WO2020028593A1 - Méthode de traitement de cancers du sein exprimant un mutant er avec des modulateurs sélectifs du récepteur des androgènes (sarm) - Google Patents

Méthode de traitement de cancers du sein exprimant un mutant er avec des modulateurs sélectifs du récepteur des androgènes (sarm) Download PDF

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WO2020028593A1
WO2020028593A1 PCT/US2019/044550 US2019044550W WO2020028593A1 WO 2020028593 A1 WO2020028593 A1 WO 2020028593A1 US 2019044550 W US2019044550 W US 2019044550W WO 2020028593 A1 WO2020028593 A1 WO 2020028593A1
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breast cancer
positive
subject
treating
subject suffering
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WO2020028593A9 (fr
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Ramesh Narayanan
Thamarai PONNUSAMY
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Oncternal Therapeutics, 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • This invention relates to the treatment of androgen receptor-positive breast cancer in a subject, for example a female subject. Accordingly, this invention provides methods of: a) treating a subject suffering from breast cancer; b) treating a subject suffering from metastatic breast cancer; c) treating a subject suffering from refractory breast cancer; d) treating a subject suffering from AR-positive breast cancer; e) treating a subject suffering from AR-positive refractory breast cancer; f) treating a subject suffering from AR-positive metastatic breast cancer; g) treating a subject suffering from AR-positive and ER-positive breast cancer; h) treating a subject suffering from AR- positive breast cancer with or without expression of estrogen receptor (ER), progesterone receptor (PR), and/or human epidermal growth factor receptor 2 (HER2); i) treating a subject suffering from triple negative breast cancer (TNBC); j) treating a subject suffering from advanced breast cancer; k) treating a subject suffering from breast cancer that has failed selective estrogen receptor modulator (SERM) (SERM)
  • Breast cancer is a disease that kills over 45,000 women each year in the United States alone. Over 180,000 new cases of breast cancer are diagnosed annually, and it is estimated that one in eight women will develop breast cancer. These numbers indicate that breast cancer is one of the most dangerous diseases facing women today. Cancer research has been unable to determine the cause of breast cancer, and has not found a suitable method of therapy or prevention.
  • Genotyping has long been used to screen women who may be genetically predisposed to developing breast cancer. It is another diagnostic or prognostic tool that can be used to determine the availability of therapies. Certain women are predisposed to develop breast cancer based on the presence of germline (i.e., inherited) mutations in the breast cancer susceptibility genes ( BRCA ) type 1 ( BRCA1 ) or BRCA2.
  • BRCA breast cancer susceptibility genes
  • a couple of SERMs, tamoxifen in 1999 and raloxifene in 2007, were approved for the primary prevention of breast cancer in patient populations that are high risk based on family history and/or genotype considerations. However, hysterectomy or prophylactic mastectomy was often considered in these patients as a more definite preventative.
  • olaparib (Lynparza), an inhibitor of the enzyme poly ADP ribose polymerase (PARP), was approved for metastatic ER-positive and HER2-negative breast cancer patients with certain inherited BRCA mutations who have received chemotherapy (and hormone therapy if ER-positive).
  • PARP poly ADP ribose polymerase
  • the standard of care currently includes screening the tumor for the expression levels of the hormone receptors, estrogen receptor (ER) and progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) kinase.
  • ER estrogen receptor
  • PR progesterone receptor
  • HER2 human epidermal growth factor receptor 2
  • a woman diagnosed with breast cancer may be treated preliminarily with surgery, chemotherapy (optional in some cases), and radiation before targeted therapy is initiated.
  • Hormone receptor-positive breast cancers are susceptible to hormone therapies (also referred to as endocrine therapies) with selective estrogen receptor modulators or SERMs (e.g., tamoxifen, toremifene, raloxifene), aromatase inhibitors (e.g., anastrozole), or selective estrogen receptor degraders or SERDs (e.g., fulvestrant).
  • SERMs selective estrogen receptor modulators
  • SERMs e.g., tamoxifen, toremifene, raloxifene
  • aromatase inhibitors e.g., anastrozole
  • SERDs selective estrogen receptor degraders
  • Hormone therapies such as gonadotropin-releasing hormone (GnRH) agonists (typically used in pre- and peri- menopausal women) and aromatase inhibitors (AI) (typically used in post-menopausal women or together with GnRH agonists in pre- or peri-menopausal women) block production of estrogens in the body, whereas SERMs and SERDs block the proliferative action of estrogens on the breast cancer cells. While the prognosis of most early stage ER-positive breast cancer patients is relatively good compared to non-hormonal cancers, adjuvant hormone therapy failures do occur resulting in recurrence, including distant metastases (i.e, advanced breast cancer).
