WO2017091574A1 - Riluzole et associations médicamenteuses à base de riluzole pour le traitement du cancer de la prostate - Google Patents

Riluzole et associations médicamenteuses à base de riluzole pour le traitement du cancer de la prostate Download PDF

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WO2017091574A1
WO2017091574A1 PCT/US2016/063326 US2016063326W WO2017091574A1 WO 2017091574 A1 WO2017091574 A1 WO 2017091574A1 US 2016063326 W US2016063326 W US 2016063326W WO 2017091574 A1 WO2017091574 A1 WO 2017091574A1
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riluzole
prostate cancer
androgen
agent
individual
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PCT/US2016/063326
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English (en)
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Shahriar Koochekpour
Seyedeh SHOURIDEH-ZIABARI
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Health Research, Inc.
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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
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic 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
    • A61K31/41—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
    • A61K31/4166—1,3-Diazoles having oxo groups directly attached to the heterocyclic ring, e.g. phenytoin
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/58—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids containing heterocyclic rings, e.g. danazol, stanozolol, pancuronium or digitogenin
    • 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

Definitions

  • the present disclosure relates generally to treatment of prostate cancer, and more specifically to use of Riluzole and combinations of Riluzole and other chemotherapeutic agents for treating primary, metastatic and castrate-recurrent or resistant prostate cancer.
  • PCa Primary prostate cancer growth and progression to metastatic or castrate- recurrent or resistant (CR) state is dependent on androgen receptor (AR) (1, 2).
  • AR exists as normal (wild type), mutated forms, or spliced (truncated) variants (e.g., AR-V7) (1, 2, 3).
  • the mutated AR occurs at low rate in primary but at a higher rate in metastatic PCa (2).
  • male hormones testosterone and dihydrotestosterone
  • this receptor will be activated and promotes PCa growth (1, 2).
  • AR-spliced variants mostly exist or develop in PCa that are refractory or resistant to recent modern therapeutic agents (e.g., Abiraterone, Eznalutamide) (3-6).
  • Available treatments for Castrate-recurrent PCa patients include mitoxantrone, zolendronic acid, radioactive isotops, docetaxel, and second generation antiandrogens such as abiraterone (an inhibitor of androgen synthesis) and enzalutamide (an AR-inhibitor or antagonist) (7-9).
  • abiraterone an inhibitor of androgen synthesis
  • enzalutamide an AR-inhibitor or antagonist
  • AR-V7 is the clinically most important spliced variant of AR. In vitro and in vivo studies including clinical
  • This disclosure provides in certain embodiments methods for inhibiting growth of prostate cancer cells in an individual by administering Riluzole to the individual.
  • the individual has a form of prostate cancer that is resistant to an anti-androgen or an anti-androgen receptor (AR) agent, or to both agents.
  • AR anti-androgen receptor
  • Riluzole administered to prostate cancer patients as a stand-alone treatment, and also provides for use of Riluzole to sensitize prostate cancer cells such that they overcome resistance to anti- AR agents and/or anti-androgen agents.
  • the disclosure accordingly comprises in various embodiments administering Riluzole to a prostate cancer patient, and concurrently or subsequently administering to the individual one or more anti-androgen agents, and/or one or more anti-AR agents.
  • the disclosure comprises using Riluzole to sensitize prostate cancer cells to non-steroidal anti-androgen agents, including but not necessarily limited to enzalutamide and bicalutamide.
  • the disclosure comprises diagnosing, and/or selecting an individual who has been diagnosed with prostate cancer, and administering Riluzole to the individual.
  • the method comprises selecting an individual who has prostate cancer that is resistant to an anti-androgen and/or to anti- AR therapy, and subsequently administering Riluzole to the individual to sensitize the prostate cancer to the anti-androgen agent and/or to the anti- AR agent.
  • the individual's prostate cancer is resistant to an anti- AR agent prior to the administration of the Riluzole, and the anti- AR agent is adminsistered with the Riluzole, or subsequent to administration of the Riluzole.
