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WO2008154382A1 - Inhibiteurs de hdac et médicaments ciblant une hormone pour le traitement du cancer - Google Patents

Inhibiteurs de hdac et médicaments ciblant une hormone pour le traitement du cancer Download PDF

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Publication number
WO2008154382A1
WO2008154382A1 PCT/US2008/066120 US2008066120W WO2008154382A1 WO 2008154382 A1 WO2008154382 A1 WO 2008154382A1 US 2008066120 W US2008066120 W US 2008066120W WO 2008154382 A1 WO2008154382 A1 WO 2008154382A1
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Prior art keywords
cancer
cells
hormone
inhibitor
histone deacetylase
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Vincent C. O. Njar
Robert D. Bruno
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University of Maryland Baltimore
University of Maryland College Park
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University of Maryland Baltimore
University of Maryland College Park
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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
    • A61K31/495—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
    • 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
    • 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 invention relates at least to the fields of medicine and oncology. More specifically, the present invention relates to the methods of treating cancers, including hormone-resistant cancers, for example. In addition to treating the exemplary hormone-resistant cancers, the present invention can be used to increase the sensitivity of cancers to therapy, such as increasing the sensitivity of hormone-resistant cancers to hormonal therapeutic agents, by administering a combination of one or more histone deacetylase inhibitors and one or more hormonal therapeutic agents.
  • Hormone resistance is a particular problem in cancers such as prostate cancer and breast cancer. Androgens, acting via androgen receptors, are essential for normal growth and function of the prostate gland and have been implicated in the progression of prostate cancer. Selective androgen receptor modulators (SARMs) -drugs intended to inhibit the activity of androgen receptors— are therefore standard treatment for prostate cancer. However, prostate cancers often become resistant to such treatment. A similar phenomenon can also occur in breast cancers treated with drugs that target the hormone receptor for estrogen.
  • SARMs selective androgen receptor modulators
  • Breast cancer is the most prevalent form of cancer among women in the United States and second leading cause of cancer related deaths (Jemal et al., 2006). According to 2006 cancer statistics, approximately 40,000 women are expected to die from breast cancer in the US (Jemal et al. 2006). Although, in the year 2003, a marked 7% decrease in the incidence of breast cancer was reported, this decrease mainly was associated with ER+ breast cancers (Ravdin et al. 2006). ER- breast cancer still is essentially incurable and aggressive. Although, breast cancer treatment has undergone significant improvement, cancer develops resistance to almost all forms of therapy. Additionally, there has been no improvement in the treatment of ER- breast cancer. The high prevalence of breast cancer and development of resistance to effective treatments provides a strong stimulus for the development of additional, targeted therapies with minimum toxicity.
  • AEs/ AIs are currently used for postmenopausal ER positive breast cancer agents (Brodie, 1990; Baum, 2002; Baum et al., 2002). The clinical use of these agents is hampered by development of resistance and the presence of ER- cancer phenotype. Loss of AE/ AI sensitivity has been associated with lack of ER expression.
  • BPH benign prostatic hypertrophy
  • prostate cancer are decreased or not detected in eunuchs and are linked not only to advancing age but the presence of testes and androgen function (Gao et al., 1997; Chiarodo, 1991; Sakti and Crawford, 1993).
  • PSA prostate specific antigen
  • AR androgen receptor
  • Androgens play a vital role in the development, growth, and progression of PCa (McConnell, J.D., Urol Clin North Am, 1991. 18(1): p. 1-13).
  • androgens mainly testosterone (T) and dihydrotestosterone (DHT), bind to the AR and initiate transcription of genes involved in cell proliferation and survival (Edwards et al. BJU Int, 2005. 95(9): p. 1320-6; Klaassen et al. Br J Cancer, 2001. 85(4): p. 630-5).
  • the testes synthesize about 90% of T, with the remaining 10% produced by the adrenal glands.
  • T can be subsequently converted DHT by the enzyme steroid 5 ⁇ -reductase that is localized primarily in the prostate (Bruchovsky et al. J Biol Chem, 1968. 243(8): p. 2012-21).
  • Prostate cancer therapy is dependent on the stage of the tumor and AR expression.
  • Early stage androgen-responsive prostate cancers can be treated by castration or with antiandrogens or drugs that block androgen-induced responses including steroidal antiandrogens (cyproterone), LHRH analogs, nonsteroidal antiandrogens (flutamide, nilutamide, bicalutamide), and the potent estrogenic drug diethylstilbestrol (reviewed in (Sadar et al., 1999; Klotz, 2000; Morris et al., 2000; Boccardo, 2000).
  • Ligands for nuclear receptors are also being developed for treatment of prostate cancer through inhibitory NR-AR crosstalk that involves various ligands or drugs that bind the retinoid acid/X-receptors (retinoids), vitamin D receptor (calcitrol), and peroxisome proliferator activate receptor ⁇ (trogilatazone)
  • retinoid acid/X-receptors retinoids
  • vitamin D receptor vitamin D receptor
  • peroxisome proliferator activate receptor ⁇ trogilatazone
  • the present invention is the first to use a combination of a targeted hormone agent and histone deacetylase inhibitors to treat hormone resistant cancers.
  • the present invention concerns treating endocrine- regulated cancers, including, by way of non-limiting example, prostate, testicular, seminal vesicle, breast, uterine, ovary, and cervical cancer.
  • the present invention concerns treating benign prostatic hyperplasia.
  • the present invention concerns diagnosing prostate cancer or benign prostatic hyperplasia.
  • the endocrine-regulated cancer is resistant to one or more therapies, whereas in other aspects the cancer is sensitive to one or more therapies.
  • the endocrine-regulated cancer is resistant to one or more hormone therapies, whereas in other aspects the cancer is sensitive to one or more hormone therapies.
  • the cancer is hormone-resistant cancer, such as, for example, androgen resistant cancer.
  • the invention is drawn to a method of treating a hyperplasia disease, which was originally hormone dependent but has become refractory to hormone therapy, comprising administering to a subject having or suspected of having the hyperplasia disease a histone deacetylase inhibitor and a compound which is both an androgen receptor antagonist and a 17alpha-hydroxylase-C17,20-lyase inhibitor, in an effective amount to treat the hyperplasia disease.
  • the hyperplasia disease is a refractory cancer.
  • the hyperplasia disease is selected from the group consisting of prostate cancer, testicular cancer and cancer of the seminal vesicles.
  • the hyperplasia disease is prostate cancer.
  • the hyperplasia disease is selected from the group consisting of breast cancer, uterine cancer, ovarian cancer, and cervical cancer.
  • the hyperplasia disease is benign prostatic hyperplasia.
  • the histone deacetylase inhibitor is selected from the group consisting of suberoylanilide hydroxamic acid (SAHA), CI-994, MS-275, 3-(l- Methyl-4-phenylacetyl-lH-2-pyrrolyl)-N-hydroxy-2-propenamide (APHA), apicidin, sodium butyrate, (-)-depudecin, scriptaid, sirtinol, trichostatin A, romidepsin, belinostat, LAQ-824, LBH-589, MGCD-0103, KD-5170, depsipeptide, and any combination thereof.
  • SAHA suberoylanilide hydroxamic acid
  • CI-994 MS-275
  • apicidin sodium butyrate
  • (-)-depudecin scriptaid, sirtinol,
  • the histone deacetylase inhibitor is SAHA. In other further embodiments, the histone deacetylase inhibitor is romidepsin.
  • the compound which is both an androgen receptor antagonist and a 17-alpha-hydroxylase-C17,20-lyase inhibitor is 3beta-hydroxy-17-(lH- benzimidazole- 1 -yl)androsta-5 , 16-diene.
  • methods of the invention further comprise administering an effective amount of an androgen receptor antagonist selected from the group consisting of bicalutamide, flutamide, cyproterone acetate and/or a hormone therapy selected from ketoconazole or abiraterone.
  • an androgen receptor antagonist selected from the group consisting of bicalutamide, flutamide, cyproterone acetate and/or a hormone therapy selected from ketoconazole or abiraterone.
  • the histone deacetylase inhibitor and the compound which is both an androgen receptor antagonist and a 17-alpha-hydroxylase-C17,20- lyase inhibitor are administered simultaneously.
  • the histone deacetylase inhibitor is administered prior to the administration of the compound which is both an androgen receptor antagonist and a 17-alpha-hydroxylase-C17,20-lyase inhibitor.
  • the histone deacetylase inhibitor is administered subsequent to the administration of the compound which is both an androgen receptor antagonist and a 17-alpha-hydroxylase-C17,20-lyase inhibitor.
  • the histone deacetylase inhibitor and the compound which is both an androgen receptor antagonist and a 17-alpha-hydroxylase-C17,20-lyase inhibitor act synergistically.
  • the invention is drawn to a method of treating a refractory prostate cancer comprising the step of administering to a subject having or suspected of having the cancer, SAHA or romidepsin and 3beta-hydroxy-17-(lH-benzimidazole-l- yl)androsta-5,16-diene, in a combined effective amount to treat the cancer.