  • GnRH gonadotropin-releasing hormone
  • AI aromatase inhibitors
  • SERMs and SERDs block the proliferative action of estrogens on the breast cancer cells. While the prognosis of most early stage ER-positive breast cancer patients is relatively good
  • Metastatic or advanced breast cancer is often still ER-positive and still dependent on the ER axis for growth.
  • the treatment of advanced breast cancer is rapidly evolving from the use of an endocrine monotherapy such as SERM or AI or fulvestrant, to combinations of an endocrine therapy with recently approved kinase inhibitors, including the cyclin-dependent kinase 4/6 (CDK4/6) inhibitors (palbociclib (approved 2015), ribociclib (approved 2017), or abemaciclib (approved 2017)), or mechanistic target of rapamycin (mTOR) inhibitor (everolimus (approved 2012)).
  • CDK4/6 cyclin-dependent kinase 4/6
  • mTOR mechanistic target of rapamycin
  • tumor genotyping deep DNA sequencing
  • Certain common mutations of the estrogen receptor alpha can be treatment emergent and confer resistance to the approved endocrine therapies even when combined with various kinase therapies as discussed above.
  • at least one mutation e.g. Y537S
  • SERM, AI, and fulvestrant resistance is still sensitive to the androgen agonists of this invention. Consequently, even late stage ER-positive AR-positive breast cancer patients which have been exposed to the full endocrine- and directed- therapy milieu may still have further hormonal treatment options before being relegated to chemotherapies. If screening reveals certain ER mutants then their treatment can be personalized to include the use of SARMs to delay progression of the disease and/or regress tumors.
  • HER2-positive breast cancers are susceptible to HER2 kinase inhibitors (e.g., trastuzumab, lapatinib, and neratinib) and are generally used in metastatic disease.
  • Anti- angiogenic therapy (bevacizumab) was also approved in metastatic disease, but the FDA removed this for bevacizumab in 2011. Despite these multiple tiers of targeted treatments, patients often have or develop refractory forms of breast cancer.
  • refractory breast cancer examples include primary tumors which are triple- negative (lacking ER, PR, HER2), hormone resistant (SERM-, SERD-, or AI-resistant), or kinase inhibitor resistant (e.g., inhibitors of CDK 4/6, mTor, and/or HER2), or metastatic breast cancer tumors.
  • kinase inhibitor resistant e.g., inhibitors of CDK 4/6, mTor, and/or HER2
  • metastatic breast cancer tumors include metastatic breast cancer tumors.
  • Current chemotherapies available for the treatment of refractory breast cancer include anthracyclines, taxanes, and epothilones, which are toxic, dangerous, costly, and often are ineffective, especially in the treatment of metastatic disease.
  • TNBC Triple Negative Breast Cancer
  • the AR is the most highly expressed steroid receptor in breast cancer with up to 95% of ER-positive breast cancers expressing AR (see Example 9 infra). In TNBC, up to 30% of cancers may express AR. Historically, AR has been considered anti-proliferative and beneficial in hormone receptor positive breast cancers. In TNBC, data demonstrates that the presence of AR and androgen synthesizing enzymes is associated with lower proliferation, lower tumor grade, better overall survival, and more favorable clinical outcomes as compared to those patients with TNBC not expressing AR. Evidence also suggests that the AR target gene prostate specific antigen (PSA) is a favorable prognostic marker in breast cancer (not just TNBC). Based on these findings, research is focused on AR as a potential therapeutic target.
  • PSA prostate specific antigen
  • Prolonged treatment of cancers with estrogen synthesis inhibitors (AI or GnRH agonists) or ER antagonists (SERMs or SERDs) results in mutations in the target protein and activation of resistance pathways.
  • AI estrogen synthesis inhibitors
  • SERMs or SERDs ER antagonists
  • continued treatment of ER- positive breast cancers with ER antagonists or aromatase inhibitors (AI) results in resistance due to mutations in the ER ligand binding domain (LBD).
