapy.
  • the invention also provides mebendazole for use as an immunotherapy, for example for the treatment of cancer, for instance by down regulating C5a.
  • the invention relates to the use of mebendazole, or a pharmaceutically acceptable form thereof, for the manufacture of a medicament for the treatment of cancer, optionally wherein the cancer overexpresses RAN or its protein product Ran.
  • the resultant medicament may be provided in a package with instruction for use in the treatment of a cancer that overexpresses RAN or its protein product Ran.
  • the resultant medicament may be provided in a package with instruction for use in combination with an EGFR inhibitor such as gefitinib.
  • the invention provides a package comprising mebendazole or a pharmaceutically acceptable form thereof and instructions for its use in the treatment of a cancer that overexpresses RAN or its protein product Ran or instructions for its use in the treatment of a cancer that overexpresses epidermal growth factor receptor (EGFR) tyrosine kinase.
  • EGFR epidermal growth factor receptor
  • Figure 1 shows the effects of drug treatment on A) cell morphology and B) survival of HCC827 lung cancer cells on exposure to control (DMSO), mebendazole (0.1 ⁇ , 0.5 ⁇ , 1 ⁇ ), gefitinib (1 ⁇ ) and dasatinib (1 ⁇ ) and combinations of gefitinib and dasatinib with mebendazole.
  • Figure 2 shows the effects of drug treatment on A) cell morphology and B) survival of HCC827 GR5 (gefitinib resistant) lung cancer cells on exposure to control (DMSO), mebendazole (0.1 ⁇ , 0.5 ⁇ , 1 ⁇ ), gefitinib (1 ⁇ ) and dasatinib (1 ⁇ ) and combinations of gefitinib and dasatinib with mebendazole.
  • DMSO control
  • mebendazole 0.1 ⁇ , 0.5 ⁇ , 1 ⁇
  • gefitinib (1 ⁇ ) and dasatinib (1 ⁇ ) and combinations of gefitinib and dasatinib with mebendazole.
  • Figure 3 shows the relative gene expression (fold change) in HCC827 cells treated with mebendazole (0.1 ⁇ , 0.5 ⁇ ) for 24h relative to control.
  • Figure 4 shows the relative gene expression (fold change) in HCC827 GR5 (gefitinib resistant) cells treated with mebendazole (0.1 ⁇ , 0.5 ⁇ ) for 24h relative to control.
  • Figure 5 show the results of immunoblotting for A) Ran (28 kDa, rabbit, 1 :3000 dil in 5% milk powder), B) pBad (27 kDa, mouse, 1 :3000 dil in 5% BSA), C) Actin (40 kDa, mouse, 1 : 10 000 dil in 5% milk powder) in the lysate obtained from HCC827 GR5 cells treated with 1) Control (DMSO), 2) 1 ⁇ Gefitinib, 3) 300 nM osimertinib, 4) 100 nM mebendazole, 5) 100 nM mebendazole + 1 ⁇ Gefitinib, 6) 100 nM mebendazole + 300 nM osimertinib, 7) 500 nM mebendazole, 8) 500 nM mebendazole + 1 ⁇ Gefitinib and 9) 500 nM mebendazole + 300 nM os
  • Figure 6 shows the effect on HCC827 human cancer cell survival following treatment with A) gefitinib, B) pimozide and C) various concentrations of pimozide in combination with 300 nM gefitinib.
  • Figure 7 shows the effect on HCC827 GR5 (gefitinib resistant) human cancer cell survival following treatment with A) gefitinib B) pimozide and C) various concentrations of pimozide in combination with 300 nM gefitinib.
  • the present invention relates to mebendazole, or a pharmaceutically acceptable form thereof, for use as a Ran inhibitor for the treatment of cancer, for example in patients identified as having a cancer that overexpresses RAN or Ran, for example a cancer in which atypically high elevated levels of Ran mRNA and/or Ran protein are present in the cancerous cells.
  • Ran a protein product of the gene RAN, is a member of the Ras superfamily that regulates nucleocytoplasmic transport, mitotic spindle fibre assembly and post-mitotic nuclear envelope dynamics. Ran acts as a molecular switch through a GTP-GDP cycle in which the conversion between GTP-bound and GDP-bound conformations controls its interaction with different effectors.
  • RanGTP is formed inside the nucleus by interaction of Ran with its specific guanine nucleotide exchange factor (GEF), referred to herein as RCC1 , which catalyses the exchange of GDP for GTP (and vice versa) on the nucleotide binding pocket of Ran.
  • GEF guanine nucleotide exchange factor
  • RAN, and its protein product Ran are known to be overexpressed in a number of cancers including those in which the PI3K/Akt/mTORC1 and Ras/MEK/ERK pathways are activated.
  • Diseases overexpressing Ran include but are not limited to certain breast, lung, prostate, ovarian, blood, brain and renal cancers as well as certain cancers currently associated with poor patient prognosis such as triple negative breast cancer.
  • Mebendazole methyl (5-benzoyl-1 H-benzimidazol-2-yl)carbamate (Formula I below), is a broad spectrum antihelmintic drug sold under trade names such as VermoxTM and EmvermTM indicated for the treatment of nematode infestations, including roundworm, hookworm, whipworm, threadworm, pinworm, and the intestinal form of trichinosis prior to its spread into the tissues beyond the digestive tract.
  • mebendazole as an antihelmintic agent is thought to stem from selective inhibition of the synthesis of microtubules in parasitic worms through binding at the colchicine site of tubulin. Destruction of extant cytoplasmic microtubes in the worm intestinal cells, blocks the uptake of glucose and other nutrients, resulting in the gradual immobilization and eventual death of the helminths.
  • mebendazole has activity against the proliferation of cancers cells in in vivo and in vitro models of cancer (see e.g. Mukhopadhyay et al, Clin Cancer Res 8(9) 2963-9).