  • the invention is drawn to a method of diagnosing prostate cancer or benign prostatic hyperplasia comprising administering to a patient to be diagnosed, a histone deacetylase inhibitor and a compound which is both an androgen receptor antagonist and a 17-alpha-hydroxylase-C17,20-lyase inhibitor, in a combined amount effective to induce sloughing of prostate cells into the urine or seminal fluid, obtaining a sample of said prostate cells in the urine or seminal fluid, and analyzing the sample for the presence of cancer cells.
  • the histone deacetylase inhibitor is SAHA or romidepsin.
  • the compound which is both an androgen receptor antagonist and a 17-alpha-hydroxylase-C17,20-lyase inhibitor is 3beta-hydroxy-17-(lH-benzimidazole-l- yl)androsta-5,16-diene.
  • FIG. IA-FIG. ID show that ER-breast cancer cells lines incubated with HDACi (SAHA or MS-275) reduced cell viability.
  • FIG. 2 shows that in the letrozole resistant cells HDACi upregulates ERa.
  • FIG. 3 demonstrates that aromatase activity in MDA-MB-231 cells.
  • FIG. 4 shows that HDACis stimulate aromatase activity.
  • FIG. 5 demonstrates that HDACis upregulate ER and aromatase protein expression.
  • FIG. 6 shows cell viability following delivery of a combination of letrozole with HDACi.
  • FIG. 7 shows the structure for 3beta-hydroxy-17-(lH-benzimidazole-l- yl)androsta-5,16-diene (VN/124-1)
  • FIG. 8A-FIG. 8B shows cell viability following delivery of a combination of SAHA and 3beta-hydroxy-17-(lH-benzimidazole-l-yl)androsta-5,16-diene (VN/124-1).
  • FIG. 9A-FIG. 9B shows cell viability following delivery of a combination of SAHA and bicalutamide.
  • FIG. 10 shows cell viability following delivery of a combination of SAHA in the presence and absence of androgen.
  • “about” refers to a numeric value, including, for example, whole numbers, fractions, and percentages, whether or not explicitly indicated.
  • the term “about” generally refers to a range of numerical values (e.g., +/- 5-10% of the recited value) that one of ordinary skill in the art would consider equivalent to the recited value (e.g., having the same function or result). In some instances, the term “about” may include numerical values that are rounded to the nearest significant figure.
  • the term "acquired resistance” as used herein refers to resistance that is acquired after at least one treatment with a given agent. Prior to the at least one treatment, the disorder does not possess a resistance to the agent (and, as such, the disorder responds to the first treatment as would a non-resistant disorder).
  • a hormone-resistant cancer is one that initially responds to at least one treatment of a hormone or endrocrine therapy and thereafter develops a resistance to subsequent treatments of the hormone or endrocrine therapy.
  • androgen receptor antagonist refers to inhibition (partial or complete) of binding between an adrogen and an androgen receptor.
  • An adrogen receptor antagonist includes, for example, a small molecule, or other type of drug or drug-like compound or agent.
  • Examples of an androgen receptor antagonist include, for example, bicalutamide, flutamide, and cyproterone acetate.
  • de novo resistance refers to resistance that exists prior to treatment with a given agent. Therefore, de novo hormone-resistant cancers are resistant to hormone or endocrine therapy prior to the administration of at least one treatment of a hormone or endrocine therapy.
  • a cancer that is de novo resistant to hormone or endocrine therapy is a cancer that is hormone receptor negative (e.g., estrogen receptor negative, progesterone receptor negative or androgen receptor negative).
  • an effective amount or "therapeutically effective amount” as used herein is defined as an amount of the agent that will decrease, reduce, inhibit or otherwise abrogate the growth of a neoplasm, induce apoptosis, inhibit angiogenesis of a neoplasm, inhibit metastasis, or induce cytotoxicity in a neoplasm.
  • an effective amount is an amount sufficient to detectably and repeatedly ameliorate, reduce, minimize or limit the extent of the disease or its symptoms.
  • disease-free survival is defined as a time between the first diagnosis and/or first surgery to treat a cancer patient and a first reoccurrence.
  • a disease-free survival is "low” if the cancer patient has a first reoccurrence within five years after tumor resection, and more specifically, if the cancer patient has less than about 55 % disease- free survival over 5 years.
  • a high disease-free survival refers to at least about 55% disease-free survival over 5 years.
  • endocrine-regulated cancer refers to cancers that progress, at least at some stage of their progression, in a manner dependent on the expression of a hormone or a hormone receptor, including, by way of non-limiting example, estrogen, progesterone, androgen and/or the receptors thereof.
  • hormone-resistant cancer refers to a cancer that has a decreased or eliminated response to a hormone therapy or endocrine therapy when compared to a non-hormone-resistant cancer. From a biological and clinical standpoint, several patterns of resistance can be distinguished: A) tumors that are inherently insensitive to endocrine receptor (e.g., estrogen receptor or androgen receptor) targeting despite endocrine receptor expression (pan-endocrine therapy resistance or de novo resistance); B) tumors that are hormone dependent but resistant to one or more specific endocrine therapies (agent- selective resistance; for example responded to tamoxifen but not aromatase inhibitor); and C) tumors that initially respond to endocrine therapy but subsequently progress (acquired resistance).
  • endocrine receptor e.g., estrogen receptor or androgen receptor
  • the hormone-resistant cancer is a cancer that is hormone-resistant prior to the administration of a hormone or endrocine therapy (i.e., it is de novo hormone-resistant). In other embodiments, the hormone-resistant cancer is a cancer that is initially not hormone-resistant, but becomes hormone-resistant after at least one treatment of a hormone or endocrine therapy.
  • hormone therapy or "endocrine therapy” as used herein is defined as a treatment pertaining to blocking or removing hormones.
  • the treatment may remove the gland that synthesizes the hormone or the prohormone, block or inhibit hormone synthesis, or prevent or inhibit the hormone from binding to its receptor, or down-regulate or degrade the hormone receptor.
  • a hormone therapy of the present invention comprises administration of a compound that is capable of preventing or inhibiting the biologic effects of androgens, including, for example, spironolactone (Aldactone, Spiritone), cyproterone acetate (Androcur, Climen, Diane 35, Ginette 35), flutamide (Eulexin), nilutamide (Anandron, Nilandron), bicalutamide (Casodex), ketoconazole (Nizoral), finasteride (Proscar, Propecia), dutasteride (Avodart), and abiraterone.
  • spironolactone Aldactone, Spiritone
  • cyproterone acetate Androcur, Climen, Diane 35, Ginette 35
  • flutamide Eulexin
  • nilutamide Anandron, Nilandron
  • bicalutamide Cisodex
  • ketoconazole Nizoral
  • finasteride Pros
  • hormone agent or “targeted hormone agent” or “hormone targeted drug” is an agent that blocks or inhibits hormone synthesis, prevents or inhibits the hormone from binding to its receptor, or down-regulates or degrades the hormone receptor.
  • the "hormone agent” or “targeted hormone agent” or “hormone targeted drug” is a compound which is an androgen receptor antagonist and a 17alpha-hydroxylase- C17,20-lyase inhibitor, a 17alpha-hydroxylase-C17,20-lyase inhibitor and a 5-alpha-reductase inhibitor, a 5-alpha-reductase inhibitor, or a combination of the foregoing including, but is not limited to, those agents described in US Pat. No. 5,264,427; US Pat. No. 5,994,334; US Pat. No. 5,994,335; US Pat. No. 6,133,280; US Pat. No. 6,444,683; International Application No.
  • the "hormone agent” or “targeted hormone agent” or “hormone targeted drug” is a compound which is both an androgen receptor antagonist and a 17alpha-hydroxylase-C17,20-lyase inhibitor.
  • a compound which is both an androgen receptor antagonist and a 17alpha-hydroxylase-C17,20-lyase inhibitor is VN/124-1.
  • hyperplasia disease as used herein is defined as a condition comprising an abnormal increase in the number of cells, including benign hyperplasia, in an organ or tissue.
  • the organ or tissue includes a reproductive organ or tissue, including, for example, prostate, testicles, seminal vesicles, breast, uterus, ovaries, and cervix.
  • a hyperplasia disease is begnin prostatic hyperplasia.
  • a hyperplasia disease is a refractory cancer, which may be, for example, a prostate refractory cancer.
  • endocrine therapy-resistant or “hormone resistant” as used herein is defined as a subject receiving an endocrine therapy or hormonal therapy and lacks demonstration of a desired physiological effect, such as a therapeutic benefit, from the administration of the therapy.
  • neoplasm refers to an abnormal formation of tissue, for example, a tumor.
  • a neoplasm encompasses benign tumors and/or malignant tumors.
  • the terms “neoplasm” and “tumor” are interchangeable.
  • non-androgen responsive or “androgen resistant” or “androgen negative” refers to a neoplasm that does not utilize an androgen or a derivative thereof or is not sensitive to an androgen or derivative thereof to develop, proliferative and/or metastasize.