  • prostate cancer cells in the individual express an androgen receptor V7 (AR-V7) splice variant, and/or increased glucocorticoid receptor a (GRa) relative to a non-cancer control, and subsequent to the Riluzole administration expression of the AR-V7 splice variant, and/or expression of the GRa is reduced.
  • AR-V7 androgen receptor V7
  • GRa glucocorticoid receptor a
  • FIG. 1 Riluzole decreased dihydrotestosterone upregulation of prostate-specific antigen in androgen-stimulated prostate cancer cell line, LNCaP.
  • FIG. 1 Riluzole decreases nuclear AR full-length and AR-V7 expression in castrate-recurrent prostate cancer cell lines, 22Rvl and CWR-R1.
  • Figure 4. Riluzole decreased prostate cancer growth in an in vivo tumorigenesis assay. Left panel: Riluzole decreases prostate cancer growth in mice. Right panel: Riluzole does not affect mice body weight in in vivo tumorigenesis assay
  • compositions and methods for treatment of prostate cancer including in individuals who have primary prostate cancer, metastatic prostate cancer, or castrate-resistant prostate cancer.
  • the individual has metastatic castration-resistant prostate cancer.
  • the disclosure comprises administering to an individual with prostate cancer an effective amount of Riluzole such that growth of the prostate cancer is inhibited.
  • the disclosure includes administering Riluzole to individuals whose prostate cancer has developed resistance, or is at risk for developing resistance, to other chemotherapeutic agents, such as anti-androgen or anti-androgen receptor (AR) agents.
  • the individual has a form of prostate cancer that is resistant to a non-steroidal anti-androgen agent, non-limiting examples of which include enzalutamide and bicalutamide.
  • the individual may have a form of prostate cancer that is resistant to a steroidal anti-androgen agent, a non-limiting example of which is abiraterone acetate.
  • the method of the invention results in inhibiting the function and/or expression of AR by prostate cancer cells, including various mutant AR and AR splice variants, and/or results in decreased glucocorticoid receptor (GR) expression and/or GR function by prostate cancer cells.
  • GR glucocorticoid receptor
  • the present disclosure provides demonstrations that Riluzole decreases prostate cancer growth in an in vivo tumorigenesis assay in mice, and also decreases weight of prostate gland in athymic nude mice xenografted with the well-known prostate cancer cell line LNCaP. It is well-know that prostate gland is an androgen-dependent (sensitive) organ and its normal growth, development, and maintenance is dependent on availability of male hormone (androgen, e.g. testosterone) acting through AR.
  • the present disclosure demonstrates that Riluzole is effective at decreasing AR-V7 and glucocorticoid receptor (GRa) expression in enzalutamide and abiraterone-resistant Castrate-recurrent PCa cell lines.
  • the disclosure comprises reducing expression of AR-V7 and GRa. Reductions in such expression can be determined using methods apparent to those skilled in the art, such as by determining transcription and/or protein expression, and by comparison of such measurements to any suitable control.
  • the control comprises a value obtained from determining AR-V7 and GRa expression by non- cancer cells.
  • the disclosure provides for use of Riluzole for treating prostate cancer that is resistant to anti-androgens or anti-ARs and makes available for the first time a combined approach whereby a combination of Riluzole and an anti-androgen or anti-AR agent is used for treating a variety of prostate cancer patients, including those who have developed anti-androgen therapy resistance.
  • the disclosure relates to treatment patients who have primary prostate cancer, metastatic prostate cancer, and castrate-recurrent or resistant prostate cancer.
  • Riluzole As is known in the art, Riluzole (marketed under the trade name RILUTEK®) is a well-tolerated oral medicine, and is the only FDA-approved treatment for Amyotrophic Lateral Sclerosis (ALS). For ALS, it is administered at 100 to 200 mg per day, typically for a period of several weeks or months. It is expected that a similar dosing regimen, or a higher dosage using a similar or modified schedule, will be suitable for use in anti-prostate cancer treatment modalities in human patients.