  • mebendazole could inhibit RAN or production of its protein product Ran, nor was it known that mebendazole inhibits RAN at a transcriptional level.
  • the identification of mebendazole as a Ran inhibitor that acts by inhibiting RAN at a transcriptional level, thereby suppressing the downstream effects of the RAN gene, for example Ran mRNA expression provides a new and advantageous option for therapy of patients with cancers that overexpress RAN or its protein product Ran.
  • the present invention advantageously allows identification of groups of cancer patients that are indicated for mebendazole treatment and advantageously allows a therapeutic intervention for such patients that is targeted to the genetic profile of their cancer.
  • the present invention thus potentially provides for improved therapeutic outcomes for cancer patients with cancers including solid and blood cancers (including solid and blood cancers, e.g. acute lymphoblastic leukaemia, acute myeloid leukaemia, chronic lymphocytic leukaemia, chronic myeloid leukaemia, lymphoma and myeloma) that overexpress RAN and its protein product Ran.
  • solid and blood cancers including solid and blood cancers, e.g. acute lymphoblastic leukaemia, acute myeloid leukaemia, chronic lymphocytic leukaemia, chronic myeloid leukaemia, lymphoma and myeloma
  • the invention provides mebendazole, or a pharmaceutically acceptable form thereof, for use as an inhibitor of RAN at a transcriptional level.
  • the mebendazole for use as an inhibitor of RAN at a transcriptional level is for use in the treatment of cancer, for example a cancer that overexpresses RAN or its protein product Ran.
  • the mebendazole for use as an inhibitor of RAN at a transcriptional level in the treatment of cancer is for use in patients identified as having a cancer that overexpresses RAN or its protein product Ran.
  • cancer types that are known to overexpress RAN or its protein product Ran, and for which mebendazole as a Ran inhibitor is indicated for use include, but are not limited to certain breast, lung, prostate, ovarian, bladder, colorectal, blood, brain and renal cancers as well as certain cancers currently associated with poor patient prognosis such as triple negative breast cancer.
  • the selection of patients to be treated with mebendazole for use according to the invention is advantageously performed by establishing that they have a cancer that overexpresses RAN or its protein product Ran. This selection may be performed by obtaining a sample from the candidate patient, for example a tumour biopsy or a blood sample, and analysing the sample for the presence of RAN or a biomarker for RAN expression.
  • a tumour biopsy sample can be stained with a stain comprising a RAN selective antibody linked to a visualising means such as an enzyme or fluorophore.
  • the stained tumour biopsy can then be categorised as a RAN overexpressing tumour or a non-RAN overexpressing tumour. This categorisation can be done by a visual or automated scoring.
  • the present invention also relates to a Ran inhibitor, for example mebendazole, for use in combination with a tyrosine kinase inhibitor, for example a receptor tyrosine kinase inhibitor such as an inhibitor of EGFR tyrosine kinase or a non-receptor tyrosine kinase inhibitor such as a Bcr-Abl kinase inhibitor, for the treatment of cancer.
  • a tyrosine kinase inhibitor for example a receptor tyrosine kinase inhibitor such as an inhibitor of EGFR tyrosine kinase or a non-receptor tyrosine kinase inhibitor such as a Bcr-Abl kinase inhibitor
  • receptor tyrosine kinases inhibitors that may be used in combination with a Ran inhibitor such as mebendazole include inhibitors of PDGFR and FGFR kinases.
  • Other non-receptor tyrosine kinases inhibitors that may be used in combination with a Ran inhibitor such as mebendazole include inhibitors of SRC, FAK and JAK.
  • Other Ran inhibitors such as small molecule, peptide, protein or antibody inhibitors of Ran, may be used in conjunction with a tyrosine kinase inhibitor.
  • a new approach for the treatment of cancers that are indicated for tyrosine kinase inhibitor therapy involves co-administration of the appropriate tyrosine kinase inhibitor with a Ran inhibitor.
  • the Ran inhibitor may be a small molecule inhibitor of RAN at a transcriptional level such as mebendazole or pimozide, a peptide inhibitor of the Ran / RCC- 1 interaction or an antibody.
  • the tyrosine kinase inhibitor may be as a small molecule or an antibody tyrosine kinase inhibitor.
  • tyrosine kinase inhibitors that may be used in combination with a Ran inhibitor for the treatment of cancer include afatinib (GiotrifTM), axitinib (InlytaTM), bosutinib (BosulifTM), crizotinib (XalkoriTM), dasatinib (SprycelTM), erlotinib (Tarceva), gefitinib (IressaTM), osimertinib (TagrissoTM), imatinib (GlivecTM), lapatinib (TyverbTM), nilotinib (TasignaTM), pazopanib (VotrientTM), regorafenib (StivargaTM), sorafenib (NexavarTM), sunitinib (SutentTM) and ibrutinib (ImbruvicaTM).
  • afatinib GaotrifTM
  • the Ran inhibitor for use with a tyrosine kinase inhibitor is an inhibitor of RAN at a transcriptional level such as mebendazole.
  • the co-administration of a Ran inhibitor and tyrosine kinase inhibitor may be simultaneous, sequential or separate.
  • c-MET amplification which leads to activation of the PI3K/AKT and MEK/ERK pathway promotes gefitinib resistance in lung cancer cells.
  • Gefitinib-resistant cells, with c-Met amplification have been shown to have an increased apoptotic response to Ran silencing compared to their wild-type counterparts, indicating that cells with c-MET amplification are more susceptible to apoptosis in the presence of Ran silencing. These results were confirmed using a MTT cell survival assay. Furthermore, inhibition of the PI3K/AKT and RAS/MEK/ERK pathways significantly reduced c-MET-mediated sensitization to Ran knock-down (p ⁇ 0.01).
  • mebendazole is used as an inhibitor of RAN in combination with an inhibitor of an epidermal growth factor receptor (EGFR) tyrosine kinase such as the small molecules gefitinib, erlotinib, afatinib, brigatinib, icotinib, or osimertinib or the antibodies cetuximab, panitumumab, zalutumumab, nimotuzumab, or matuzumab.