  • Clinical studies have estimated that over 30% of breast cancers treated with tamoxifen become refractory and recur as a resistant cancer and over 40% of recurrent breast cancers express mutated ER.
  • mutant ERs have escaped inhibition of the hormonal axis fail to respond to endocrine therapy and, consequently, these patients will need to be treated with chemotherapeutic agents.
  • Such cancers require new non- or less- toxic effective endocrine therapies.
  • One possibility is the pharmacogenomic screening of tumors or circulating tumor cells for the present of mutant ERs that would confer resistance to current endocrine therapies. This could be done upon molecular phenotyping as ER- positive (i.e., early disease) or, alternatively, in patients that have failed endocrine therapies (i.e, late disease) such as SERM, AI, SERD and/or GnRH agonist whether or not combined with CDK 4/6 or mTor inhibitors.
  • SARMs are compounds which demonstrate AR-mediated tissue selective activity. Unlike their steroidal precursors, SARMs are non-aromatizable, generally demonstrate no activity at other steroidal receptors including ER and PR, and are non-virilizing. Further, SARMs may be beneficial in refractory breast cancer patients due to their hypermyoanabolic effects that should improve their tolerance of high-dose chemotherapy. Further, SARMs have beneficial osteoblastic and anti-osteoclastic effects in bones that may decrease the risk of metastasis to the bones or may decrease risk of osteoporosis during endocrine and/or chemotherapies.
  • New innovative approaches are urgently needed at both the basic science and clinical levels to develop compounds which are useful for: a) treating a subject suffering from breast cancer; b) treating a subject suffering from metastatic breast cancer; c) treating a subject suffering from refractory breast cancer; d) treating a subject suffering from AR-positive breast cancer; e) treating a subject suffering from AR-positive refractory breast cancer; f) treating a subject suffering from AR-positive metastatic breast cancer; g) treating a subject suffering from AR-positive and ER-positive breast cancer; h) treating a subject suffering from AR-positive breast cancer with or without expression of ER, PR, and/or HER2; i) treating a subject suffering from triple negative breast cancer; j) treating a subject suffering from advanced breast cancer; k) treating a subject suffering from breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH)
  • this invention is directed to a method of treating a subject suffering from ER mutant expressing breast cancer, comprising the step of administering to said subject a selective androgen receptor modulator (SARM) compound represented by a structure of Formula I:
  • SARM selective androgen receptor modulator
  • X is a bond, O, CH 2 , NH, S, Se, PR, NO or NR;
  • G is O or S
  • T is OH, OR, -NHCOCHs, or NHCOR;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH;
  • Ri is CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R 2 is H, F, Cl, Br, I, CH 3 , CF 3 , OH, CN, N0 2 , NHCOCH 3 ,
  • NHCOCF 3 NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , or SR;
  • R 3 is H, F, Cl, Br, I, CN, N0 2 , COR, COOH, CONHR, CF 3 , Sn(R) 3 , or R 3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
  • Z is N0 2 , CN, COR, COOH, or CONHR;
  • Y is CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;
  • Q is CN, alkyl, halogen, N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHS0 2 CH 3 , NHS0 2 R, OR, COR, OCOR, OS0 2 R, S0 2 R or SR;
  • n is an integer of 1-4;
  • n is an integer of 1-3.
  • the SARM compound is represented by a structure of Formula XIII:
  • the SARM compound is represented by a structure of
  • X is a bond, O, CH 2 , NH, Se, PR, or NR;
  • G is O or S
  • T is OH, OR, -NHCOCHs, or NHCOR;
  • Z is N0 2 , CN, COR, COOH or CONHR;
  • Y is I, CFs, Br, Cl, or Sn(R) 3 ;
  • Q is CN, alkyl, halogen, N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCFs, NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR, OSO2R, S0 2 R or SR;
  • R is a C1-C4 alkyl, aryl, phenyl, alkenyl, hydroxyl, a C1-C4 haloalkyl, halogen, or haloalkenyl;
  • Ri is CHs, CF S , CH 2 CH 3 , or CF 2 CF 3 .
  • said SARM compound is represented by a structure of
  • the ER mutant expressing breast cancer is Y537S mutation expressing breast cancer.
  • the method of this invention comprises administering an isomer, a racemic mixture containing a SARM compound of this invention, a metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, A-oxide, or crystal of said selective androgen receptor modulator, or any combination thereof.
