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WO2018191541A1 - Compositions, produits pharmaceutiques conditionnés, et méthodes d'utilisation de posaconazole pour la sensibilisation de tumeurs résistantes - Google Patents

Compositions, produits pharmaceutiques conditionnés, et méthodes d'utilisation de posaconazole pour la sensibilisation de tumeurs résistantes Download PDF

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Publication number
WO2018191541A1
WO2018191541A1 PCT/US2018/027371 US2018027371W WO2018191541A1 WO 2018191541 A1 WO2018191541 A1 WO 2018191541A1 US 2018027371 W US2018027371 W US 2018027371W WO 2018191541 A1 WO2018191541 A1 WO 2018191541A1
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Prior art keywords
chemotherapeutic agent
posaconazole
inhibitor
administered
cancer
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PCT/US2018/027371
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English (en)
Inventor
Vikash J. BHAGWANDIN
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Bhagwandin Vikash J
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Priority to CA3063115A priority Critical patent/CA3063115A1/fr
Priority to EP18783809.9A priority patent/EP3609329A4/fr
Priority to KR1020197033474A priority patent/KR20200059188A/ko
Priority to AU2018253189A priority patent/AU2018253189A1/en
Priority to CN201880038812.1A priority patent/CN111093373A/zh
Publication of WO2018191541A1 publication Critical patent/WO2018191541A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
    • 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
    • A61K31/475—Quinolines; Isoquinolines having an indole ring, e.g. yohimbine, reserpine, strychnine, vinblastine
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • cancer stem cells may be "intrinsically" resistant to chemotherapy or that resistance is induced during first-line of therapy via acquisition of mutations, which are carried into and exist during the second-line of therapy settings.
  • the targeting of cancer stem cells as a first- line of therapy setting may eliminate intrinsically resistant cancer cells, prevent acquisition of resistance mutations, limit further progression and metastasis of cancer, and may also be applicable in the second-line therapy setting where responsive cancer cells can exist.
  • Cancer cells and more specifically cancer stem cells, can express one or multiple ATP Binding Cassette (ABC) transporters as a mechanism of resistance to chemotherapy drugs.
  • ABC transporter proteins can facilitate the efflux of drugs from cancer cells rendering them resistant.
  • the efflux of drugs from cancer cells means that higher concentrations of drug are required to achieve cell death, and at those concentrations the drug can be toxic to patients, essentially reducing the therapeutic index of the drug.
  • ABC transporters such as verapamil, reserpine, and cyclosporine
  • verapamil reserpine
  • cyclosporine when used sequentially or in combination with other drugs, directly reduce or prevent the removal of the chemotherapeutic drug from the cell, making the drug more effective at lower concentrations.
  • concentration of ABC transporter inhibitor necessary to turn off the transporters is too toxic to be used in patients, and the inhibitors are therefore not effective for use in combination therapy.
  • ABC transporter activity is tightly regulated by sequestration of the transporter to intracellular compartments.
  • Rocchi et al. (2000) Biochem. Biophys. Res. Commun. 271:42-6.
  • Akt inhibitors such as, Gleevec, LY294002, or LY335979, have been shown to reduce or completely eliminate translocation of transporter to the cell membrane and either reduce or completely abrogate transporter activity, thereby sensitizing resistant cells to drugs. Shepard et al. (2003) Int. J. Cancer 103: 121-5; Nakanishi et al. (2006) Blood 108:678-84; Burger et al. (2005) Cancer Biol. Ther. 4:747-52; Ozvegy-Laczka et al. (2004) Mol. Pharmacol. 65: 1485-95; Houghton et al. (2004) Cancer Res.
  • Another strategy for overcoming ABC transporter-related drug resistance is to inhibit pathways that control ABC transporter expression in the resistant cancer cells, including cancer stem cells.
  • Smo (smoothened) antagonist, cyclopamine, with chemotherapy drugs has been shown to reduce ABCG2 and ABCB l/MDRl activity and to increase cancer cell death as compared to drug alone in vitro, by mechanisms that have yet to be identified.
  • cyclopamine is a toxic alkaloid that is lethal to humans with no feasible therapeutic application.