  • the term "refractory” means a cancer that does not respond to treatment.
  • the cancer may be resistant at the beginning of treatment or it may become resistant during treatment.
  • subject as used herein, is taken to mean any mammalian subject to which a composition of the present invention is administered according to the methods described herein.
  • the methods of the present invention are employed to treat a human subject.
  • Another embodiment includes treating a human subject suffering from a prostate or breast neoplasm.
  • the terms “synergistic” or “synergistically” as used herein refer to two or more compounds providing a therapeutic effect that is greater than the sum of the therapeutic effects of the two compounds provided as therapy alone.
  • a therapeutic benefit refers to anything that promotes or enhances the well-being of the subject with respect to the medical treatment of his condition, which includes treatment of pre-cancer, cancer, and hyperproliferative diseases.
  • a list of nonexhaustive examples of this includes extension of the subject's life by any period of time, decrease or delay in the neoplastic development of the disease, decrease in hyperproliferation, reduction in tumor growth, delay of metastases, reduction in cancer cell or tumor cell proliferation rate, and a decrease in pain to the subject that can be attributed to the subject's condition.
  • a therapeutic benefit refers to reversing de novo hormone therapy-resistance or preventing the patient from acquiring an hormone therapy-resistance
  • the present invention provides methods for the treatment of hormone resistant cancers.
  • the present invention relates to a histone deacetylase inhibitor (HDACi) and targeted hormone agents or drugs that shows unexpected, potent synergistic anti-cancer activity.
  • HDACi histone deacetylase inhibitor
  • the HDACi increases the sensitivity of the cells to the targeted hormone agent, thus, this combination of HDACi and traditional hormone therapy can be used to treat cancers that are typically not treatable with hormone therapy.
  • the present invention provides a treatment for hormone resistant cancers in a subject.
  • a targeted hormone agent or drug is a compound which is both an androgen receptor antagonist and a 17alpha-hydroxylase-C17,20-lyase inhibitor.
  • the compound which is both an androgen receptor antagonist and a 17alpha- hydroxylase-C17,20-lyase inhibitor is VN/124-1.
  • the HDACi and a targeted hormone agent or drug are administered to a cell.
  • Cells that are encompassed by the present invention include, but are not limited to prostate cells or breast cells. More specifically, the breast or prostate cell is a cancer cell, a non-cancerous cell or a benign hyperplastic cell.
  • a prostate or breast cancer cell may include, cells that are drug-resistant, primary cancer cells and/or metastatic cancer cells.
  • Certain embodiments include methods for treating or inhibiting the development of breast cancer in a subject at risk, treating or inhibiting breast cancer metastasis in a subject with primary breast cancer, and/or treating or inhibiting breast cancer progression. Also within the scope of the invention is a method of treating benign breast hyperplasia in a human subject afflicted with benign breast hyperplasia comprising administering a HDACi and a targeted hormone agent thereof to the subject in an amount and duration sufficient to result in cell killing or decreases in cell viability.
  • an effective amount of a HDACi and a targeted hormone agent may be administered to a subject suffering from prostate cancer, more specifically, recurrent prostate cancer, more specifically, hormone resistant prostate cancer.
  • a targeted hormone agent e.g., a compound which is both an androgen receptor antagonist and a 17alpha- hydroxylase-C17,20-lyase inhibitor
  • the effectiveness of the therapy according to the present invention can be determined in the treatment of prostate cancer by diagnostic methods that are known and used in the art, for example, but not limited to, analysis of prostate specific antigen (PSA), a prostate biopsy, a rectal exam, or analysis of PSA and rectal exam.
  • PSA prostate specific antigen
  • Other embodiments include methods for inhibiting development of prostate cancer in a subject at risk, inhibiting prostate cancer metastasis in a subject with primary prostate cancer, and/or inhibiting prostate cancer progression in subjects.
  • Benign prostatic hyperplasia or benign prostatic hypertrophy is a condition characterized by overgrowth of prostate tissue that, for example, pushes against the urethra and/or the bladder thereby blocking the flow of urine.
  • Treating benign prostatic hyperplasia or benign prostatic hypertrophy encompasses, for example, methods that reduce prostate tissue, reduce the rate of overgrowth of prostate tissue, or facilitate the maintenance of prostate tissue growth (e.g., inhibit further overgrowth).
  • the levels of prostate specific antigen (PSA) produced by the hyperplastic cells could also be stabilized or reduced upon treatment with a HDACi and a targeted hormone agent.
  • the targeted hormone agent is a compound which is both an androgen receptor antagonist and a 17alpha-hydroxylase-C17,20-lyase inhibitor.
  • the compound which is both an androgen receptor antagonist and a 17alpha-hydroxylase-C17,20-lyase inhibitor is VN/ 124-1.
  • embodiments can include a method of increasing the sensitivity of androgen negative cancer cells or cancer cells that are resistant to hormone therapy by administering an HDACi.
  • the HDACi By administering the HDACi to these androgen negative cancer cells or cancer cells that are resistant to hormone therapy, the HDACi, without being bound by theory, increases expression of androgen receptors thereby increasing the sensitivity of these cells to hormone therapy.
  • Still other embodiments can include a method of increasing the sensitivity of androgen positive cancer cells by administering an HDACi.
  • the HDACi By administering the HDACi to these androgen positive cancer cells, the HDACi down regulates expression of the androgen receptors thereby increasing the sensitivity of these cells to hormone therapy.
  • the cancer cells are androgen positive and the HDACi resensitizes the cells to androgen synthesis inhibitors such as a compound which is both an androgen receptor antagonist and a 17alpha-hydroxylase-C17,20-lyase or a luteinizing hormone-releasing hormone ("LHRH”) agonist.
  • LHRH agonists include leuprolide, goserelin, and triptorelin.
  • HDACs histone deacetylases
  • class I HDACs including, for example, HDACl, HDAC2, HDAC3, HDAC8, HDACI l
  • class II HDACs including, for example, HDAC4, HDAC5, HDAC6, HDAC7, HDAC9, HDAClO
  • class III HDACs class IV HDACs
  • HDAC inhibitors induce hyperacetylation of histones that modulate chromatin structure and gene expression. These inhibitors also induce growth arrest, cell differentiation, and apoptosis of tumor cells. Recently it was reported that HDAC inhibition restores the expression of functional ERa ER- breast cancer cells (Margueron et al. 2004; Sharma et al.
  • HDACis Histone deacetylase inhibitors
  • HDACi such as butyric acid (BA), 4-phenylbutyric acid and trichostatin A reverse this suppression by specific inhibition of HDAC activity, leading to histone hyperacetylation, chromatin relaxation, and enhanced transcription.
  • BA butyric acid
  • 4-phenylbutyric acid and trichostatin A reverse this suppression by specific inhibition of HDAC activity, leading to histone hyperacetylation, chromatin relaxation, and enhanced transcription.
  • HDAC inhibitors are used to increase the sensitivity or to sensitize hormone resistant cancer cells to hormonal therapy.
  • HDACi include, for example, and can be divided into the following groups: short-chain fatty acid derivatives (e.g., sodium butyrate (Cousens et al., J. Biol. Chem. 254, 1716-1723 (1979)); isovalerate (McBain et al., Biochem. Pharm.
  • valerate McBain et al., supra
  • A- phenylbutyrate (4-PBA) Lea and Tulsyan, Anticancer Research, 15, 879-873 (1995)
  • phenylbutyrate PB
  • propionate McBain et al., supra
  • butyramide Lea and Tulsyan, supra
  • isobutyramide Lea and Tulsyan, supra
  • phenylacetate Lea and Tulsyan, supra
  • 3-bromopropionate Lea and Tulsyan, supra
  • tributyrin Guan et al., Cancer Research, 60, 749-755 (2000)
  • valproic acid valproate and Pivanex.TM.
  • hydroxamic acid derivatives e.g., suberoylanilide hydroxamic acid and
  • azelaic bishydroxamic acid (ABHA) (Andrews et al., supra); azelaic- l-hydroxamate-9-anilide (AAHA) (Qiu et al., MoI. Biol. Cell 11, 2069-2083 (2000)); 6-(3-chlorophenylureido) carpoic hydroxamic acid (3C1-UCHA); oxamflatin [(2E)-5-[3-[(phenylsufonyl)amino]phenyl]-pent-2-en-4- ynohydroxamic acid] (Kim et al.
  • cyclic tetrapeptides and derivatives e.g., trapoxin and derivatives, including, for example, trapoxin A (TPX)-cyclic tetrapeptide (cyclo-(L-phenylalanyl-L-phenylalanyl-D- pipecolinyl-L-2-amino-8-oxo-9,10-- epoxy decanoyl)) (Kijima et al., J Biol. Chem.
  • FR901228 FK 228, depsipeptide
  • FR225497 cyclic tetrapeptide
  • FR901228 apicidin cyclic tetrapeptide [cyclo(N-O-methyl-L-tryptophanyl-L- isoleucinyl-D-pipecolinyl-L-2-amino-8— oxodecanoyl)] (Darkin-Rattray et al., Proc.