  • said administering comprises intravenously, intraarterially, or intramuscularly injecting to said subject said pharmaceutical product in liquid form; subcutaneously implanting in said subject a pellet containing said pharmaceutical product; orally administering to said subject said pharmaceutical product in a liquid or solid form; or topically applying to the skin surface of said subject said pharmaceutical product.
  • said pharmaceutical product is a pellet, a tablet, a capsule, a solution, a suspension, an emulsion, an elixir, a gel, a cream, a suppository or a parenteral formulation.
  • Figure IA- Figure 1J illustrate that DHT and a compound of Formula IX inhibit MDA-MB-231 triple negative breast cancer cell growth.
  • Figure 1A shows MDA- MB-231 cell expression of AR following transfection.
  • Figure 1B shows the IC50 in AR- positive MDA-MB-231 cells.
  • Figure 1C- Figure 1J show the effects of DHT, Formula IX, bicalutamide and the ( R) enantiomer of Formula IX on percent (%) cell survival.
  • Figure 1C, Figure 1E, Figure 1G and Figure II cells were treated in charcoal stripped FBS.
  • Figure 1D, Figure 1F, Figure 1H and Figure 1J cells were treated in full serum).
  • Figure 2A- Figure 2H illustrate that DHT and Formula IX inhibit HCC-38 triple negative breast cancer cell growth.
  • Figure 2 A shows HCC-38 cell expression of AR following transfection.
  • Figure 2B shows the IC50 in AR-positive HCC-38 cells.
  • Figure 2A- Figure 2H show the effects of DHT, Formula IX and Bicalutamide on percent (%) cell survival.
  • Figure 2C, Figure 2E and Figure 2G cells were treated in charcoal stripped FBS.
  • Figure 2D, Figure 2F and Figure 2H cells were treated in full serum).
  • Figure 3A- Figure 3E illustrate that the effect of DHT and Formula IX on MDA-MB-231 cells was reversed by bicalutamide.
  • Figure 3A- Figure 3D show the effects of DHT or Formula IX in the presence or absence of bicalutamide, on percent (%) cell survival.
  • Figure 3A and Figure 3C cells were treated in charcoal stripped FBS.
  • Figure 3B and Figure 3D cells were treated in full serum).
  • Figure 3E shows IC50 values in AR-positive cells in the presence or absence of pretreatment with bicalutamide.
  • Figure 4A- Figure 4Q illustrate that AR agonists inhibit triple negative breast cancer cell growth.
  • Figure 4 A, Figure 4B, Figure 4E, Figure 4F, Figure 4G, Figure 4H, Figure 4K, Figure 4L, Figure 4M, Figure 4N, Figure 40 and Figure 4P show effect of AR agonists on percent (%) cell survival.
  • Figure 4C and Figure 4D show the effect of AR antagonist on percent (%) cell survival.
  • Figure 41 and Figure 4J show the effect of AR non-binder on percent (%) cell survival.
  • Figure 4A, Figure 4C, Figure 4E, Figure 4G, Figure 41, Figure 4M and Figure 40 cells were treated in charcoal stripped FBS.
  • Figure 4B, Figure 4D, Figure 4F, Figure 4H, Figure 4J, Figure 4L, Figure 4N and Figure 4P cells were treated in full serum.
  • Figure 4Q shows EC50 and IC50 values in AR- positive cells.
  • Figure 5 illustrates that growth inhibitory ligands are AR agonists in MDA- MB-231 cells.
  • Figure 6A- Figure 6E illustrate that growth inhibitory effects in MDA-MB-231 cells are selective to AR.
  • Figure 6A and Figure 6B show the expression of ERa or ERb in MDA-MB-231 cells following transfection, respectively.
  • Figure 6C, Figure 6D and Figure 6E show the effects of estradiol (E2) or ICI 182,780 (ICI) on percent (%) cell survival.
  • Figure 6C cells were treated in charcoal stripped semm.
  • Figure 6D and Figure 6E cells were treated in full serum).
  • Figure 7 shows DHT alters the morphology of MDA-MB-231 cells.
  • Figure 8 illustrates the effect of Formula VIII on steroid receptor transactivation (agonist mode).
  • Figure 9 depicts a dose response curve of PR activity (antagonist mode) for compound of Formula VIII, Formula IX, / ⁇ -enantiomer of Formula IX and RU486.