  • RILUTEK® is a well-tolerated oral medicine, and is the only FDA-approved treatment for Amyotrophic Lateral Sclerosis (ALS). For ALS, it is administered at 100 to 200 mg per day, typically for a period of several weeks or months. It is expected that a similar dosing regimen, or a higher dosage using a similar or modified schedule, will be suitable for use in anti-prostate cancer treatment modalities in human patients.
  • the disclosure comprises selecting an individual who has been diagnosed with any of the aforementioned forms of prostate cancer and administering to the individual an effective amount of Riluzole-containing composition such that growth of the prostate cancer is inhibited.
  • the disclosure comprises testing to determine if the individual has a form of prostate cancer that is resistant to one or more anti-androgen or anti- AR drugs and, subsequent to determining a resistant form of prostate cancer, administering to the individual an effective amount of Riluzole such that growth of the prostate cancer is inhibited.
  • the disclosure includes administering an effective amount of a Riluzole -containing composition to an individual diagnosed or suspected of having, or at risk for recurrence, of an anti-androgen resistant form of prostate cancer.
  • the disclosure comprises administering to an individual diagnosed with any form of prostate cancer a combination of Riluzole and an anti-androgen or anti-AR agent, including but not necessarily limited to non-steroidal anti-androgen agents, examples of which include but are not limited to enzalutamide, abiraterone, and bicalutamide.
  • the disclosure includes receiving a diagnostic result that identifies an individual as having primary prostate cancer, metastatic prostate cancer, or metastatic castration-resistant prostate cancer, and administering to the individual an effective amount of Riluzole, which may be administered in combination with at least one additional chemotherapeutic agent, such as an anti-androgen or anti-AR drug.
  • the disclosure includes receiving a diagnostic result that identifies an individual as having a form of prostate cancer that is resistant to at least one anti-androgen drug and administering to the individual an effective amount of Riluzole alone, or Riluzole in
  • the disclosure comprises administering Riluzole to an individual such that prostate cancer in the individual becomes more sensitive to a distinct chemotherapeutic agent, such as an anti-androgen or anti-AR agent.
  • the disclosure accordingly includes sensitizing prostate cancer to one or more agents to which the prostate cancer was previously resistant.
  • the disclosure excludes administering a Riluzole-containing composition to a prostate cancer patient who has not also been diagnosed with ALS. In embodiments, the disclosure excludes administering a Riluzole-containing composition to an individual who has been diagnosed with or is suspected of having psychological (e.g. depression) or other benign neurological disorders (e.g., Parkinson's disease, Alzheimer).
  • psychological e.g. depression
  • other benign neurological disorders e.g., Parkinson's disease, Alzheimer
  • the disclosure includes combining Riluzole with at least one additional chemotherapeutic agent by mixing them with a standard pharmaceutically acceptable carrier according to known techniques.
  • a standard pharmaceutically acceptable carrier can be found in: Remington: The Science and Practice of Pharmacy (2005) 21st Edition, Philadelphia, PA. Lippincott Williams & Wilkins.
  • Riluzole-containing compositions of the invention may be used to introduce the Riluzole-containing compositions of the invention to an individual. These methods include but are not limited to intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous, oral, intranasal and intra-tumoral routes. Further, even though certain dosing parameters for use of Riluzole are established for ALS, it will be recognized by those of skill in the art that the form and character of the particular dosing regimen employed in the method of the invention will be affected by the route of administration and other well-known variables, such as the size, age and overall health of the individual, and the stage and type of the particular stage of prostate cancer being treated.
  • inhibition of prostate cancer growth comprises a reduction in tumor size, and/or an inhibition of metastasis and/or the formation of metastatic foci, and/or an extension of the life span of an individual diagnosed with prostate cancer relative to an individual who does not receive a Riluzole treatment.
  • the method of the invention can be performed in conjunction with conventional anti-cancer therapies.
  • Such therapies can include but are not limited to other chemotherapies and anti-prostate cancer approaches, such as androgen deprivation therapy, surgical
  • compositions of the invention could be administered prior to, concurrently, or subsequent to such anti-cancer therapies.