  • Itraconazole is a prescription-only antifungal agent that has been used to treat fungal infections such as, nail fungus, Aspergillosis, Candidiasis,
  • Itraconazole is currently in clinical trials for the treatment of several tumor types that are driven by the deregulation of the hedgehog pathway. Itraconazole has been shown to inhibit ABCG2 and ABCB 1/MDRl in cells that were artificially engineered to replicate acquired chemoresistance or in cells from heavily pretreated patients or patients treated as second-line of therapy in vitro. However, these experiments were performed using cytotoxic and non-therapeutic dosages in combination with dye substrates as a readout.
  • acquired chemoresistance may be defined by when cancer cells are exposed to chemotherapeutic drugs until the cell "acquires" mutations that activate mechanisms and render the cancer cells resistant to chemotherapies.
  • Itraconazole has also been shown to increase survival of patients when administered in combination with second-line therapy for AML (acute
  • Posaconazole is a prescription antifungal agent that is used to treat fungal infections such as Aspergillosis, Candidiasis, Mucor, and Zygomycetes. Schiller et al. (2007) Clinical Therapeutics 29: 1862-1886. Similar to itraconazole, posaconazole is known to be a strong inhibitor of CYP3A4 (cytochrome P450 subunit 3A4). Unlike itraconazole, however, posaconazole has never been shown to inhibit P-gp/MDR-l/ABCB l directly.
  • Posaconazole has also not been used in combination with chemotherapeutic s, but has been used as a single agent to inhibit growth of tumors containing a deregulated hedgehog pathway or mutations in Ptc, Smo, or Gli proteins. Chen et al. (2016) Mol. Cancer Therap. 15(5):866-876.
  • U.S. Patent Publication No. 2007/0281040 Al discloses the use of a highly toxic hedgehog inhibitor, cyclopamine, to treat cells having an activated hedgehog pathway, where the hedgehog pathway of the cells is targeted directly by the inhibitor, rather than by sensitization of the cells to the chemotherapeutic agent.
  • the present invention addresses these and other problems by providing in various aspects compositions, packaged pharmaceuticals, and methods for modulating the hedgehog pathway in order to reduce or eliminate MYC expression or modulate the activity of other regulators that can lead to the down-regulation of ABC transporter expression and that alleviate chemoresistance in cancer cells.
  • the modulation of the hedgehog pathway is used in combination with chemotherapy drugs to increase the therapeutic index in patients for several cancer types and to reduce related side effects of these drugs.
  • the compositions, packaged pharmaceuticals, and methods for modulating the hedgehog pathway in order to reduce or eliminate MYC expression or modulate the activity of other regulators that can lead to the down-regulation of ABC transporter expression and that alleviate chemoresistance in cancer cells.
  • the modulation of the hedgehog pathway is used in combination with chemotherapy drugs to increase the therapeutic index in patients for several cancer types and to reduce related side effects of these drugs.
  • pharmaceuticals, and methods may include any chemotherapy drug class, formulation, dosage, or therapeutic schedule determined by pre-clinical and clinical trials for each cancer type as a first-line of therapy or for responsive cells in the second-line of therapy.
  • the invention relates to the repurposing of a hedgehog pathway modulator, including posaconazole, itraconazole, arsenic trioxide, vitamin D3, and various other agents, to reduce or eliminate ABC transporter expression, and therefore to reduce or eliminate ABC transporter activity in resistant cancer cells and thus to increase the therapeutic index of chemotherapy drugs.
  • a hedgehog pathway modulator including posaconazole, itraconazole, arsenic trioxide, vitamin D3, and various other agents.
  • the hedgehog pathway modulator is posaconazole.
  • the invention provides for the repurposing of experimental and FDA approved therapeutic compounds that are intended for the inhibition of molecules or pathways unrelated to the hedgehog pathway, but that can have inhibitory effects on the hedgehog pathway for the inactivation of ABC transporters. These compounds are less toxic and more tolerable to patients when used in combination with drugs that improve the therapeutic index of the drug and reduce the related side effects of the drug as compared to when the drug is used alone.
  • FIG. 1 A diagram of the hedgehog pathway regulation of ABC transporters, which depicts exemplary points of inhibition where the invention can be applied to reduce ABC transporter expression.