  • Figure 10A- Figure 10B demonstrate that SARM (Formula VIII) inhibits MDA-MB-231-AR tumor growth.
  • Body weight (10A) and tumor size (10B) were measured for 35 days in intact female nude mice having 150-200 mm 3 tumors from MDA-MB-231-AR triple negative breast cancer cells and then orally administered vehicle (*) or 30 mg/ kg of Formula VIII ( ⁇ ).
  • FIG. 11 demonstrates that SARM (Formula VIII) inhibits MDA-MB-231- AR tumor growth.
  • Tumor size in mm 3 (left pane) and % change in tumor size (middle pane), as well as tumor weight (right pane) were measured after 35 days in intact female nude mice having 150-200 mm 3 tumors from MDA-MB-231-AR triple negative breast cancer cells and then receiving oral administration of vehicle or 30 mg/kg of Formula
  • Figure 12 demonstrates the morphology of MDA-MB-231 breast cancer cells stably transfected with AR (MDA-MB-231-AR cells).
  • AR agonists, DHT, Formula IX, and Formula VIII altered the morphology into a more anchored phenotype compared to vehicle, bicalutamide or an inactive isomer of Formula
  • IX This may be indicative of a less metastatic breast cancer phenotype.
  • Figure 13A- Figure 13C demonstrate binding and transactivation of the indicated ligands to HEK-293 (13A) or MDA-MB-231 (13B & 13C) cells.
  • DHT, Formula IX and Formula VIII are agonists of AR in breast cancer cells. (Example 16)
  • Figure 14 demonstrates anti-proliferative activity of DHT and SARMs in MDA-MB-231 breast cancer cells stably transfected with AR.
  • MDA-MB-231 cells stably transfected with AR using lentivirus were treated with the indicated ligands for 6 days and the number of cells counted using Coulter counter.
  • Figure 15 presents microarray results showing that activated AR (AR activated by compound of Formula VIII) suppressed the expression of more genes than it induced in MDA-MB-231-AR xenograft breast cancer cells.
  • Figure 16 depicts validation of microarray results.
  • Figure 17 illustrates that Formula VIII inhibited the growth of MCF-7-AR triple positive xenograft.
  • Figure 18 presents inhibition of utems weight gain in estrogen supplemented animals treated with Formula VIII, demonstrating the ability of a SARM to counteract estrogenic stimuli in vivo.
  • Figure 19 shows that the AR expression pattern in response to an AR-agonist (Formula VIII) is similar to that observed in prostate cancer cells.
  • Figure 20 depicts validation of microarray results.
  • Figure 21 demonstrates up-regulation of JNK phosphorylation in MCF7-AR tumors using Formula VIII.
  • Figure 22 shows inhibition of triple negative breast cancer (TNBC) growth using Formulae VIII and IX.
  • TNBC triple negative breast cancer
  • Formula VIII and Formula IX demonstrated -85% TGI at all doses tried (5, 10 mg per kg for Formula VIII; 5, 10, 30 mg per kg for Formula IX) in the TNBC model using MDA-MB-231-AR cells in nude mice.
  • Figure 23 demonstrates inhibition of triple negative breast cancer using Formulae VIII and IX.
  • the tumor weights were likewise reduced for all doses of Formula VIII and Formula IX.
  • Spleen enlargement (680 mg vs. 200-300 mg for normal mice) was seen only in vehicle treated mice, possibly indicative of prevention by the SARMs of tumor metastasis to the spleen.
  • Figure 24 shows increased body weight by the SARMs at all doses of Formula VIII and Formula IX, indicative of healthy growth and a lack of toxicity. By comparison, the vehicle treated animals did not grow as robustly.
  • Figure 25A - Figure 25E depict antagonism by SARM regarding the ability of estradiol to activate ER target genes in MCF-7-AR cells.
  • Figure 25B and Figure 25D show that adding AR (as opposed to Green Fluorescent Protein (GFP) as seen in Figures 25A and 25C) to MCF-7-AR cells increases the effects of estradiol (when unopposed) on the ER target genes PR and PS2, respectively.
  • GFP Green Fluorescent Protein
  • FIG. 26 A and Figure 26B depict immunohistochemistry of two regions of the same BR-0001 tumor, a triple negative breast cancer (TNBC). They show that AR expression is consistent throughout this formalin-fixed, paraffin-embedded (FFPE) tissue stained with AR antibody (AR N20 from SCBT).