  • EGFR inhibitors an enzyme that inhibit epidermal growth factor receptor (EGFR) tyrosine kinase.
  • mebendazole and an EGFR inhibitor may be simultaneous, sequential or separate. It has been demonstrated that the combination of mebendazole and an EGFR inhibitor, namely gefitinib, has a synergistic effect against cancer cell proliferation (see Figure 1). It has also been shown that mebendazole can restore sensitivity of gefitinib resistant cancer cells to gefitinib treatment therefore providing a new therapeutic approach for the treatment of patients who have progressed on EGFR inhibitor therapy and, potentially, a new mechanism to prevent development of EGFR inhibitor resistance (see Figure 2).
  • the Ran inhibitor mebendazole can eradicate the induction of Ran stimulated by the EGFR inhibitors gefitinib and osimertinib thus indicating that co-administration of a Ran inhibitor with a tyrosine kinase inhibitor may overcome or substantially delay acquired resistance to tyrosine kinase inhibitor therapy.
  • Identification of the patients indicated for combination therapy with a Ran inhibitor and a tyrosine kinase inhibitor may involve testing for mutation status of a tyrosine kinase such as EGFR. Testing for tyrosine kinase expression/mutation status can be by the methods available in the art, for example the commercially available testing kits produced by Genzyme, QIAGEN and Argenomics S.A. for predicting response to the various tyrosine kinase inhibitors.
  • mebendazole can down regulate C5a ( Figures 3 and 4). This finding indicates that mebendazole may be used to potentiate or promote an innate immune response to cancer cells/tumours.
  • the invention thus provides mebendazole for use to potentiate or promote any innate immune response to cancer cells/tumours (i.e. as an immunotherapy) for the treatment of cancer via to its ability to down regulate C5a.
  • the patient is a mammal and in most preferred cases the patient is a human patient.
  • the mebendazole for use is administered in a dosage of from 1 to 5000 mg/day.
  • the invention also relates to a method of treatment of a cancer that overexpresses RAN, or its protein product Ran or Ran mRNA, comprising a step of administering to a patient in need thereof an effective amount of mebendazole or a pharmaceutically acceptable form thereof.
  • This method of treatment may further comprise a step of testing a sample obtained from said patient to determine whether said patient has a RAN overexpressing cancer prior to said administration step.
  • the invention also provides a method of treatment of a cancer that overexpresses RAN, or its protein product Ran or Ran mRNA, comprising the step of administering to a patient who has been identified as having a cancer that overexpresses RAN, or its protein product Ran, an effective amount of mebendazole or a pharmaceutically acceptable form thereof.
  • This method of treatment may further comprise a step of testing a sample obtained from said patient to determine whether said patient has a RAN overexpressing cancer prior to said administration step.
  • the invention also provides a method of treatment of a cancer that overexpresses RAN, or its protein product Ran or Ran mRNA, comprising the steps of selecting a patient who has a cancer that overexpresses RAN or its protein product Ran or Ran mRNA, and administering an effective amount of mebendazole or a pharmaceutically acceptable form thereof to that patient.
  • This method of treatment may further comprise a step of testing a sample obtained from said patient to determine whether said patient has a RAN overexpressing cancer prior to said administration step.
  • the invention also provides a method of treatment for cancer in a patient diagnosed as having a cancer characterised by an overexpression of RAN or its protein product Ran or Ran mRNA involving administration to a patient in need thereof an effective amount of mebendazole.
  • the cancer characterised by an overexpression of RAN may be triple negative breast cancer.
  • the cancer characterised by an overexpression of RAN may be lung cancer, and in particular lung cancers that have previously been treated with a tyrosine kinase inhibitor, for example wherein the previous treatment involved administration of an tyrosine kinase inhibitor such as an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor such as gefitinib, erlotinib, afatinib, brigatinib, icotinib or osimertinib to a lung cancer patient and wherein the disease no longer responds to the treatment with the EGFR inhibitor.
  • EGFR epidermal growth factor receptor
  • Such methods may involve coadministration of the previously used tyrosine kinase inhibitor with a Ran inhibitor, preferably wherein the Ran inhibitor is mebendazole.
  • the invention also provides a method of treatment for cancer in a patient diagnosed as having a cancer characterised by an overexpression of a tyrosine kinase, such as a mutated epidermal growth factor receptor (EGFR) tyrosine kinase, involving administering mebendazole in combination with an inhibitor of the tyrosine kinase that is overexpressed, for example in a cancer with a mutation in the EGFR tyrosine kinase domain, an EGFR inhibitor may be used.
  • the administration of mebendazole and an EGFR inhibitor may be simultaneous, sequential or separate.
  • the combination of mebendazole and an EGFR inhibitor may prevent or substantially delay the emergence of resistance to the EGFR inhibitor associated with EGFR inhibitor monotherapy.
  • the combination of mebendazole and an EGFR inhibitor may resensitize a tumour to treatment with an EGFR inhibitor to which the patient no longer responds as a monotherapy.
  • the invention relates to the use of mebendazole, or a pharmaceutically acceptable form thereof, for the manufacture of a medicament for the treatment of cancer, wherein the cancer overexpresses RAN or its protein product Ran or wherein the cancer is indicated for tyrosine kinase inhibitor therapy.
  • the resultant medicament may be provided in a package with instruction for use in the treatment of a cancer that overexpresses RAN or its protein product Ran or for use in combination with a tyrosine kinase inhibitor for the treatment of cancer.
  • the medicament is to be used in combination with a second pharmacologically active agent the administration of mebendazole and the second pharmacologically active agent may be simultaneous, sequential or separate.
  • the resultant, mebendazole containing medicament may be provided in a package with instruction for use in combination with an EGFR inhibitor such as gefitinib.