  • FIG. 2 A diagram illustrating an embodiment of the invention that uses competitive inhibitors or scavengers of the ligand Sonic and Indian hedgehog proteins to reduce MYC expression or other regulators and subsequently reduce downstream ABC transporter expression.
  • FIGs. 3A-3B Diagrams illustrating embodiments of the invention involving the induction of patched or stabilization of the Ptc:Smo complex for the inhibition of smoothened receptor signaling to reduce MYC expression or other regulators and subsequently reduce downstream ABC transporter expression.
  • FIGs. 4A-4B Diagrams illustrating embodiments of the invention using inhibitors of the cholesterol synthesis pathway or prevention of the sterolization or specifically cholesterolization of Smo.
  • FIG. 5 A diagram illustrating an embodiment of the invention involving the direct inhibition of smoothened receptor signaling to reduce MYC expression or other regulators and subsequently reduce downstream ABC transporter expression.
  • FIG. 6 A diagram illustrating an embodiment of the invention involving inhibition of effectors that relay signals to and activate SUFU for the reduction of MYC expression or other regulators and subsequently reduce downstream ABC transporter expression.
  • FIG. 7 A diagram illustrating an embodiment of the invention involving inhibition of Glil, Gli2 and induction of Gli3 to reduce MYC expression or other regulators and subsequently reduce downstream ABC transporter expression.
  • FIG. 8 A diagram illustrating an embodiment of the invention that uses the inhibition or reduction of MYC to directly or indirectly downregulate ABC transporter expression.
  • FIG. 9 A diagram illustrating a preferred embodiment of the invention demonstrating the use of itraconazole or posaconazole to inhibit Smo signaling thereby reducing MYC expression or other regulators and subsequently reduce downstream ABC transporter expression and thus sensitizing resistant cancer cells to chemotherapy drugs.
  • FIGs. 10A-10L A set of pre-clinical data demonstrating a preferred embodiment of the invention demonstrating a "dose de-escalation" strategy with the use of cyclopamine (a positive control and toxic antagonist of the hedgehog pathway), and itraconazole combined with vinca alkaloid; vincristine, and taxane; docetaxel in H295 (adrenal cortical carcinoma), Kelly (neuroblastoma (childhood brain cancer)), HeLa (cervical cancer) and Caco-2 (colon or colorectal cancer) cell lines.
  • FIG. 11 A set of pre-clinical data demonstrating a preferred embodiment of the invention demonstrating a "dose de-escalation" strategy with the use of cyclopamine (a positive control and toxic antagonist of the hedgehog pathway), and itraconazole combined with vinca alkaloid; vincristine, and taxane; docetaxel in H295 (adrenal cortical carcinoma), Kelly (neuroblastoma (childhood brain cancer)
  • FIGs. 12A-12D and 13A-13D A set of pre-clinical data demonstrating a preferred embodiment of the invention demonstrating a measurement of cytoxicity for tomatidine (a structural analog of cyclopamine and negative control), cyclopamine (an experimental positive control and toxic antagonist of the hedgehog pathway), itraconazole (a strong hedgehog pathway antagonist, positive control), and posaconazole (experimental agent) (12A, 12C, 13A, and 13C) and a set of pre-clinical data demonstrating a preferred embodiment of the invention demonstrating a "dose de-escalation" strategy with the use of posaconazole (a strong hedgehog pathway antagonist, sensitizing agent) (12B , 12D, 13B, and 13D) combined with vinca alkaloid; vincristine, in various colon cancer cell lines: Caco- 2 (12A, 12B), DLD-1 (12C, 12D), HT-29 (13A, 13B), and HCT-15 (13C, 13D).
  • Caco- 2
  • FIGs. 14A-14D A set of pre-clinical data demonstrating a preferred embodiment of the invention demonstrating a measurement of cytoxicity for tomatidine (a structural analog of cyclopamine and negative control), cyclopamine (an experimental positive control and toxic antagonist of the hedgehog pathway), itraconazole (a strong hedgehog pathway antagonist, positive control), and posaconazole (experimental agent) (14A, 14C) and a set of pre-clinical data demonstrating a preferred embodiment of the invention demonstrating a "dose de- escalation" strategy with the use of posaconazole (a strong hedgehog pathway antagonist, sensitizing agent) (14B, 14D) combined with vinca alkaloid; vincristine in two small-cell lung cancer cell lines: H69 (14A, 14B) and H146 (14C, 14D).