  • apicidin including, for example, apicidin Ia, apicidin Ib, apicidin Ic, apicidin Ha, and apicidin lib (P.
  • HDAC inhibitors include those mentioned throughout the specification and those known to one of ordinary skill in the art, and include, but are not limited to, 3-(l-Methyl-4- phenylacetyl-lH-2-pyrrolyl)-N-hydroxy-2-propenamide (APHA Compound 8), Cyclo[(2S)-2- amino-8-oxodecanoyl-l-methoxy-L-tryptophyl-L-isoleucyl-(2R)-2-piperidinexcarbonyl] (Apicidin), Butyric Acid Sodium salt (Sodium Butyrate), 4,5:8, 9-Dianhydro- 1,2,6,7, 11- pentadeoxy-D-threo-D-ido-undeca-l,6-dienitol ((-)-Depudecin), 6-(l,3-Dioxo-lH, 3H- benzo[de]isoquinolin-2-yl)-hexanoic acid hydroxy
  • HDACi described in US Pat. Application Publication Nos. 20080119424, 20080085902, 20070060614 and US Patent Nos. 6,673,587, 6,706,686, and those identified by methods for identifying HDACi, including, for example, methods described in US Pat. Application Publication No. 20080057529; and any combination thereof.
  • the HDACi which are commerically available from Sigma-Aldrich Co. (St.
  • Louis, MO can include, SAHA, CI-994, MS-275, 3-(l- Methyl-4-phenylacetyl-lH-2-pyrrolyl)-N-hydroxy-2-propenamide (APHA), apicidin, sodium butyrate, (-)-depudecin, scriptaid, sirtinol, and trichostatin A.
  • Treatment methods will involve treating an individual with an effective amount of a HDACi and a targeted hormone agent or drug.
  • An effective amount is described, generally, as that amount sufficient to detectably and repeatedly to ameliorate, reduce, minimize or limit the extent of a disease or its symptoms. More specifically, it is envisioned that the treatment with the HDACi and targeted hormone agent will kill cells, inhibit cell growth, inhibit metastasis, decrease tumor size and otherwise reverse or reduce the malignant phenotype of tumor cells.
  • An effective amount of an HDACi and a targeted hormone agent or drug that may be administered to a cell includes a dose of about O.OOl ⁇ M to about 1000 ⁇ M; about O.Ol ⁇ M to about 1000 ⁇ M; about O.l ⁇ M to about 1000 ⁇ M; about O.OOl ⁇ M to about 100 ⁇ M; about O.Ol ⁇ M to about 100 ⁇ M; about O.l ⁇ M to about 100 ⁇ M; about O.OOl ⁇ M to about 10 ⁇ M; about O.Ol ⁇ M to about 10 ⁇ M; about O.l ⁇ M to about 10 ⁇ M; about O.OOl ⁇ M to about 1 ⁇ M; about O.Ol ⁇ M to about 1 ⁇ M; and about O.l ⁇ M to about 1 ⁇ M.
  • doses of an HDACi and a target hormone agent or drug to be administered are from about about about O.Ol ⁇ M to about 0.1 ⁇ M; about O.Ol ⁇ M to about 0. 2 ⁇ M; about O.Ol ⁇ M to about 0.3 ⁇ M; about O.Ol ⁇ M to about 0.4 ⁇ M; about O.Ol ⁇ M to about 0.5 ⁇ M; about O.Ol ⁇ M to about 0.6 ⁇ M; about O.Ol ⁇ M to about 0.7 ⁇ M; about O.Ol ⁇ M to about 0.8 ⁇ M; about O.Ol ⁇ M to about 0.9 ⁇ M; O.OOl ⁇ M to about 0.01 ⁇ M; about O.OOl ⁇ M to about 0.02 ⁇ M; about O.OOl ⁇ M to about 0.03 ⁇ M; about O.OOl ⁇ M to about 0.04 ⁇ M; about O.OOl ⁇ M to about 0.05 ⁇ M; about O.OOl ⁇ M to about 0.06 ⁇ M; about O.OOl ⁇ M to
  • the effective amount or "therapeutically effective amounts" of the HDACi and a targeted hormone agent or drug to be used are those amounts effective to produce beneficial results, particularly with respect to cancer treatment, in the recipient animal or patient. Such amounts may be initially determined by reviewing the published literature, by conducting in vitro tests or by conducting metabolic studies in healthy experimental animals. Before use in a clinical setting, it may be beneficial to conduct confirmatory studies in an animal model, preferably a widely accepted animal model of the particular disease to be treated.
  • Preferred animal models for use in certain embodiments are rodent models, which are preferred because they are economical to use and, particularly, because the results gained are widely accepted as predictive of clinical value.
  • a specific dose level of active compounds such as HDACi and a targeted hormone agent or drug any particular patient depends upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy. The person responsible for administration will determine the appropriate dose for the individual subject. Moreover, for human administration, preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biologies standards.
  • a therapeutically effective amount of HDACi and a targeted hormone agent or drug as a treatment varies depending upon the host treated and the particular mode of administration.
  • the dose range of the HDACi and a targeted hormone agent or drug will be about 0.5 mg/kg body weight to about 500 mg/kg body weight.
  • body weight is applicable when an animal is being treated. When isolated cells are being treated, “body weight” as used herein should read to mean “total cell weight”. The term “total weight” may be used to apply to both isolated cell and animal treatment. All concentrations and treatment levels are expressed as “body weight” or simply “kg” in this application are also considered to cover the analogous "total cell weight” and “total weight” concentrations.
  • a variety of different dosage levels will be of use, for example, about 0.001 mg/kg, 0.01 mg/kg, 0.1 mg/kg, 0.2 mg/kg, 0.3 mg/kg, 0.4 mg/kg, 0.5 mg/kg, 0.6 mg/kg, 0.7 mg/kg, 0.8 mg/kg, 0.9 mg/kg, 1 mg/kg, 2 mg/kg, 3 mg/kg, 4 mg/kg, 5 mg/kg, 7.5 mg/kg, 10 mg/kg, 12.5 mg/kg, 15 mg/kg, 17.5 mg/kg, 20 mg/kg, 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 60 mg/kg, 70 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 120 mg/kg, 140 mg/kg, 150 mg/kg, 160 mg/kg, 180 mg/kg, 200 mg/kg, 225 mg/kg, 250mg/kg, 275mg/kg, 300 mg
  • administration of the HDACi SAHA can be, for example, 400 mg or about 400 mg given orally once daily with food (SAHA can also be given without food). If the subject exhibits dose-limiting toxicities to this dose, the dose may be reduced to 300 mg or about 300 mg orally once daily with food. If necessary, the dose may be further reduced to 300 mg or about 300 mg once daily with food for 5 consecutive days each week, or every other day each week.
  • the dose of SAHA can be signigicantly reduced (e.g., 300 mg or about 300 mg given orally once daily with food, 250 mg or about 250 mg given orally once daily with food, 200 mg or about 200 mg given orally once daily with food, 150 mg or about 150 mg given orally once daily with food, 100 mg or about 100 mg given orally once daily with food, 50 mg or about 50 mg given orally once daily with food) while still providing therapeutic benefit when administered in combination with a compound which is both an androgen receptor antagonist and a 17-alpha-hydroxylase- C17,20-lyase inhibitor (e.g., VN/124-1).
  • a compound which is both an androgen receptor antagonist and a 17-alpha-hydroxylase- C17,20-lyase inhibitor e.g., VN/124-1).
  • the treatments may include various "unit doses.”
  • Unit dose is defined as containing a predetermined quantity of the HDACi and targeted hormone agent calculated to produce the desired responses in association with its administration, i.e., the appropriate route and treatment regimen.
  • the quantity to be administered, and the particular route and formulation, are within the skill of those in the clinical arts.
  • Also of import is the subject to be treated, in particular, the state of the subject and the protection desired.
  • a unit dose need not be administered as a single injection but may comprise continuous infusion over a set period of time.
  • the tumor may be infused or perfused with the composition using any suitable delivery vehicle.
  • Continuous administration also may be applied where appropriate, for example, where a tumor is excised and the tumor bed is treated to eliminate residual, microscopic disease. Delivery via syringe or catherization is preferred. Such continuous perfusion may take place for a period from about 1-2 hours, to about 2-6 hours, to about 6-12 hours, to about 12-24 hours, to about 1-2 days, to about 1-2 wk or longer following the initiation of treatment.
  • the dose of the therapeutic composition via continuous perfusion will be equivalent to that given by a single or multiple injections, adjusted over a period of time during which the perfusion occurs.
  • the volume to be administered will be about 4-10 ml (preferably 10 ml), while for tumors of ⁇ 4 cm, a volume of about 1-3 ml will be used (preferably 3 ml).
  • Multiple injections delivered as single dose comprise about 0.1 to about 0.5 ml volumes.
  • the tumor being treated may not, at least initially, be resectable.