  • the invention provides a package comprising mebendazole or a pharmaceutically acceptable form thereof and instructions for its use in the treatment of a cancer, wherein the cancer overexpresses RAN or its protein product Ran or Rna mRNA or instructions for its use in the treatment of a cancer that overexpresses a tyrosine kinase such as epidermal growth factor receptor (EGFR) tyrosine kinase.
  • EGFR epidermal growth factor receptor
  • the combination of mebendazole with a EGFR tyrosine kinase inhibitor can be used for the treatment of a cancer that is naive to EGFR treatment or that has previously been treated with an EGFR inhibitor, for example a cancer that has previously responded to treatment with a first EGFR inhibitor and that has subsequently developed resistance to that first EGFR inhibitor.
  • a Ran inhibitor in combination with an EGFR inhibitor derives from the synergistic effect observed in combinations of mebendazole with gefitinib shown in Figures 1 and 2.
  • mebendazole herein and above relates to mebendazole itself or a pharmaceutically acceptable form of mebendazole.
  • Pharmaceutically acceptable forms of mebendazole include prodrugs of mebendazole, that is to say compounds which break down and/or are metabolised in vivo to provide an active compound of formula (I).
  • General examples of prodrugs include simple esters, and other esters such as mixed carbonate esters, carbamates, glycosides, ethers, acetals and ketals.
  • Prodrug motifs may, for example, be directly introduced at the benzimidazole NH position of mebendazole.
  • references to pharmaceutically acceptable forms of mebendazole expressly include reference to known prodrugs of mebendazole, for example /V-alkoxycarbonyl prodrugs as described in Int J Pharmaceutics 1994 (10) p 231-239 that advantageously improve aqueous solubility and, as result, oral bioavailability of mebendazole.
  • /V-methoxycarbonyl, /V-ethoxy carbonyl and N- propoxycarbonyl forms of mebendazole at the benzimidazole NH position of mebendazole), in their respective isomeric forms, are examples of prodrugs that are pharmaceutically acceptable forms of mebendazole.
  • mebendazole include metabolites of mebendazole, in particular metabolites that retain an inhibitory effect on RAN transcription.
  • a metabolite, as employed herein, is a compound that is produced in Vo from the metabolism of mebendazole, such as, without limitation, oxidative metabolites.
  • mebendazole also include deuterated forms of mebendazole.
  • Deuterated forms of mebendazole are derivatives of pimozide in which one or more aliphatic or aromatic hydrogen atom is substituted for a deuterium atom.
  • a hydrogen atom at a site susceptible to metabolism may be replaced by a deuterium atom to reduce metabolism at that site.
  • mebendazole examples include formulations of mebendazole, for example formulations that exhibit a pharmacological profile that is different to the clinical formulations presently in use for treatment of neurological conditions.
  • mebendazole or a pharmaceutically acceptable form thereof, as an inhibitor of RAN transcription for use as a medicament.
  • the present invention provides methods for treatment or alleviation of a cancer over expressing RAN, or its protein product Ran or Ran mRNA, in the tissue of one or more organs as mentioned herein, comprising the step of administering mebendazole or a pharmaceutically acceptable form thereof to a patient in need thereof.
  • the method treatment is for patients with a cancer that have been diagnosed as having a cancer that overexpresses RAN or Ran or Ran mRNA.
  • Such methods according to the present invention may comprise one or more steps of administration or release of an effective amount of mebendazole or a pharmaceutically acceptable form thereof, or a pharmaceutical composition comprising mebendazole or a pharmaceutically acceptable form thereof, to an individual in need thereof.
  • steps of administration or release according to the present invention is simultaneous, sequential or separate.
  • An individual in need as referred to herein may be an individual that benefits from the administration of a mebendazole or a pharmaceutically acceptable form thereof, in particular an individual with a cancer that overexpresses RAN or its protein product Ran or Ran mRNA.
  • Such an individual in one embodiment suffers from a malignant neoplasm (tumour) in the tissue of one or more organs.
  • the tumour(s) overexpresses Ran on treatment with a second pharmacologically active agent that induces RAN or its protein product Ran.
  • the cancer may be selected from cancers of the breast, lung, ovary or kidney or a leukaemia.
  • the cancer may be one in which the PI3K/Akt/mTORC1 and/or Ras/MEK/ERK pathways are activated.
  • the cancer may be triple negative breast cancer.
  • the individual may be any human being, male or female, infant, middle-aged or old.
  • the individual may be a non-human mammal, for example a mammal from the members of the Canidae, Felinae, Bovidae, Equidae, Suidae, Camelini and Cervidae families.
  • Identification of the patient to be treated in the methods of the invention can be achieved in a number of ways.
  • the identification may involve analysis of a sample obtained from a patient, for example a blood sample or a tumour biopsy sample. Analysis of a patient blood sample may be performed by isolating the serum exosome and then carrying out an ELISA or quantitative real time PCR (q RT-PCR) analysis to provide the necessary tumour/patient classification.
  • q RT-PCR quantitative real time PCR
  • a tumour biopsy sample can be stained with a stain comprising a RAN selective antibody linked to a visualising means such as an enzyme or fluorophore.
  • the stained tumour biopsy can then be categorised as a RAN overexpressing tumour or a non-RAN overexpressing tumour. This categorisation may be performed by a visual or automated scoring.
  • scoring of Ran immunohistochemically stained tumour biopsy sample slides can be performed under a light microscope and that an assessment of the % of tumour cells staining over the whole section provides a method to identify tumours that overexpress RAN.
  • treatment refers to the management and care of a patient for the purpose of combating a condition, disease or disorder.
  • the term is intended to include the full spectrum of treatments for a given condition from which the patient is suffering, such as administration of mebendazole or a pharmaceutically acceptable form thereof for the purpose of: alleviating or relieving symptoms or complications; delaying the progression of the condition, partially arresting the clinical manifestations, disease or disorder; curing or eliminating the condition, disease or disorder; and/or preventing or reducing the risk of acquiring the condition, disease or disorder, wherein "preventing” or “prevention” is to be understood to refer to the management and care of a patient for the purpose of hindering the development of the condition, disease or disorder, and includes the administration of the active compounds to prevent or reduce the risk of the onset of symptoms or complications.