  • tomatidine a structural analog of cyclopamine and negative control
  • cyclopamine an experimental positive control and toxic antagonist of the hedgehog pathway
  • FIGs. 15A-15D and 16A-16D A set of pre-clinical data demonstrating a preferred embodiment of the invention demonstrating a measurement of cytoxicity for tomatidine (a structural analog of cyclopamine and negative control), cyclopamine (an experimental positive control and toxic antagonist of the hedgehog pathway), itraconazole (a strong hedgehog pathway antagonist, positive control), and posaconazole (experimental agent) (15A,15C, 16A, and 16C) and a set of pre-clinical data demonstrating a preferred embodiment of the invention demonstrating a "dose de-escalation" strategy with the use of posaconazole (a strong hedgehog pathway antagonist, sensitizing agent) (15B, 15D, 16B, and 16D) combined with vinca alkaloid; vincristine in various neuroblastoma cell lines; Kelly (15A, 15B), SK-N-SH (15C, 15D), SH-5YSY (16A, 16B), and Lan-5 (16C, 16D).
  • tomatidine a
  • the present invention relates in general to the field of cancer therapy.
  • the invention relates to the sensitization of chemoresistant cancer cells using modulators of the hedgehog pathway.
  • the invention relates to the sensitization of chemoresistant cancer cells through the reduction, elimination and/or inactivation of pumps responsible for the removal of chemotherapy drugs from cancer cells.
  • the invention relates to the modulation of signaling pathways that regulate pump expression in cancer cells.
  • the present invention relates to the modulation of any component of the hedgehog pathway that can result in the down-regulation of MYC an activator or other regulators of ABC transporters, and can render chemoresistant cancer cells vulnerable to chemotherapy drugs.
  • the invention is also further applicable to the repurposing of experimental and FDA approved compounds that can modulate the hedgehog pathway and can lead to the sensitization of chemoresistant cancer cells to chemotherapy drugs.
  • the present disclosure provides methods of achieving enhanced synergistic killing of chemoresistant cancer cells when compounds are combined, one is a modulator of the hedgehog pathway, and the second is a chemotherapy drug that is a known substrate of ABC transporters.
  • the combination makes the cells vulnerable to chemotherapy drugs at lower concentrations while reducing the toxicity to the patient.
  • compositions and methods may include any chemotherapy drug class, formulation, dosage and therapeutic schedule determined by pre-clinical and clinical trials for each cancer type as a first-line of therapy or for responsive cells in the second-line of therapy.
  • the hedgehog pathway contains several points of regulation that can be exploited as targets for the downregulation of ABC transporters, outlined in FIG. 1.
  • Compounds or biologies are used to modulate the hedgehog pathway at any of the regulatory points indicated in FIG. 1, which results in the downregulation of MYC or other regulators of ABC transporters.
  • MYC or other regulators When MYC or other regulators are downregulated the ABC transporters are downregulated.
  • the downregulation of ABC transporters renders the cell sensitive to lower concentrations of
  • the binding of Sonic or Indian hedgehog (SHH or IHH) to Ptc can be disrupted using competitive inhibitors (compounds or biologies) that occupy the binding site of SHH and IHH on Ptc (FIG. 2, left side). Also, the binding of SHH and IHH on Ptc can be prevented using therapies (compounds or biologies) that act as scavengers and bind SHH and IHH directly where they would normally bind Ptc (FIG. 2, right side). This would either prevent the activation of the pathway or inhibit an active pathway, which reduces MYC expression or activity of other regulators and subsequently ABC transporter expression.
  • therapies compounds or biologies
  • compounds or biologies are used to induce Ptc activity to inhibit Smo activity or are used to stabilize the Ptc:Smo complex that results in the inhibition of the hedgehog pathway (FIGs. 3A-3B).