  • Treatments with a HDACi and a targeted hormone agent may increase the resectability of the tumor due to shrinkage at the margins or by elimination of certain particularly invasive portions. Following treatments, resection may be possible. Additional treatments subsequent to resection will serve to eliminate microscopic residual disease at the tumor site.
  • HDACi and the targeted hormone agent thereof may be used in combination with an additional therapeutic agent to more effectively treat the cancer.
  • Anticancer agents may include but are not limited to, radiotherapy, chemotherapy, gene therapy, or immunotherapy that targets cancer/tumor cells.
  • the effective amounts of the additional therapeutic agent may simply be defined as that amount effective to inhibit and/or reduce the cancer growth when administered to an animal in combination with the HDACi and the hormonal therapy agents. This may be easily determined by monitoring the animal or patient and measuring those physical and biochemical parameters of health and disease that are indicative of the success of a given treatment. Such methods are routine in animal testing and clinical practice.
  • compositions of the present invention To kill cells, induce cell-cycle arrest, inhibit cell growth, inhibit metastasis, inhibit angiogenesis or otherwise reverse or reduce the malignant phenotype of cancer cells, using the methods and compositions of the present invention, one would generally contact a cell with HDACi and the hormonal therapy agent thereof in combination with an additional therapeutic agent. These compositions would be provided in a combined amount effective to inhibit cell growth and/or induce apoptosis in the cell. This process may involve contacting the cells with HDACi and the hormonal therapy agent thereof in combination with an additional therapeutic agent or factor(s) at the same time.
  • This may be achieved by contacting the cell with a single composition or pharmacological formulation that includes both agents, or by contacting the cell with two distinct compositions or formulations, at the same time, wherein one composition includes the HDACi and the hormonal therapy agent thereof and the other includes the additional agent.
  • treatment with HDACi and the hormonal therapy agent may precede or follow the additional agent treatment by intervals ranging from minutes to weeks.
  • the additional agent is applied separately to the cell, one would generally ensure that a significant period of time did not expire between the time of each delivery, such that the agent would still be able to exert an advantageously combined effect on the cell.
  • chemotherapy may be administered, as is typical, in regular cycles.
  • a cycle may involve one dose, after which several days or weeks without treatment ensues for normal tissues to recover from the drug's side effects. Doses may be given several days in a row, or every other day for several days, followed by a period of rest. If more than one drug is used, the treatment plan will specify how often and exactly when each drug should be given. The number of cycles a person receives may be determined before treatment starts (based on the type and stage of cancer) or may be flexible, in order to take into account how quickly the tumor is shrinking. Certain serious side effects may also require doctors to adjust chemotherapy plans to allow the patient time to recover.
  • Chemotherapeutic agents that may be used in combination with the present invention, include, but are not limited to cisplatin (CDDP), carboplatin, procarbazine, mechlorethamine, cyclophosphamide, camptothecin, ifosfamide, melphalan, chlorambucil, busulfan, nitrosurea, dactinomycin, daunorubicin, doxorubicin, bleomycin, plicomycin, mitomycin, etoposide (VP16), tamoxifen, raloxifene, estrogen receptor binding agents, gemcitabien, navelbine, farnesyl-protein tansferase inhibitors, transplatinum, 5-fluorouracil and methotrexate, or any analog or derivative variant of the foregoing.
  • CDDP cisplatin
  • carboplatin carboplatin
  • procarbazine mechlorethamine
  • cyclophosphamide camp
  • Radiotherapeutic agents may also be use in combination with the compounds of the present invention in treating a cancer.
  • factors that cause DNA damage and have been used extensively include what are commonly known as ⁇ -rays, X-rays, and/or the directed delivery of radioisotopes to tumor cells.
  • Other forms of DNA damaging factors are also contemplated such as microwaves and UV-irradiation. It is most likely that all of these factors effect a broad range of damage on DNA, on the precursors of DNA, on the replication and repair of DNA, and on the assembly and maintenance of chromosomes.
  • Dosage ranges for X-rays range from daily doses of 50 to 200 roentgens for prolonged periods of time (3 to 4 wk), to single doses of 2000 to 6000 roentgens.
  • Dosage ranges for radioisotopes vary widely, and depend on the half-life of the isotope, the strength and type of radiation emitted, and the uptake by the neoplastic cells.
  • Immunotherapeutic s may also be employed in the present invention in combination with HDACi and the hormonal therapy agent in treating cancer.
  • Immunotherapeutic s generally, rely on the use of immune effector cells and molecules to target and destroy cancer cells.
  • the immune effector may be, for example, an antibody specific for some marker on the surface of a tumor cell.
  • the antibody alone may serve as an effector of therapy or it may recruit other cells to actually effect cell killing.
  • the antibody also may be conjugated to a drug or toxin (chemotherapeutic, radionuclide, ricin A chain, cholera toxin, pertussis toxin, etc.) and serve merely as a targeting agent.
  • the effector may be a lymphocyte carrying a surface molecule that interacts, either directly or indirectly, with a tumor cell target.
  • Various effector cells include cytotoxic T cells and NK cells.
  • the tumor cell must bear some marker that is amenable to targeting, i.e., is not present on the majority of other cells.
  • Common tumor markers include carcinoembryonic antigen, prostate specific antigen, urinary tumor associated antigen, fetal antigen, tyrosinase (p97), gp68, TAG-72, HMFG, Sialyl Lewis Antigen, MucA, MucB, PLAP, estrogen receptor, laminin receptor, erb B and pi 55.
  • the tumor suppressor oncogenes function to inhibit excessive cellular proliferation.
  • the inactivation of these genes destroys their inhibitory activity, resulting in unregulated proliferation.
  • the tumor suppressors p53, pl6 and C-CAM are described below.
  • mutant p53 has been found in many cells transformed by chemical carcinogenesis, ultraviolet radiation, and several viruses.
  • the p53 gene is a frequent target of mutational inactivation in a wide variety of human tumors and is already documented to be the most frequently mutated gene in common human cancers. It is mutated in over 50% of human NSCLC (Hollstein et al., 1991) and in a wide spectrum of other tumors.
  • the p53 gene encodes a 393-amino acid phosphoprotein that can form complexes with host proteins such as large-T antigen and ElB.
  • the protein is found in normal tissues and cells, but at concentrations which are minute by comparison with transformed cells or tumor tissue.
  • Wild-type p53 is recognized as an important growth regulator in many cell types. Missense mutations are common for the p53 gene and are essential for the transforming ability of the oncogene. A single genetic change prompted by point mutations can create carcinogenic p53. Unlike other oncogenes, however, p53 point mutations are known to occur in at least 30 distinct codons, often creating dominant alleles that produce shifts in cell phenotype without a reduction to homozygosity. Additionally, many of these dominant negative alleles appear to be tolerated in the organism and passed on in the germ line. Various mutant alleles appear to range from minimally dysfunctional to strongly penetrant, dominant negative alleles (Weinberg, 1991).
  • Another inhibitor of cellular proliferation is pi 6.
  • the major transitions of the eukaryotic cell cycle are triggered by cyclin-dependent kinases, or CDK' s.
  • CDK cyclin-dependent kinase 4
  • the activity of this enzyme may be to phosphorylate Rb at late Gl .
  • the activity of CDK4 is controlled by an activating subunit, D-type cyclin, and by an inhibitory subunit, the pl6INK4 has been biochemically characterized as a protein that specifically binds to and inhibits CDK4, and thus may regulate Rb phosphorylation (Serrano et al., 1993; Serrano et al., 1995). Since the pl6INK4 protein is a CDK4 inhibitor (Serrano, 1993), deletion of this gene may increase the activity of CDK4, resulting in hyperphosphorylation of the Rb protein. pl6 also is known to regulate the function of CDK6.
  • pl6INK4 belongs to a newly described class of CDK-inhibitory proteins that also includes pl6B, pl9, p21WAFl, and p27KIPl.
  • the pl6INK4 gene maps to 9p21, a chromosome region frequently deleted in many tumor types. Homozygous deletions and mutations of the pl6INK4 gene are frequent in human tumor cell lines. This evidence suggests that the pl6INK4 gene is a tumor suppressor gene.
  • genes that may be employed according to the present invention include Rb, mda-7, APC, DCC, NF-I, NF-2, WT-I, MEN-I, MEN-II, zacl, p73, VHL, MMAC1/PTEN, DBCCR-I, FCC, rsk-3, p27, p27/pl6 fusions, p21/p27 fusions, anti-thrombotic genes (e.g., COX-I, TFPI), PGS, Dp, E2F, ras, myc, neu, raf, erb, fms, trk, ret, gsp, hst, abl, ElA, p300, genes involved in angiogenesis (e.g., VEGF, FGF, thrombospondin, BAI-I, GDAIF, or their receptors) and MCC.
  • angiogenesis e.g., VEGF, FGF
  • Apoptosis or programmed cell death, is an essential process in cancer therapy (Kerr et al., 1972).