  • the patient to be treated is preferably a mammal, in particular a human being. Treatment of animals, such as mice, rats, dogs, cats, cows, horses, sheep and pigs, is, however, also within the scope of the present invention.
  • the patients to be treated according to the present invention can be of various ages, for example, adults, children, children under 16, children age 6-16, children age 2-16, children age 2 months to 6 years or children age 2 months to 5 years.
  • the invention is thus, in one embodiment, directed to mebendazole or a pharmaceutically acceptable form thereof for use in the treatment of cancer in the tissue of one or more organs of a mammal.
  • said treatment is ameliorative and/or curative.
  • said mammal is a human (homo sapiens).
  • said organ is in one embodiment selected from the group consisting of breast, lung, ovarian, prostate, blood, brain and renal cancers
  • Mebendazole or a pharmaceutically acceptable form thereof for use as described herein, for example in the treatment of cancer that overexpresses RAN, or its protein product Ran may be provided as a pharmaceutical composition comprising mebendazole or a pharmaceutically acceptable form thereof in combination with one or more pharmaceutically acceptable diluents or carriers.
  • the formulation may be a formulation currently used in the clinic for mebendazole or may be a new formulation specifically adapted to the purpose of treating RAN overexpressing cancers or cancers indicated for tyrosine kinase inhibitor therapy.
  • Diluents and carriers may include those suitable for parenteral, oral, topical, mucosal and rectal administration.
  • the present invention also provides a process for preparing such a pharmaceutical composition (for example a pharmaceutical composition for parenteral, oral, topical, mucosal or rectal administration), said process comprising mixing the ingredients.
  • compositions may be prepared e.g. for parenteral, subcutaneous, intramuscular or intravenous administration, particularly in the form of liquid solutions or suspensions; for oral administration, particularly in the form of tablets or capsules; for topical e.g. pulmonary or intranasal administration, particularly in the form of powders, nasal drops or aerosols and transdermal administration; for mucosal administration e.g. to buccal, sublingual or vaginal mucosa, and for rectal administration e.g. in the form of a suppository.
  • compositions may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985).
  • Formulations for parenteral administration may contain as excipients sterile water or saline, alkylene glycols such as propylene glycol, polyalkylene glycols such as polyethylene glycol, oils of vegetable origin, hydrogenated naphthalenes and the like.
  • Formulations for nasal administration may be solid and may contain excipients, for example, lactose or dextran, or may be aqueous or oily solutions for use in the form of nasal drops or metered sprays.
  • typical excipients include sugars, calcium stearate, magnesium stearate, pregelatinated starch, and the like.
  • compositions suitable for oral administration may comprise one or more physiologically compatible carriers and/or excipients and may be in solid or liquid form.
  • Tablets and capsules may be prepared with binding agents, for example, syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone (PVP); fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc, polyethylene glycol, or silica; and surfactants, such as sodium lauryl sulfate.
  • binding agents for example, syrup, acacia, gelatin, sorbitol, tragacanth, or polyvinylpyrollidone (PVP); fillers, such as lactose, sucrose, corn starch, calcium phosphate, sorbitol, or glycine; lubricants, such as magnesium stearate, talc,
  • Liquid compositions may contain conventional additives such as suspending agents, for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats; emulsifying agents such as lecithin, or acacia; vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil; preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
  • suspending agents for example sorbitol syrup, methyl cellulose, sugar syrup, gelatin, carboxymethyl-cellulose, or edible fats
  • emulsifying agents such as lecithin, or acacia
  • vegetable oils such as almond oil, coconut oil, cod liver oil, or peanut oil
  • preservatives such as butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT).
  • BHA butylated hydroxyanisole
  • BHT butylated hydroxytoluen
  • Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules.
  • a dry shell formulation typically comprises of about 40% to 60% w/w concentration of gelatin, about a 20% to 30% concentration of plasticizer (such as glycerin, sorbitol or propylene glycol) and about a 30% to 40% concentration of water.
  • plasticizer such as glycerin, sorbitol or propylene glycol
  • Other materials such as preservatives, dyes, opacifiers and flavours also may be present.
  • the liquid fill material comprises a solid drug that has been dissolved, solubilized or dispersed (with suspending agents such as beeswax, hydrogenated castor oil or polyethylene glycol 4000) or a liquid drug in vehicles or combinations of vehicles such as mineral oil, vegetable oils, triglycerides, glycols, polyols and surface-active agents.
  • suspending agents such as beeswax, hydrogenated castor oil or polyethylene glycol 4000
  • a liquid drug in vehicles or combinations of vehicles such as mineral oil, vegetable oils, triglycerides, glycols, polyols and surface-active agents.
  • mebendazole or a pharmaceutically acceptable form thereof, for use or for use in a method of treatment as described herein, can be combined with or comprise one or more second active ingredients which are understood as other therapeutic compounds or pharmaceutically acceptable derivatives thereof.
  • Methods for treatment according to the present invention may comprise one or more steps of administration of one or more second active ingredients, either concomitantly or sequentially, and in any suitable ratios.
  • second active ingredients are, for example, selected from compounds used to treat or prevent cancer in the tissue of one or more organs or symptoms or used to treat or prevent complications associated with treatment of cancer in the tissue of one or more organs.
  • second active ingredients may be intended for the treatment of the side effects associated with the primary treatment or may be aimed at overcoming or suppressing resistance that may arise in the cancer.
  • the one or more second active ingredients may be directed to the treatment of cancer, the treatment or suppression of emesis, the blockage of drug efflux pumps or potentiation of the anti-cancer effect of mebendazole.