  • the induction of Ptc activity is accomplished using compounds or biologies that cause
  • FIG. 3A The stabilization of the Ptc:Smo complex is accomplished using compounds or biologies that have the ability to crosslink the two receptors or by stabilization of the bound state of the two receptors (FIG. 3B). These compounds or biologies downregulate or prevent activation of the hedgehog pathway, which reduce MYC expression or activity of other regulators and subsequently ABC transporter expression.
  • compounds or biologies are used to prevent the cholesterol dependent activation of Smo by inhibition of enzymes in the cholesterol synthesis pathway.
  • the inhibition of any enzymes that generate cholesterol precursors leads to the reduction of intracellular cholesterol that is necessary for Smo signaling activity (FIG. 4A).
  • the induction of Ptc pump activity can increase the removal the intracellular cholesterol that is necessary for Smo signaling activity (FIG. 4B).
  • the reduction of cholesterol by either point of inhibition or induction either prevents the activation of the pathway or inhibits an active pathway, which reduces MYC expression or activity of other regulators and subsequently ABC transporter expression.
  • compounds or biologies are used to inhibit the activity of Smo. This is accomplished by using compounds or biologies that bind and antagonize Smo, which reduces MYC expression or activity of other regulators and subsequently downstream ABC transporter expression (FIG. 5).
  • compounds or biologies are used to inhibit signaling molecules that induce SUFU activity (e.g. , at location "A" in FIG. 6, right side).
  • the inactive state of SUFU sequesters downstream effector proteins such as Glil and Gli2, which stop downstream pathway activation.
  • compounds and biologies are used to inhibit SUFU activity (e.g. , at location "B” in FIG. 6, right side) or stabilize SUFU:Gli complexes (e.g. , at location "C” in FIG. 6, right side) directly and render the pathway inactive, which reduces MYC expression or activity of other regulators and subsequently downstream ABC transporter expression.
  • compounds or biologies are used to inhibit molecules that induce Glil or Gli2 transcription factor activity (e.g. , at location "A" in FIG. 7, left side).
  • compounds or biologies are used to inhibit Glil or Gli2 transcription factor activity directly (e.g. , at location "B” in FIG. 7, right side) or to induce the activity of Gli3 (e.g. , at location "C” in FIG. 7, right side), which reduces MYC expression or activity of other regulators and subsequently downstream ABC transporter expression.
  • compounds or biologies are used to inhibit the activity of MYC transcription factor for the reduction of ABC transporter expression. This is accomplished by using compounds or biologies to disrupt the binding of MYC to DNA binding sites through inhibition of MYC (e.g. , FIG. 8, top), or by disruption of MYC:MAX complex formation (e.g., FIG. 8, bottom) that prevents the activation of target genes, specifically ABC transporters.
  • synergistic killing of resistant cancer cells is achieved by combining the FDA approved drugs, for example posaconazole, itraconazole, arsenic trioxide, vitamin D3, or various other hedgehog pathway modulators (see Table 1), with a chemotherapeutic drug.
  • Posaconazole, itraconazole, and the other hedgehog pathway modulators can make resistant cancer cells vulnerable to chemotherapeutic drugs at lower concentrations while reducing the toxicity to the patient.
  • FIG. 9 shows how the inhibition of Smo signaling by posaconazole or itraconazole reduces MYC expression or activity of other regulators and subsequent downstream ABC transporter expression and thus sensitizes resistant cancer cells to chemotherapy drugs.
  • Chemotherapeutic drugs for use in all aspects of the invention include, without limitation, vinca alkaloids, taxanes, platinums, anthracyclines,
  • Chemotherapeutic drugs should be understood to include all types of anti-cancer agents, both conventional chemotherapeutic drugs, as well as more recently developed targeted cancer therapeutics. See, for example, Baudino (2015) Curr. Drug Disc. Tech. 12:3-20 and the web site of My Cancer Genome
  • the drugs are excreted from cells by ABC transporters, and the use of posaconazole, itraconazole, arsenic trioxide, vitamin D3, or other hedgehog pathway modulators, in combination with one or more of the chemotherapeutic drugs provides an improved therapeutic index for the drug or drugs.