  • the Bcl-2 family of proteins and ICE-like proteases have been demonstrated to be important regulators and effectors of apoptosis in other systems.
  • the Bcl-2 protein discovered in association with follicular lymphoma, plays a prominent role in controlling apoptosis and enhancing cell survival in response to diverse apoptotic stimuli (Bakhshi et al., 1985; Cleary and Sklar, 1985; Cleary et al., 1986; Tsujimoto et al., 1985; Tsujimoto and Croce, 1986).
  • the evolutionarily conserved Bcl-2 protein now is recognized to be a member of a family of related proteins, which can be categorized as death agonists or death antagonists.
  • Bcl-2 that function to promote cell death such as, Bax, Bak, Bik, Bim, Bid, Bad and Harakiri, are contemplated for use in combination with HDACi and a homonal therapy agent thereof in treating cancer.
  • a surgical procedure may be employed in the present invention.
  • Approximately 60% of persons with cancer will undergo surgery of some type, which includes preventative, diagnostic or staging, curative and palliative surgery.
  • Curative surgery includes resection in which all or part of cancerous tissue is physically removed, excised, and/or destroyed.
  • Tumor resection refers to physical removal of at least part of a tumor.
  • treatment by surgery includes laser surgery, cryosurgery, electro surgery, and miscopically controlled surgery (Mohs' surgery).
  • the present invention may be used in conjunction with removal of superficial cancers, precancers, or incidental amounts of normal tissue.
  • a cavity may be formed in the body.
  • Treatment may be accomplished by perfusion, direct injection or local application of the area with an additional anti-cancer therapy.
  • Such treatment may be repeated, for example, every 1, 2, 3, 4, 5, 6, or 7 days, or every 1, 2, 3, 4, and 5 weeks or every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months.
  • These treatments may be of varying dosages as well.
  • agents may be used in combination with the present invention to improve the therapeutic efficacy of treatment.
  • additional agents include immunomodulatory agents, agents that affect the upregulation of cell surface receptors and GAP junctions, cytostatic and differentiation agents, inhibitors of cell adhesion, or agents that increase the sensitivity of the hyperproliferative cells to apoptotic inducers.
  • Immunomodulatory agents include tumor necrosis factor; interferon alpha, beta, and gamma; IL- 2 and other cytokines; F42K and other cytokine analogs; or MIP-I, MIP-lbeta, MCP-I, RANTES, and other chemokines.
  • cell surface receptors or their ligands such as Fas / Fas ligand, DR4 or DR5 / TRAIL would potentiate the apoptotic inducing abilities of the present invention by establishment of an autocrine or paracrine effect on hyperproliferative cells. Increased intercellular signaling by elevating the number of GAP junctions would increase the anti-hyperproliferative effects on the neighboring hyperproliferative cell population.
  • cytostatic or differentiation agents can be used in combination with the present invention to improve the anti-hyperproliferative efficacy of the treatments.
  • Inhibitors of cell adhesion are contemplated to improve the efficacy of the present invention.
  • cell adhesion inhibitors are focal adhesion kinase (FAKs) inhibitors and Lovastatin. It is further contemplated that other agents that increase the sensitivity of a hyperproliferative cell to apoptosis, such as the antibody c225, could be used in combination with the present invention to improve the treatment efficacy.
  • FAKs focal adhesion kinase
  • Lovastatin Lovastatin
  • compositions of HADCi and/or hormone therapy agents it will be necessary to prepare pharmaceutical compositions of HADCi and/or hormone therapy agents, or any additional therapeutic agent disclosed herein in a form appropriate for the intended application. Generally, this will entail preparing compositions that are essentially free of pyrogens, as well as other impurities that could be harmful to humans or animals.
  • compositions of the present invention in an effective amount may be dissolved or dispersed in a pharmaceutically acceptable carrier or aqueous medium. Such compositions also are referred to as inocula.
  • pharmaceutically or pharmacologically acceptable refers to molecular entities and compositions that do not produce adverse, allergic, or other untoward reactions when administered to an animal or a human.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like.
  • the use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the vectors or cells of the present invention, its use in therapeutic compositions is contemplated. Supplementary active ingredients also can be incorporated into the compositions.
  • composition(s) of the present invention may be delivered orally, nasally, intramuscularly, intraperitoneally, or intratumorally.
  • local or regional delivery of the composition thereof, alone or in combination with an additional therapeutic agent, to a patient with cancer or pre-cancer conditions will be a very efficient method of delivery to counteract the clinical disease.
  • chemo- or radiotherapy may be directed to a particular, affected region of the subject' s body.
  • Regional chemotherapy typically involves targeting anticancer agents to the region of the body where the cancer cells or tumor are located.
  • Other examples of delivery of the compounds of the present invention that may be employed include intra-arterial, intracavity, intravesical, intrathecal, intrapleural, and intraperitoneal routes.
  • Intra-arterial administration is achieved using a catheter that is inserted into an artery to an organ or to an extremity. Typically, a pump is attached to the catheter. Intracavity administration describes when chemotherapeutic drugs are introduced directly into a body cavity such as intravesical (into the bladder), peritoneal (abdominal) cavity, or pleural (chest) cavity. Agents can be given directly via catheter. Intravesical chemotherapy involves a urinary catheter to provide drugs to the bladder, and is thus useful for the treatment of bladder cancer.
  • Intrapleural administration is accomplished using large and small chest catheters, while a Tenkhoff catheter (a catheter specially designed for removing or adding large amounts of fluid from or into the peritoneum) or a catheter with an implanted port is used for intraperitoneal chemotherapy. Because most drugs do not penetrate the blood/brain barrier, intrathecal chemotherapy is used to reach cancer cells in the central nervous system. To do this, drugs are administered directly into the cerebrospinal fluid. This method is useful to treat leukemia or cancers that have spread to the spinal cord or brain.
  • Intravenous therapy can be implemented in a number of ways, such as by peripheral access or through a vascular access device (VAD).
  • a VAD is a device that includes a catheter, which is placed into a large vein in the arm, chest, or neck. It can be used to administer several drugs simultaneously, for long-term treatment, for continuous infusion, and for drugs that are vesicants, which may produce serious injury to skin or muscle.
  • vascular access devices are available.
  • compositions of the present invention may include classic pharmaceutical preparations Administration of these compositions according to the present invention will be via any common route so long as the target tissue is available via that route. This includes but is not limited to, oral, nasal, or buccal routes. Alternatively, administration may be by orthotopic, intradermal, subcutaneous, intramuscular, intraperitoneal or intravenous injection. Such compositions would normally be administered as pharmaceutically acceptable compositions, described supra.
  • the drugs and agents also may be administered parenterally or mtraperitoneally.
  • parenteral is generally used to refer to drugs given intravenously, intramuscularly, or subcutaneously.
  • Solutions of the active compounds as free base or pharmacologically acceptable salts can be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions also can be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
  • compositions of the present invention may be administered in the form of injectable compositions either as liquid solutions or suspensions; solid forms suitable for solution in, or suspension in, liquid prior to injection may also be prepared. These preparations also may be emulsified.
  • a typical composition for such purpose comprises a pharmaceutically acceptable carrier.
  • the composition may contain 10 mg, 25 mg, 50 mg or up to about 100 mg of human serum albumin per milliliter of phosphate buffered saline.
  • Other pharmaceutically acceptable carriers include aqueous solutions, non-toxic excipients, including salts, preservatives, buffers and the like.
  • non-aqueous solvents examples include propylene glycol, polyethylene glycol, vegetable oil and injectable organic esters such as ethyloleate.
  • Aqueous earners include water, alcoholic/aqueous solutions, saline solutions, parenteral vehicles such as sodium chlo ⁇ de, Ringer's dextrose, etc.
  • Intravenous vehicles include fluid and nutrient replenishers.
  • Preservatives include antimicrobial agents, antioxidants, chelating agents and inert gases. The pH, exact concentration of the various components, and the pharmaceutical composition are adjusted according to well known parameters.
  • Suitable excipients for formulation include croscarmellose sodium, hydroxypropyl methylcellulose, iron oxides synthetic), magnesium stearate, microcrystallme cellulose, polyethylene glycol 400, polysorbate 80, povidone, silicon dioxide, titanium dioxide, and water (purified).
  • Oral formulations include such typical excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate and the like.
  • the compositions take the form of solutions, suspensions, tablets, pills, capsules, sustained release formulations or powders.
  • the route is topical, the form may be a cream, ointment, salve or spray.
  • kits Any of the compositions described herein may be comprised in a kit.
  • an HDAC inhibitor and/or a compound that is both an androgen receptor antagonist and a 17alpha-hydroxylase-C17,20-lyase inhibitor may be comprised in a kit.
  • the kits may comprise a suitably aliquoted HDAC inhibitor and compound that is both an androgen receptor antagonist and a 17alpha-hydroxylase-C17,20-lyase inhibitor, and the components of the kits may be packaged either in aqueous media or in lyophilized form.