  • a preferred class of second active ingredient for use in combination with mebendazole are tyrosine kinase inhibitors.
  • the tyrosine kinase inhibitor may be as a small molecule or an antibody tyrosine kinase inhibitor.
  • tyrosine kinase inhibitors that may be used in combination with a Ran inhibitor, for example mebendazole, for the treatment of cancer include afatinib (GiotrifTM), axitinib (InlytaTM), bosutinib (BosulifTM), crizotinib (XalkoriTM), dasatinib (SprycelTM), erlotinib (Tarceva), gefitinib (IressaTM), osimertinib (TagrissoTM), imatinib (GlivecTM), lapatinib (TyverbTM), nilotinib (TasignaTM), pazopanib (VotrientTM), regorafenib (StivargaTM), sorafenib (NexavarTM), sunitinib (SutentTM) and ibrutinib (ImbruvicaTM).
  • Examples of EGFR tyrosine kinase inhibitors that may be used in combination with a Ran inhibitor, for example mebendazole, for the treatment of cancer include the small molecules gefitinib, erlotinib, afatinib, brigatinib, icotinib, and osimertinib and the antibodies cetuximab, panitumumab, zalutumumab, nimotuzumab, or matuzumab.
  • Methods of treatment according to the present invention in embodiments include a step wherein mebendazole is administered simultaneously, sequentially or separately in combination with one or more second active ingredients.
  • the action of the second therapeutic agent and mebendazole is synergistic.
  • kits according to the present invention in one embodiment comprises mebendazole or a pharmaceutically acceptable form thereof or a composition thereof as defined herein for treatment of cancer in the tissue of one or more organs in combination with a further active ingredient as described herein, for example a tyrosine kinase inhibitor such as an inhibitor of EGFR.
  • Kits according to the present invention in one embodiment allows for simultaneous, sequential or separate administration of mebendazole and one or more second active ingredients as described herein and are optionally provided with instructions therefore.
  • the invention provides a package containing mebendazole or a pharmaceutically acceptable form thereof and instructions for its use for the treatment of cancer, for example for patients with a cancer that overexpresses RAN or its protein product Ran or that is indicated for tyrosine kinase inhibitor therapy.
  • Administration and dosage for example for patients with a cancer that overexpresses RAN or its protein product Ran or that is indicated for tyrosine kinase inhibitor therapy.
  • a composition comprising mebendazole or a pharmaceutically acceptable form thereof is in embodiments administered to a cancer patient having a cancer that overexpresses RAN or its protein product Ran in a pharmaceutically effective dose or a therapeutically effective amount.
  • a composition comprising mebendazole or a pharmaceutically acceptable form thereof may be administered to a cancer patient that is receiving or that has already received tyrosine kinase inhibitor therapy.
  • a therapeutically effective amount of mebendazole or a pharmaceutically acceptable form thereof according to the present invention is an amount sufficient to cure, prevent, reduce the risk of, alleviate or partially arrest the clinical manifestations of a cancer that overexpresses RAN or its protein product Ran or that has been or is being treated with tyrosine kinase inhibitor therapy.
  • the amount that is effective will depend on the severity of the cancer as well as on the weight and general state of the subject. An amount adequate to accomplish this is defined as a "therapeutically effective amount”.
  • the composition is administered in doses of from 1 mg/day to 5000 mg/day.
  • Mebendazole or a pharmaceutically acceptable form thereof, may be administered as an oral formulation, for instance in the form of a tablet.
  • the administration may be in the form a local infusion or injection, or an intravenous or subcutaneous injection depending on the location of the cancer to be treated.
  • the route of administration allows for introducing mebendazole, or a pharmaceutically acceptable form thereof, for use into the blood stream to ultimately target the desired site(s) of action.
  • the route of administration is any suitable route, such as an enteral route (including the oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal and intraperitoneal administration), and/or a parenteral route (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal administration).
  • an enteral route including the oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal and intraperitoneal administration
  • a parenteral route including subcutaneous, intramuscular, intrathecal, intravenous and intradermal administration.
  • Appropriate dosage forms for such administration may be prepared by conventional techniques.
  • Parenteral administration is any administration route not being the oral/enteral route whereby the medicament avoids first-pass degradation in the liver. Accordingly, parenteral administration includes any injections and infusions, for example bolus injection or continuous infusion, such as intravenous administration, intramuscular administration or subcutaneous administration. Furthermore, parenteral administration includes inhalations and topical administration.
  • the composition may in embodiments be administered topically to cross any mucosal membrane of an animal to which the substance or peptide is to be given, e.g. in the nose, vagina, eye, mouth, genital tract, lungs, gastrointestinal tract, or rectum, for example the mucosa of the nose, or mouth, and accordingly, parenteral administration may also include buccal, sublingual, nasal, rectal, vaginal and intraperitoneal administration as well as pulmonal and bronchial administration by inhalation or installation. In some embodiments, the composition is administered topically to cross the skin.
  • intravenous, subcutaneous and intramuscular forms of parenteral administration may be employed.
  • the mebendazole composition according to the invention is used as a local treatment, i.e. is introduced directly to the site(s) of action. Accordingly, mebendazole may be applied to the skin or mucosa directly, or may be injected into the site of action, for example into the diseased tissue or to an end artery leading directly to the diseased tissue.
  • mebendazole or a pharmaceutically acceptable form thereof according to the present invention or pharmaceutically acceptable derivatives thereof are administered alone or in combination with pharmaceutically acceptable carriers or excipients, in either single or multiple doses.
  • the pharmaceutical compositions or compounds according to the invention may be formulated with pharmaceutically acceptable carriers or diluents as well as any other known adjuvants and excipients in accordance with conventional techniques such as those disclosed in Remington: The Science and Practice of Pharmacy, 20th Edition, Gennaro, Ed., Mack Publishing Co., Easton, PA, 2000.
  • pharmaceutically acceptable form in present context includes pharmaceutically acceptable salts, which indicate a salt which is not harmful to the patient.