  • Any agent (biologic or small molecule) that modulates immunological targets for therapeutic benefit in cancer such as; PD-1, PD-L1, PD-L2, CTLA-4, CD4, CD28, CD38, CD80, CD86, CD47, CD19, CD20, CD27, CD137, LAG- 3, GITR, CD40, OX40, 4- IBB, GR-1, Ly6G, NKG2D, BTLA, ICOS, KIR, TIM-3, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12, IL-17, IFN-gamma, IDO/TDO, ADCs, and CAR T-cells, should also be considered a chemotherapeutic agent for purposes of the instant disclosure.
  • compositions, packaged pharmaceuticals, and methods of the instant disclosure are advantageous in their use of an approved FDA antineoplastic agent, posaconazole, itraconazole, arsenic trioxide, vitamin D3, or another hedgehog pathway modulator, not as a single agent to treat tumors with tumorigenic mutations in the hedgehog pathway, but to inhibit hedgehog signaling to reduce MYC expression or activity of other regulators and subsequently ABC transporter expression that confers resistance in tumors.
  • the dosages, toxicities, and ADME information have been well documented for posaconazole,
  • itraconazole arsenic trioxide, vitamin D3, and other hedgehog pathway modulators, and therefore can be more tolerable to the patient as compared to cyclopamine or new experimental drugs.
  • the dosages needed in humans to down- regulate hedgehog regulated chemoresistance in cancer cells are readily determined during clinical trials, as is understood by those of ordinary skill in the art.
  • the minimum effective dose (MED) and maximum tolerated dose (MTD) of posaconazole, itraconazole, arsenic trioxide, vitamin D3, and other hedgehog pathway modulators provide parameters for more effective treatment of these tumors.
  • hedgehog pathway modulators usefully employed in the instant compositions, packaged pharmaceuticals, and methods include the agents listed in Table 1, without limitation.
  • the hedgehog pathway modulator may be provided as a solid dispersion of the modulator in a polymer, for example to improve the absorption of drugs in the gastrointestinal tract and thus to achieve bioavailability compared to conventional formulations.
  • Such dispersions may, for example, improve the dissolution of poorly soluble drugs compared to their normal crystalline forms.
  • Itraconazole has been formulated in such dispersions in combination with HP-50 (see, SUBA Itraconazole from MaynePharma, Raleigh, NC 27609, USA). Posaconazole can be formulated in a similar manner.
  • hedgehog pathway modulator administering to a mammalian subject a hedgehog pathway modulator; and administering to the subject a chemotherapeutic agent; wherein the subject suffers from cancer, and wherein the hedgehog pathway modulator is administered in an amount effective to sensitize a tumor cell in the subject to the
  • the chemotherapeutic agent is administered at a lower dose than would be required in the absence of the hedgehog pathway modulator.
  • the hedgehog pathway modulator is
  • hedgehog pathway modulator is administered simultaneously or nearly simultaneously.
  • the hedgehog pathway modulator is administered prior to administration of the chemotherapeutic agent. Variants of these methods comprise the single step of:
  • previous administration of the hedgehog pathway modulator may be done at any suitable time prior to administration of the chemotherapeutic agent, so long as a sufficient sensitization effect from the hedgehog pathway modulator administration remains in the subject, as would be understood by those of ordinary skill in the art.
  • a hedgehog pathway modulator is administered after the administration of a chemotherapeutic agent.
  • the mammalian subject has not previously been treated with a chemotherapeutic agent prior to treatment with a hedgehog pathway modulator.
  • the hedgehog pathway modulator and the chemotherapeutic agent are each independently administered orally,
  • the subject suffers from an adrenal cortical carcinoma, a neuroblastoma, a cervical cancer, a colon cancer, a colorectal cancer, or a small-cell lung cancer.
  • the hedgehog pathway modulator is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoe-N-oxide
  • the hedgehog pathway modulator is posaconazole.
  • compositions, packaged pharmaceuticals, and methods of treatment according to the following numbered paragraphs:
  • composition comprising:
  • a chemotherapeutic agent a chemotherapeutic agent. 2. The composition of paragraph 1, wherein the hedgehog pathway modulator sensitizes a tumor cell to the chemotherapeutic agent.
  • composition of paragraph 1 further comprising a pharmaceutically acceptable carrier.
  • a packaged pharmaceutical comprising a hedgehog pathway modulator, a chemotherapeutic agent, and instructions for using the composition to treat cancer in a mammalian subject.