  • the container means of the kits will generally include at least one vial, test tube, flask, bottle, syringe or other container means, into which a component may be placed, and preferably, suitably aliquoted. Where there are more than one component in the kit, the kit also will generally contain a second, third or other additional container into which the additional components may be separately placed. However, various combinations of components may be comprised in a vial.
  • the kits of the present invention also will typically include a means for containing the HDAC inhibitor and/or compound that is both an androgen receptor antagonist and a 17alpha-hydroxylase- C17,20-lyase inhibitor and any other reagent containers in close confinement for commercial sale. Such containers may include injection or blow molded plastic containers into which the desired vials are retained.
  • kits of the invention may also comprise, and/or be packaged with, an instrument for assisting with the injection/administration and/or placement of a component of the kit within the body of an animal or a cell therefrom.
  • an instrument may be a syringe, pipette, forceps, and/or any such medically approved delivery vehicle, for example.
  • MTT assay was performed to measure viability of breast cancer cells after treatment with various test compounds (Sabnis let al. 2005). ICso and IC25 values for inhibitors is calculated from the linear regression line of the plot of percentage inhibition versus log inhibitor concentration. These IC50 values is used for combination or sequencing studies. The effect of combination or sequence of treatment is be determined at IC25 of each agent.
  • ELISA based ERE activity assay are used. This assay is performed on nuclear extracts of untreated or HDACi pretreated malignant breast cells preparation of nuclear extracts and ERE activity assay is performed as per manufacture's instructions (Panomics).
  • ER- MD A-MB -231 cells This cell line exhibits no ERa protein expression by western blotting and are refractory to growth inhibitory effects of AEs such as tamoxifen and fulvestrant or AIs such as letrozole, exemestane and anastrozole. In addition, proliferation of these cells was not affected by E 2 . On the other hand, these cells were significantly inhibited by HDACis SAHA and MS-275 as shown in FIG. IA - FIG. IB. The IC 50 values for SAHA was 205.1 nM. The IC 50 value for MS-275 was 81.72 nM.
  • FIG. ID shows that letrozole alone did not inhibit growth of MDA-MB-231 cells, however, when combined with SAHA, the combination was found to synergistically inhibit cell growth in a dose dependent manner. Similar results were also obtained in cells that have acquired resistance to letrozole (LTLT-Ca).
  • ERa protein expression of ERa was up-regulated 9.9 and 8 fold after treatment with HDACis SAHA, MS-275 (1OnM) respectively.
  • ERa protein expression was up-regulated 15 fold after treatment with l ⁇ M BA for 24 hours. This restoration of ERa was also associated with restoration of response to tamoxifen.
  • the combination of HDACi with tamoxifen was significantly better than single agent alone (p ⁇ 0.01).
  • Aromatse activity was measured by Yue et al. (1997). In addition, the expression and activation of aromatase was seen after treatment with HDACi. The basal level of aromatase activity in MDA-MB-231 cells was found to be 3.02 pmoles/ ⁇ g of protein/hour. When treated with MS-275 (l ⁇ M) for 24 hours and then incubated with l ⁇ -3H-Androstenedione for 18 hours, the aromatase activity was found to be 15.193 pmoles/ ⁇ g of protein/hour. This up- regulation of aromatase activity was dose dependent. A similar increase in aromatase activity was observed after pre-treatment with butyric acid. Also, a 24 hour treatment of MDA-MB-231 cells with MS-275 (1OnM), SAHA (1OnM) and BA (l ⁇ M) up-regulated the expression of aromatase by 2.6, 1.77 and 1.2 fold respectively.
  • MDA-MB-231 and SKBr3 tumors using in vivo mouse xenograft model are estrogen independent ER- cell lines.
  • SKBr3 cells are essentially used for studies with AIs, since these cells have endogenous high levels of aromatase, which is inhibited by AIs.
  • This model simulates advanced and ER-, hormone refractory breast cancer, which is usually associated with mortality of the disease.
  • the xenograft studies are performed as described by Long et al. 2004; Takabatake et al. 2007. Each agent is given at 5 different doses (doses will depend on MED as determined in specific aim 2) po and sc and effect on the growth of tumors will be examined.
  • tumors are measured weekly with calipers and tumor volume calculated using the formula 4/3 ⁇ rl 2 r 2 .
  • the animals are euthanized, tumors and uteri are weighed and collected for further analysis.
  • the weight of the uteri is an important bioassay for estrogenic/antiestrogenic activity of the administered agent, since OVX mice have no significant source of estrogen production.
  • the tumors are examined for expression of signaling proteins in the ER pathway as well as activity of ER and downstream targets. The dose of each agent that causes maximum inhibition of tumor growth are used for combination studies.
  • Example 4 Mouse xenograft studies combination of HDACi with AEs/AIs
  • mice receive treatment for a period of at least 8 weeks.
  • the groups of treatment (n ⁇ 10) used in the experiment include (but may not be limited to) the following: Groups to be tested: l.Vehicle treated control, 2.AE alone (sc 5 times a week), 3.AI alone (sc 5 times a week), 4.HDACi alone, 5.HDACi plus AE, 6.HDACi plus AI, 8.HDACi and AE in sequence, 9.HDACi and AI in sequence.
  • the dose, frequency and route of administration for HDACi are determined from the above experiments.
  • AEs and AIs are used as determined (Lu et al., 1999) and the drugs will be given sc During the course of experiment, tumor volumes are measured weekly. After approximately 6-8 weeks, the animals are euthanized, tumors and uteri will be weighed collected for further analysis. The tumors are examined for expression of signaling proteins in the ER pathway as well as activity of ER and downstream targets.
  • MDA-MB-231 cells are injected intravenously into OVX nude mice. All the above- mentioned agents are administered and after 4 weeks, mice are sacrificed and formation of pleural metastasis are assessed.
  • MTT assay is performed to measure viability of prostate cancer cells after treatment with various test compounds (Sabnis let al. 2005). ICso and IC25 values for inhibitors is calculated from the linear regression line of the plot of percentage inhibition versus log inhibitor concentration. These ICso values is used for combination or sequencing studies. The effect of combination or sequence of treatment is be determined at IC25 of each agent.
  • the protein extracts from prostate cancer cells are subjected to western immunoblotting (Sabnis et al. 2005). Protein expression of androgen receptor are examined following HDACi treatment.
  • ELISA based activity assay To measure the transcriptional activity of re-expressed androgen receptor in the androgen receptor negative- cells ELISA based activity assay are used. This assay is performed on nuclear extracts of untreated or HDACi pretreated malignant prostate cells preparation of nuclear extracts and activity assay is performed as per manufacture's instructions (Panomics).
  • non-malignant and malignant prostate cells are pre-treated with HDACi followed by treatment with an androgen and the viability of cells measured by MTT assay.
  • Example 7 HDAC Inhibitors sensitize ER-negative breast cancer cells to aromatase inhibitors
  • Exemplary ER negative cell lines (MDA-MB-231) were used.
  • 10 4 cells were plated in a 96 well plate and treated with indicated drugs for 6 days. The medium was replaced after 3 days. On day 7, 500 ⁇ g/ml of MTT solution was added to each well and cells incubated for 3 hours. The tetrazolium dye trapped inside the mitochondria of the cells was dissolved in DMSO and the absorbance was measured at 560nm.
  • Table 1 IC 50 values of exemplary HDACis
  • the exemplary MDA-MB-231 cells are hormone refractory and ER-negative, but they have detectable levels of basal aromatase activity (FIG. 3). Also, the growth of the MDA-MB-231 cells is inhibited by HDAC inhibitors (SAHA, MS-275 and BA) in a dose dependent manner. Furthermore, HDAC inhibitors up-regulate ER and aromatase protein expression after 24 hour treatment (FIG. 5). The aromatase activity is upregulated by HDAC inhibitors SAHA, MS-275 and BA in a dose dependent manner (FIG. 4).
  • letrozole inhibits the growth of ER- negative MDA-MB-231 cells in a dose dependent manner with IC 50 values of 1.13 ⁇ M and 15.43 nM respectively (FIG. 6).
  • histone deacetylase inhibitors can upregulate ER and aromatase protein expression and upregulate aromatase activity and sensitize ER negative breast cancer cells to endocrine therapy.
  • the combination of AEs or AIs with HDAC inhibitors represents a new strategy for the treatment of cancer, including ER-negative breast cancers that otherwise are treated with chemotherapy only, for example.
  • Example 8 VN/124-1 in combination with suberoylanilide hydroxamic acid (SAHA)
  • LNCaP and LNCaP-HP were used.
  • LNCaP cells were isolated from the left supraclavicular lymph node of a 50-year-old Caucasian male with confirmed metastatic prostate cancer. These cells contain a functional AR that has a mutation in its ligand-binding domain.
  • LNCaP-HP cells were derived from the LNCaP parental line in our lab through repeated passaging (>100 passages). These cells exhibit increased AR expression and are resistance to bicalutamide treatment in comparison to the parental cell line.
  • VN/124-1 alone and in combination with SAHA can be measured by, for example, the method described above or any other method known by one of ordinary skill in the art.