  • Such salts include pharmaceutically acceptable basic or acid addition salts as well as pharmaceutically acceptable metal salts, ammonium salts and alkylated ammonium salts.
  • a pharmaceutically acceptable derivative further includes esters and prodrugs, or other precursors of a compound which may be biologically metabolized into the active compound, or crystal forms of a compound.
  • the pharmaceutical composition or pharmaceutically acceptable composition may be specifically formulated for administration by any suitable route, such as an enteral route, the oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal, intraperitoneal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.
  • a suitable route such as an enteral route, the oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal, intraperitoneal, and parenteral (including subcutaneous, intramuscular, intrathecal, intravenous and intradermal) route.
  • compositions or compounds of the present invention are formulated for crossing the blood-brain-barrier.
  • compositions for oral administration include solid dosage forms such as hard or soft capsules, tablets, troches, dragees, pills, lozenges, powders and granules. Where appropriate, they can be prepared with coatings such as enteric coatings, or they can be formulated so as to provide controlled release of the active ingredient, such as sustained or prolonged release, according to methods well known in the art. In the same solid dosage form two active ingredients may be combined so as to provide controlled release of one active ingredient and immediate release of another active ingredient.
  • Liquid dosage forms for oral administration include solutions, emulsions, aqueous or oily suspensions, syrups and elixirs.
  • compositions for parenteral administration include sterile aqueous and nonaqueous injectable solutions, dispersions, suspensions or emulsions, as well as sterile powders to be reconstituted in sterile injectable solutions or dispersions prior to use. Depot injectable formulations are also regarded as being within the scope of the present invention.
  • Suitable administration forms include suppositories, sprays, ointments, creams/lotions, gels, inhalants, dermal patches, implants, etc.
  • Mebendazole for use according to the present invention is generally utilized as the free substance or as a pharmaceutically derivative such as a pharmaceutically acceptable salt thereof
  • prodrug refers to derivatives of mebendazole that are rapidly transformed in vivo to yield mebendazole, for example, by hydrolysis in blood or by metabolism in cells, such as for example the cells of the basal ganglia.
  • prodrugs include pharmaceutically acceptable, non-toxic esters of the compounds of the present invention.
  • Suitable pharmaceutical carriers include inert solid diluents or fillers, sterile aqueous solutions and various organic solvents.
  • solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatine, agar, pectin, acacia, magnesium stearate, stearic acid and lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the pharmaceutical compositions formed by combining the compounds for use according to the present invention and the pharmaceutically acceptable carriers are then readily administered in a variety of dosage forms suitable for the disclosed routes of administration.
  • the formulations may conveniently be presented in unit dosage form by methods known in the art of
  • Formulations of the present invention suitable for oral administration may be presented as discrete units, such as capsules or tablets, which each contain a predetermined amount of the active ingredient, and which may include a suitable excipient.
  • compositions intended for oral use may be prepared according to any known method, and such compositions may contain one or more agents selected from the group consisting of sweetening agents, flavouring agents, colouring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations.
  • Tablets may contain the active ingredient(s) in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets.
  • excipients may, for example, be: inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example corn starch or alginic acid; binding agents, for example, starch, gelatine or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc.
  • the tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period.
  • a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. They may also be coated by the techniques described in U.S. Patent Nos. 4,356, 108; 4, 166,452; and 4,265,874, the contents of which are incorporated herein by reference, to form osmotic therapeutic tablets for controlled release.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as a liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavouring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active compound in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., talc, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, kaolin, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol, mannitol,
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavouring and colouring agent.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known methods using suitable dispersing or wetting agents and suspending agents described above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butanediol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
  • sterile, fixed oils are conveniently employed as solvent or suspending medium.
  • any bland fixed oil may be employed using synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • compositions may also be in the form of suppositories for rectal administration of the compounds of the invention.
  • These compositions can be prepared by mixing the compound with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will thus melt in the rectum to release the drug.
  • suitable non-irritating excipient include, for example, cocoa butter and polyethylene glycols.
  • the histogram of Figure 1 B shows the survival of HCC827 cells 24h after treatment with mebendazole, gefitinib and dasatinib, or with a combination of the Ran inhibitor mebendazole and a tyrosine kinase inhibitor with 100% survival being evaluated relative to the control (DMSO) treated cells.
  • treatment with mebendazole at concentrations of 0.1 ⁇ and 0.5 ⁇ causes a ca 30% and 65% reduction in cell survival.
  • Treatment with 1 ⁇ concentrations of gefitinib and dasatinib caused a ca 40 and 70 % reduction in survival, respectively, relative to control.
  • mebendazole at a concentration of 0.1 ⁇ , was used in combination with gefitinib and dasatinib (each at 1 ⁇ ), a 70% and 80% reduction in cell survival was observed thus indicating a synergistic effect between the Ran inhibitor (mebendazole) and the tyrosine kinase inhibitors against the survival of human cancer cells.
  • HCC827 GR5 gefitinib resistant
  • HCC827 derived gefitinib resistant cell line HCC827 GR5 from Department for Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • HCC827 GR5 from Department for Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
  • FIG 2A the effects on morphology mirrored that observed with HCC827 with the exception of the gefitinib treated cohort that were largely unaffected by treatment.
  • the lack of activity of gefitinib on the survival of these resistant cells at a concentration of 1 ⁇ can be clearly seen in figure 2B and this contrasts strongly to the 65% reduction in cell survival when gefitinib was administered with 0.1 ⁇ mebendazole.
  • the enhancement in activity of dasatinib treatment when the drug was given in combination with mebendazole demonstrates once more the synergy that can be derived from dosing of a Ran inhibitor with a second type of tyrosine kinase inhibitor (a Bcr-Abl tyrosine kinase). Effect of Ran inhibitor treatment on the expression of mRNA
  • Akt1 and Akt2 are members of the PI3K/mTOR pathway that is found to be hyperactive in most of common cancers and in 90% of tyrosine kinase resistant cancers.