  • a method of treatment comprising:
  • hedgehog pathway modulator administering to a mammalian subject a hedgehog pathway modulator; and administering to the subject a chemotherapeutic agent; wherein the subject suffers from cancer, and wherein the hedgehog pathway modulator is administered in an amount effective to sensitize a tumor cell in the subject to the
  • the hedgehog pathway modulator and the chemotherapeutic agent are each independently administered orally, intramuscularly, or intravenously.
  • the hedgehog pathway modulator is posaconazole, itraconazole, arsenic trioxide, or vitamin D3.
  • Cancer cells grown in vitro are treated with chemotherapy drugs alone or simultaneously with a hedgehog pathway modulator, including itraconazole.
  • the difference in cell death between cells treated with chemotherapy drugs alone or in simultaneous treatment with the hedgehog pathway modulators determines the degree of synergistic killing effect of the combination therapy.
  • a two-dimensional dose response where a serial ten fold dose de-escalation of cyclopamine and itraconazole was performed to demonstrate sensitization to vincristine and docetaxel in naive cell lines that have never been exposed to chemotherapy in the patients prior to isolation and establishment as a model of first-line of therapy:
  • H295, Kelly, and resistant cell lines that have been exposed to chemotherapy prior to isolation and establishment as a model of second-line of therapy: HeLa, and Caco-2 cells.
  • concentration of chemotherapy necessary to stop proliferation as well as kill half of the amount of cells (IC50) increases, but yet remains less than concentration of chemotherapy alone (FIGs. 10A-10H).
  • the HeLa and Caco-2 cell lines did not respond (FIGs. 101- 10L). This clearly demonstrates a broad range of sensitization of cancers to chemotherapies by itraconazole and suggests that other hedgehog modulators may have similar effects.
  • Modified Eagles Medium supplemented with insulin, transferring, and selenium, 10% Fetal bovine serum, and gentamicin.
  • the Kelly cell line was grown in DMEM, supplemented with 10% Fetal bovine serum, and gentamicin. Cell-based experiments were conducted in a 37 degree incubator supplemented with 5% carbon dioxide.
  • H295 cells were plated in a 96-well dish at a density of 10000 cells per well and Kelly cells were plated at a density of 2000 cells per well. After 16 hours, cells were treated with 2-fold dilutions of vincristine (VCR) or docetaxel (DTX). For sensitization experiments, tomatidine, cyclopamine, or itraconazole, were added to all of the wells at a concentration of 10 micromolar, 1 micromolar, or 0.1 micromolar. The cells were incubated until the untreated well reached maximum confluency at which time the cells do not divide rapidly.
  • VCR vincristine
  • DTX docetaxel
  • MTT Assay Drug containing media from all of the dishes were discarded and MTT solution was added at a concentration of 5 micrograms per ml. The dishes were returned to the incubator for 4 hours. The excess MTT substrate was discarded and a solubilization solution of acid treated isopropanol and triton X-100 was added to the dishes and shaken for 10 minutes. The dishes were read in a plate reader equipped to read wavelength of 570 nanometers, and 690 nanometers as reference.
  • Hedgehog pathway modulators including posaconazole and itraconazole, are used as a pretreatment to turn off the hedgehog pathway and thus to
  • Drug de-escalation determines the synergistic killing effects of the combination therapy, where a normal, determined dose of a hedgehog pathway modulator, including posaconazole and itraconazole, is given, but the dose of the chemotherapy is reduced gradually in each study. De-escalation studies demonstrate whether or not the combinations reduce side effects of the hedgehog pathway modulator and known toxicities of the chemotherapy drugs to the patient while maintaining efficacious killing of the tumor.
  • In vivo xenografts 1 million H295 cells were combined with matrigel and injected into the subcutaneous part of the skin over the left flank in NOD- SCID mice. After six weeks when tumors were grown to 0.5 centimeters, the animals were randomized and treated with saline only (untreated control), vincristine, ten times less vincristine (dose de-escalation control), itraconazole, vincristine combined with itraconazole, and ten times less vincristine combined with itraconazole (dose de-escalation). Tumors were measured once a week and size was determined using the formula (1/2W x L)/2. Tumor growth for each cohort was plotted using Graphpad Prism 6. Example 5
  • Cancer cells grown in vitro were treated with an inactive structural analog of the hedgehog modulator cyclopamine, tomatidine, cyclopamine, itraconazole, and posaconazole.