  • VN/124- 1 in combination with SAHA increased cell death when compared to VN/124-1 alone in both LNCaP cells (FIG. 8A) and LNCaP-HP cells (FIG. 8B).
  • Each drug is assessed in the range of, for example, O.OOl ⁇ M to lOO ⁇ M to develop a dose response curve.
  • LNCaP and LNCaP-HP were used.
  • LNCaP cells were isolated from the left supraclavicular lymph node of a 50-year-old Caucasian male with confirmed metastatic prostate cancer. These cells contain a functional AR that has a mutation in its ligand-binding domain.
  • LNCaP-HP cells were derived from the LNCaP parental line in our lab through repeated passaging (>100 passages). These cells exhibit increased AR expression and are resistance to bicalutamide treatment in comparison to the parental cell line.
  • Bicalutamide in combination with SAHA increased cell death when compared to bicalutamide alone in both LNCaP cells (FIG. 9A) and LNCaP-HP cells (FIG. 9B).
  • Each drug is assessed in the range of, for example, O.OOl ⁇ M to lOO ⁇ M to develop a dose response curve.
  • SAHA Suberoylanilide hydroxamic acid
  • HP-LNCaP cells were cultured in media containing charcoal stripped FBS with or without the synthetic androgen R1881 (17beta-hydroxy-17alpha-methyl-estra-4,9,ll- trien-3-one) and treated with SAHA (FIG. 10). Viability was measured at 96 hours using an MTT-based assay. In the presence of androgen the IC50 value for SAHA was 417nM whereas in the absence of androgen the IC50 for SAHA was 48nM, demonstrating almost a 9-fold decrease in the IC50 value. These data demonstrate that SAHA exhibits increased sensitivity at lower androgen concentrations. The observation that depriving cells of androgens (which is a mechanism of action of VN/ 124-1 in vivo) increases the sensitivity of SAHA supports a synergistic combination comprising SAHA and VN/124-1.
  • VN/124-1 in combination with suberoylanilide hydroxamic acid (SAHA) in vivo
  • cells are grown in complete medium. When cells reach 70-80% confluence, 3-4 hrs before harvesting, medium is replaced with fresh medium to remove dead and detached cells. Prior to removal of cells, medium is removed and cells are washed with PBS. Cells are most commonly removed from a culture substrate by treatment with trypsin, or trypsin- EDTA, which requires adding a minimum amount of either to the cells in culture so as to minimize damage to cells, followed by dispersing cells and adding complete medium (e.g., 10:1 to 5:1). Following removal of cells from the culture substrate, cells are centrifuged in the cold immediately at or below, for example, 1500 rpm for 2-5 minutes and washed twice with PBS and stored on ice.
  • trypsin or trypsin- EDTA
  • Cells are counted using, for example, a hemocytometer with dead cells being identified and excluded using, for example, trypan blue stain. Cells are finally suspended in a volume so that 300 mu.L contains the required number of cells per injection (e.g., 3.0 x l ⁇ .sup.6 cells per mjection). Following the preparation of cells, nude mice, for example, are injected with cells (3.0 x 106) subcutaneously into the lower flank.
  • mice When tumors reach an appropriate size, for example, a diameter of about 50-60 mm3, the mice are divided into 4 groups: one control group, in which tumors are not treated at all or are injected with phosphate buffered saline (PBS) in equal volumes as treatment groups, a second and a third group, which are administered VN/124- 1 and SAHA, respectively, and a fourth group, which is administered a combination of VN/124- 1 and SAHA. Animals are monitored over several weeks until control tumors reach, for example, a diameter of about 1 cm, when animals are to be euthanized. Finally, tumor size and constituents are determined.
  • PBS phosphate buffered saline

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Abstract

La présente invention concerne des procédés de traitement de cancers régulés par endocrine, comprenant par exemple, des cancers résistants aux hormones. Plus spécifiquement, l'invention concerne un procédé d'augmentation de la sensibilité de cancers résistant aux hormones à des agents thérapeutiques hormonaux. Dans des aspects particuliers, la présente invention concerne l'administration d'un inhibiteur d'histone désacétylase et d'un médicament ciblant une hormone à un individu atteint de cancer. Dans des aspects particuliers supplémentaires, l'inhibiteur d'histone désacétylase et le médicament ciblant une hormone agissent en synergie pour traiter le cancer, y compris en surmontant la résistance à une thérapie du cancer.
PCT/US2008/066120 2007-06-06 2008-06-06 Inhibiteurs de hdac et médicaments ciblant une hormone pour le traitement du cancer Ceased WO2008154382A1 (fr)

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US10098896B2 (en) 2005-03-02 2018-10-16 University Of Maryland Baltimore C-17-heteroaryl steroidal CYP17 inhibitors/antiandrogens, in vitro biological activities, pharmacokinetics and antitumor activity
GB2479337A (en) * 2009-02-05 2011-10-05 Tokai Pharmaceuticals Inc Combination of a 17 alpha-hydroxylase/c17, 20-lyase inhibitor with an additional therapeutic agent
US9359395B2 (en) 2009-02-05 2016-06-07 Tokai Pharmaceuticals, Inc. Prodrugs of steroidal CYP17 inhibitors/antiandrogens
JP2016034946A (ja) * 2009-02-05 2016-03-17 トーカイ ファーマシューティカルズ，インク． ステロイド性ｃｙｐ１７阻害剤／抗アンドロゲン剤の新しいプロドラッグ
GB2514957A (en) * 2009-02-05 2014-12-10 Tokai Pharmaceuticals Inc Combination of a 17 alpha-hydroxylase/c17, 20-lyase inhibitor with an additional therapeutic agent
WO2010091299A3 (fr) * 2009-02-05 2010-10-21 Tokai Pharmaceuticals Nouvelles polythérapies contre le cancer
US20120115804A1 (en) * 2009-03-10 2012-05-10 The John Hopkins University Compositions and methods for characterizing and treating neoplasia
WO2010149755A1 (fr) 2009-06-26 2010-12-29 Novartis Ag Dérivés d'imidazolidin-2-one 1,3-disubstitués en tant qu'inhibiteurs de cyp 17
WO2011017534A3 (fr) * 2009-08-07 2011-06-30 Tokai Pharmaceuticals, Inc. Traitement du cancer de la prostate
US9156878B2 (en) 2009-08-07 2015-10-13 Tokai Pharmaceuticals, Inc. Treatment of prostate cancer
US8791094B2 (en) 2009-08-07 2014-07-29 Tokai Pharmaceuticals, Inc. Treatment of prostate cancer
EP2640383A4 (fr) * 2010-11-18 2014-05-07 Takeda Pharmaceutical Méthode de traitement du cancer du sein et du cancer des ovaires
WO2012149413A1 (fr) 2011-04-28 2012-11-01 Novartis Ag Inhibiteurs de 17α-hydroxylase/c17,20-lyase
EP2751267A4 (fr) * 2011-09-02 2015-01-07 Syndax Pharmaceuticals Inc Méthodes de traitement du cancer du sein
EP3381454A1 (fr) * 2011-09-02 2018-10-03 Syndax Pharmaceuticals Inc. Méthodes de traitement du cancer du sein
CN103906837A (zh) * 2011-09-02 2014-07-02 辛达克斯制药股份有限公司 治疗乳腺癌的方法
US10226472B2 (en) 2011-09-02 2019-03-12 Syndax Pharmaceuticals, Inc. Methods for the treatment of breast cancer
KR20140108629A (ko) * 2011-09-02 2014-09-12 신닥스 파마슈티컬스, 인크. 유방암 치료 방법
KR101956861B1 (ko) 2011-09-02 2019-03-12 신닥스 파마슈티컬스, 인크. 유방암 치료 방법
EP2751267B1 (fr) 2011-09-02 2018-01-24 Syndax Pharmaceuticals Inc. Méthodes de traitement du cancer du sein
WO2013033656A1 (fr) 2011-09-02 2013-03-07 Syndax Pharmaceuticals, Inc. Méthodes de traitement du cancer du sein
CN107982270A (zh) * 2011-09-02 2018-05-04 辛达克斯制药股份有限公司 治疗乳腺癌的方法
US9439912B2 (en) 2013-03-14 2016-09-13 University Of Maryland, Baltimore Androgen receptor down-regulating agents and uses thereof
US9884067B2 (en) 2013-03-14 2018-02-06 University Of Maryland, Baltimore Androgen receptor down-regulating agents and uses thereof
US9808472B2 (en) 2013-08-12 2017-11-07 Tokai Pharmaceuticals, Inc. Biomarkers for treatment of neoplastic disorders using androgen-targeted therapies
US9387216B2 (en) 2013-08-12 2016-07-12 Tokai Pharmaceuticals, Inc. Biomarkers for treatment of neoplastic disorders using androgen-targeted therapies
US10722527B2 (en) 2015-04-10 2020-07-28 Capsugel Belgium Nv Abiraterone acetate lipid formulations

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