  • c-Met also called tyrosine-protein kinase Met or hepatocyte growth factor receptor (HGFR) is a protein that in humans is encoded by the MET gene.
  • the data was extracted from scanned images using NimbleScan and the Robust Multichip Average (RMA) algorithm was used to generate gene expression values.
  • Microarray data was normalised using Robust Multichip Average (RMA) method and differentially expressed genes between RAN knock-down and Control were identified by ANOVA.
  • were selected for pathway analysis using GeneGo MetaCore.
  • EMT epithelial- to-mesenchymal transition
  • microarray data showed thai
  • PDK (PDPK1), p27KIP1 , PLC-gamma 2, A20
  • tumour microenvironment is crucial for understanding cancer and is subject to varying levels of immunosurvei!!ance and immunosuppression. It is believed that the complement anaphyiatoxins C3a and C5a enhance tumour growth by shifting the balance toward immunosuppression, thus challenging longstanding dogma that complement activation is advantageous in cancer patients. Furthermore, the ability of neoplastic ceils to evade attack by complement proteins while simultaneously activating complement undermines traditional concepts of complement in tumour control. Numerous studies have investigated the relationship between local and/or systemic complement signalling, the host immune response, and tumour progression in experimental models of lymphoma and ovarian, mammary, breast, lung, and cervical cancer.
  • C3a and/or C5a signalling modifies the immune infiltrate within the tumour microenvironment and/or the peripheral blood and lymphoid organs, with consequential effects on tumour growth.
  • complement activation modulates the function or efficiency of several types of immune effector ceils.
  • mebendazole to down regulate C5a thus provide the potential to promote or potentiate any innate immune response to cancer cells in addition to direct anti-tumour effects derived from its ability to inhibit Ran. Mebendazole may therefore be used as an immunotherapy due to its ability to down regulate C5a. Without being bound by theory, it is believed that downregulation of C5a causes upreguiaiion of T ceils and NK natural killer) cells therefore promoting/potentiating the immune response. Effect of Ran inhibitor treatment and tyrosine kinases inhibitor treatment on the expression of Ran and pBad in HCC827 GR5
  • HCC827-GR5 cells in a quantity of 0.65 - 0,8 ⁇ 10 5 ) were seeded in a 10 cm petri dish and allowed to adhere overnight.
  • the ceils were then treated as with (number correspond to the lane number of the Western Blots): 1) Control (DMSQ), 2) 1 ⁇ Gefiiinib, 3) 300 nM Osimertinib, 4) 100 nM mebendazole, 5) 100 nM mebendazole + 1 ⁇ Gefiiinib, 8) 100 nM mebendazole 5 + 300 nM Osimertinib, 7) 500 nM mebendazole, 8) 500 nM mebendazole + 1 ⁇ Gefiiinib, 9) 500 nM mebendazole + 300 nM Osimertinib.
  • BAD is a member of the BCL-2 family.
  • BCL-2 family members are regulators of the programmed cell death pathways.
  • BAD induces apoptosis by inhibiting antiapoptotic BCL-2- family members - BCL-x, Bcl-2, thereby allowing two other pro-apoptotic proteins, BAK and BAX, to aggregate and induce release of cytochrome.
  • Proapoptotic activity of this protein is regulated through its phosphorylation.
  • Protein kinases AKT and MAP kinase, as well as protein phosphatase calcineurin were found to be involved in the regulation of this protein.
  • the BAD protein is a pro-apoptotic member of the Bcl-2 family whose ability to heterodimerize with survival proteins such as Bci-X(L) and to promote cell death is inhibited by phosphorylation.
  • Gefitinib treatment results in a reduction in pBad whereas osimertinib appears to have no effect, compared to control, on pBad in GR5 cells.
  • Mebendazole at 500 nM alone and in combination increases the dephosphorylation of pBad, and thus increased apoptosis, whereas the effect of 100 nM mebendazole is small after 24 hr.
  • the survival of the HCC827 cells ranges from ca 50 to 60 %.
  • Treatment with 5 ⁇ pimozide causes a reduction in cell survival relative to control of approximately 40%.
  • Treatment of HCC827 cells with gefitinib (at 300 nM) with a 5 ⁇ concentrations of pimozide causes a reduction in cell survival of ca 80%, thus illustrating a synergistic effect against cancer cell survival that is realised from the combination of a Ran inhibitor and a EGFR inhibitor (gefitinib).
  • Figure 7 shows the effects of drug treatment for 24 h on the survival of gefitinib resistant HCC827 GR5 cells, a cell line that is derived from normal HCC827 human lung cancer cells (cf Figure 6).
  • treatment with gefitinib in this instance at all of the concentrations evaluated causes no more than a 15% reduction in cell survival.
  • Pimozide treatment (Figure 7B) causes a ca 30% reduction in cell survival at a concentration of 5 ⁇ .
  • the combination of various concentrations of pimozide and gefitinib 300 nM meanwhile proved superior to either agent when they were presented as single agents.

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Abstract

La présente invention concerne des petites molécules inhibitrices de RAN à un niveau transcriptionnel et leur utilisation dans le traitement du cancer, en particulier de cancers, tels que le cancer du sein triple-négatif, qui ont été identifiés comme surexprimant le gène RAN ou son produit protéique ou l'ARNm du gène RAN. Les inhibiteurs selon l'invention sont particulièrement utiles pour le traitement de patients identifiés comme ayant une tumeur qui surexprime le gène RAN ou son produit protéique ou l'ARNm du gène RAN.
PCT/GB2018/050222 2017-01-27 2018-01-26 Mébendazole utilisé dans le traitement du cancer WO2018138510A1 (fr)

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CN115177590A (zh) * 2022-04-20 2022-10-14 南昌大学抚州医学院 一种甲苯达唑类脂质体的制备方法及应用

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