  • the cells were treated with compounds diluted two-fold and the difference in cell death between cells treated with or without each compound determined the degree of cellular cytotoxicity and cell death in colon cancer cell lines: Caco-2, DLD-1, HT-29, HCT-15; small-cell lung cancer cell lines: H69, H146; neuroblastoma cell lines: Kelly, SK-N-SH, SH-5YSY, Lan-5 (FIGs. 12A, 12C, 13A, 13C, 14A, 14C, 15A, 15C, 16A, and 16C).
  • the data presented here demonstrates that posaconazole has less cytoxicity than itraconazole, and that posaconazole has significantly higher therapeutic benefit than itraconazole.
  • posaconazole may be used to sensitize cells to chemotherapeutic agents with minimal side effects and more impactful outcomes in patients as compared to itraconazole.
  • Cancer cells grown in vitro were treated with chemotherapy drugs alone or simultaneously with a hedgehog pathway modulator, including posaconazole.
  • the difference in cell death between cells treated with chemotherapy drugs alone or in simultaneous treatment with the hedgehog pathway modulators determined the degree of synergistic killing effect of the combination therapy.
  • a two- dimensional dose response assay where a ten fold, two-fold, or three-fold dose de- escalation of posaconazole was performed to demonstrate sensitization in cell lines that are resistant to vincristine; colon cancer: Caco-2, DLD-1, HT-29, HCT-15; small-cell lung cancer: H69, H146; neuroblastoma: Kelly, SK-N-SH, SH-5YSY, Lan-5.
  • Cell culture The colon cancer cell lines; Caco-2, DLD-1, HT-29, HCT-15 and Neuroblastoma cell lines; Kelly, SK-N-SH, SH-5YSY, Lan-5 were grown in DMEM (Dulbecco's Modified Eagles Medium), supplemented with 10% Fetal bovine serum, and gentamicin.
  • DMEM Dulbecco's Modified Eagles Medium
  • the small-cell lung cancer cell lines; H69, H146 were grown in RPMI-1640 supplemented with 10% Fetal bovine serum, and gentamicin.
  • Cell-based experiments were conducted in a 37 degree incubator supplemented with 5% carbon dioxide.

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Abstract

La présente invention concerne des compositions, des produits pharmaceutiques conditionnés, et des méthodes de traitement par la sensibilisation de tumeurs résistantes. Les compositions comprennent du posaconazole et un agent chimiothérapeutique. Les cellules tumorales chez des sujets mammifères traités avec le posaconazole sont sensibilisées aux effets de l'agent chimiothérapique, augmentant ainsi l'indice thérapeutique de l'agent et réduisant également la toxicité pour le sujet.
PCT/US2018/027371 2017-04-12 2018-04-12 Compositions, produits pharmaceutiques conditionnés, et méthodes d'utilisation de posaconazole pour la sensibilisation de tumeurs résistantes WO2018191541A1 (fr)

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CA3063115A CA3063115A1 (fr) 2017-04-12 2018-04-12 Compositions, produits pharmaceutiques conditionnes, et methodes d'utilisation de posaconazole pour la sensibilisation de tumeurs resistantes
EP18783809.9A EP3609329A4 (fr) 2017-04-12 2018-04-12 Compositions, produits pharmaceutiques conditionnés, et méthodes d'utilisation de posaconazole pour la sensibilisation de tumeurs résistantes
KR1020197033474A KR20200059188A (ko) 2017-04-12 2018-04-12 내성 종양의 민감화를 위해 포사코나졸을 사용한 조성물, 패키징된 약제, 및 방법
AU2018253189A AU2018253189A1 (en) 2017-04-12 2018-04-12 Compositions, packaged pharmaceuticals, and methods of using posaconazole for the sensitization of resistant tumors
CN201880038812.1A CN111093373A (zh) 2017-04-12 2018-04-12 组合物、包装的药物和使用泊沙康唑用于敏化抗性肿瘤的方法

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EP3609329A4 (fr) 2021-03-17
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