  • Riluzole alone can be administered prior to, or subsequent to, or concurrently with any other chemotherapeutic agent.
  • Riluzole is administered to an individual who has been previously and unsuccessfully treated with an anti-androgen agent(s) and/or anti-androgen approach, such as castration, whether chemically or surgically performed.
  • Riluzole is administered with and/or to enhance the effect of another chemotherapeutic agent, non-limiting examples of which include (in addition to the chemotherapeutic agents described above) Radium -223, such as for men with prostate cancer that has metastasized to bone, docetaxel, sipuleucel-T, such as for men who have few or no symptoms produced by the prostate cancer, cabazitaxel, such as for men with prostate cancer that has worsened while receiving docetaxel, mitoxantrone, bicalutamide, Enzalutamide, ARN-509, ODM-201, flutamide, nilutamide, 5a-reductase inhibitors (Finasteride, Dutasteride), LHRH receptor agonists (e.g., Leuprolide, Goserelin, triptorelin), LHRH antagonists (e.g., Abarelix), Ketoconazole, low-dose corticosteroids, i.e.,
  • Androgen-stimulated prostate cancer cell line LNCaP was cultured in androgen- depleted or deprived (phenol red-free RPMI supplemented with 10% charcoal-stripped FBS (CS-FBS)) medium and 1% antibiotic for 48 h. Cells were then treated with dihydrotestosterone (DHT) at 0, 0.1, or 10 nM in the presence or absence of Riluzole at 0, 10, or 25 ⁇ for 4 days.
  • DHT dihydrotestosterone
  • LAPC4, VCaP, CWR-Rl) prostate cancer cell lines were cultured in androgen-deprived culture medium (10% CS-FBS in phenol red-free RPMI) for 48 h. Cells were treated in the presence or absence of Riluzole at 0, 1.0, 10, 25 ⁇ for 4 days. Whole cell lysates were prepared and 30 ⁇ g (for PSA) or 15 ug (for AR) protein for each sample was loaded in Tris-Glycine polyacrylamide gel and subjected to western blotting using the commercial antibodies against AR, PSA, and GAPDH.
  • Riluzole decreased AR and PSA (i.e, androgen and AR-target gene) protein expression in androgen-stimulated (LNCaP, LAPC4, and CWR22Pc) and CRPCa (e.g., C4-2B, CWR-Rl, and VCaP) cell lines.
  • LNCaP androgen-stimulated
  • CRPCa e.g., C4-2B, CWR-Rl, and VCaP
  • Castrate-recurrent prostate cancer cell lines (22Rvl and CWR-Rl) were grown in androgen-deprived culture medium (10% CS-FBS in phenol red-free RPMI) for 48 h. Cells were treated in the presence or absence of Riluzole at 0, 10, 25 ⁇ for 4 days. Nuclear and cytoplasmic protein were prepared using nuclear extraction kit (#40010, Active Motif). Nuclear extracts (30 ⁇ g) and cytoplasmic extracts (15 ⁇ g) were loaded in Tris-Glycine polyacrylamide gel and subjected to electrophoresis and western blotting using the commercial antibodies against AR-full length, AR-V7 (#AG 10008, Precision antibody at 2 ⁇ g/ml), and PSA. Antibody against Lamin B (sc-365962, at 1;200) was used to demonstrate loading control for nuclear proteins.
  • CRPCa cell lines express both AR-FL (wild type or full- length) and AR-V7.
  • This experiment demonstrated that Riluzole at 25 ⁇ was able to decrease both AR-FL and AR-V7 in CRPCa cell lines.
  • these data also demonstrated that Riluzole not only decreased cytoplasmic content, but also nuclear content of AR-FL and AR-V7 in both cell lines. It is noteworthy that the extent of nuclear content of AR-FL or AR-V7 reflects its activity status as a nuclear transcription factor. Therefore, these data demonstrate that Riluzole decreases AR activity in CRPCa cell lines.
  • mice were injected with LNCaP cells subcutaneously (S.Q.) at 200 ⁇ per mouse (2xl0 6 cells mixed with equal volume of Matrigel) into right flank and tumors volume were measured twice weekly. After xenografts reached to a mean volume of 100 mm 3 , mice were randomly divided into two groups. One of the two groups of mice was injected intraperitoneally either with Riluzole (20 mg/kg body wt. in 50%/50%
  • This dosage is equivalent to FDA-approved maximum human dosage (on mg/m 2 basis).
  • Mice body weight and tumors were measured twice weekly using a digital caliper, and the tumor volumes were calculated by the following formula: Length x Length x height x 0.5236. Results were expressed as mean tumor volume, as a function of time. Mice were monitored closely for a period of up to eight weeks before reaching critical tumor volume (-1.2 cm3). All animal studies were performed according to the animal protocol approved by the Roswell Park Cancer Institute Animal Care and Use Committee. For LNCaP tumorigenesis assay, the organ weights (prostate, lung, and kidney) were compared between Riluzole and vehicle treated mice using
  • Tumor volume and body weight were modeled as a function of treatment group (Riluzole versus vehicle), time, their interaction, and a random mouse effect using a first-order autoregressive mixed model.
  • Riluzole decreased tumor growth by 62 % in mice transplanted with prostate cancer cells (i.e., LNCaP) in in vivo tumorigenesis assay (Left). The decrease in tumor growth was started as early as two weeks after Riluzole injection. Riluzole administration did not show adverse effect or decrease total body weight in mice injected with prostate cancer cells (right).
  • This Example addresses the effect of Riluzole on androgen-sensitive (dependent) organ weights in mice. At the end of the experimental period, mice were subjected to necropsy and wet weight of prostate was measured. For controls, weight of androgen-insensitive or independent organs (lung and kidneys) was measured.
  • LNCaP and 22Rvl castrate-recurrent PCa cell line
  • Enzalutamide or Abiraterone under androgen-deprived (depleted) culture condition (10% CS-FBS in phenol red-free RPMI) for a period of 3 to 5 months.
  • These cells were established as Enzalutamide or Abiraterone resistant cell lines and maintained their continuous growth thereafter. Resistant cells were treated with Enzalutamide (20 ⁇ ) or
  • AR-V7 (#AG10008, Precision antibody at 2 ⁇ g/ml)
  • PSA sc-7638 at 1 :200, Santa Cruz Biotechnology
  • GRa sc-8992 at 1 :200, Santa Cruz Biotechnology
  • GAPDH GAPDH
  • LNCaP cell line wild type cells under normal growth condition expresses only
  • AR-FL LNCaP cells resistant to Enzalutamide or Abiraterone express high levels of AR-splice variant 7 (AR-V7) and GRa. With respect to 22Rvl cell type, naturally and under normal culture condition, these cells express easily detectable levels of AR-FL, AR-V7, and GRa (Fig.6). As demonstrated in this experiment, Enzalutamide or Abiraterone resistant LNCaP and 22Rvl cell line show increased levels of AR-V7 and GRa compared to control wild type cell types (Fig. 6). Riluzole treatment in Enzalutamide or Abiraterone-resistant cells decreased the expression of AR-FL (Full-length or wild type), AR-V7, and GRa in both cell lines.
  • AR-FL Full-length or wild type
  • Glucocorticoid receptor confers resistance to antiandrogens by bypassing androgen receptor blockade. Cell. 2013 Dec 5; 155(6): 1309-22.

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Abstract

L'invention concerne des méthodes de traitement du cancer de la prostate. Les méthodes consistent à administrer du Riluzole chez des patients atteints du cancer de la prostate. Le cancer de la prostate peut être résistant à un agent anti-androgène ou à un agent anti-récepteur d'androgène (AR), ou aux deux. L'invention concerne également des méthodes consistant à utiliser du Riluzole pour sensibiliser le cancer de la prostate à des agents anti-androgènes et anti-AR.
PCT/US2016/063326 2015-11-25 2016-11-22 Riluzole et associations médicamenteuses à base de riluzole pour le traitement du cancer de la prostate WO2017091574A1 (fr)

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