  • Figure 26C depicts immunohistochemistry staining of an AR-negative TNBC FFPE tumor as a negative control.
  • Figure 27A- Figure 27C depict BR-0001 tumor xenograft growth inhibition by Formula IX compared to enzalutamide (Enza) or vehicle in terms of breast cancer tumor volume (Figure 27A and Figure 27B) and weight (Figure 27C) with time.
  • Figure 27 A provides results for Experiment 1
  • Figure 27B provides results for Experiment 2
  • Figure 27C provides results for Experiment 2.
  • BR-0001 TNBC fragments of 1 mm 3 were implanted subcutaneously in NOD scid gamma (NSG) mice.
  • the animals were randomized and treated with vehicle, 10 mg/kg/day Formula IX or enzalutamide orally. Tumor volume was measured thrice weekly. Animals were sacrificed and tumors were weighed.
  • Figure 28A- Figure 28B depict immunohistochemistry of BR-0001 tumors from animals treated with vehicle or Formula IX and stained for Ki-67. Ki-67 was reduced in tumors of animals treated with Formula IX. Quantification of Ki-67 indicated an approximately 50% reduction in Ki-67 staining in 2 weeks of treatment. Tumors from experiment 2 were fixed in formalin and paraffin embedded. Slides were cut and stained with Ki-67 antibody (Figure 28A), Ki-67 staining was reduced in tumors of animals treated with Formula IX. Ki-67 positive cells in each slide (total of 200 cells per view) were counted and represented as % stained cells ( Figure 28B). As a reference, inset into the graphics are bars which are 200 microns (mhi) in length.
  • FIG. 29 depicts Z-scores of 50 genes (PAM50) used to identify BR-0001.
  • PAM50 is a set of 50 genes used to classify breast cancers.
  • PAM50 gene expression data indicated that the BR-0001 tumor belonged to basal- like breast cancer (BLBC) subtype of TNBC.
  • the expression (Z-score) of 50 genes required to classify the breast cancer is given here.
  • Figure 30A and Figure 30B depict gene expression data which is compared to the genes published (Pietenpol group) as useful to classify the Basal-Like Breast Cancer (BLBC) into subclassification. Sub-classification indicated that BR-0001 belonged to luminal androgen receptor (LAR) and mesenchymal stem-like (MSL) subtypes.
  • the six TNBC subtypes according to the Pietenpol group include two basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype.
  • GE - gene expression The six TNBC subtypes according to the Pietenpol group include two basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem-like (MSL), and a luminal androgen receptor (LAR) subtype.
  • Figure 31 depicts gene expression changes in BR-0001 tumors treated with Formula IX.
  • Figure 32 depicts reduced tumor growth of ER-positive, PR-positive, HER2- positive and AR-positive tumors composed of HCI-007 cells using Formula IX.
  • Figure 33A and Figure 33B depict potent tumor growth reduction using Formula IX in xenografts composed of HCI-013 cells.
  • HCI-013 phenotype is a triple positive and also expresses AR.
  • Figure 33A tumor volume changes (%) and
  • Figure 33B tumor weight (g).
  • Figure 34A- Figure 34E depict that AR agonists inhibited proliferation of ER- and AR- positive breast cancer cells.
  • Figure 34A depicts that Formula IX inhibited the proliferation of ZR-75-1 cells.
  • Figure 34B depicts that Formula IX inhibited proliferation of MCF-7 cells expressing AR.
  • Figure 34C depicts that breast cancer fibroblasts treated with AR agonists secreted factors that inhibited MCF-7 -GFP cells lacking supplemented AR.
  • Primary fibroblasts obtained from a breast cancer patient were cultured in growth medium and were treated in triplicates with vehicle, 10 nM DHT, 1 mM enzalutamide, or 1 mM Formula IX.
  • MCF-7 cells stably transfected with GFP were plated in growth medium. Twenty-four hours after plating, cells were fed with the conditioned medium obtained from patient-derived fibroblasts as indicated above. Cells were fed for 10 days with conditioned medium, with medium changed on days 4 and 7. After 10 days of treatment, cells were fixed, and the viability was measured by SRB assay.
  • Figure 34D depicts that AR ligands did not inhibit growth of ER-negative AR- positive HCI-9 PDX.
  • Figure 34E depicts that HCI-13 ER-a was resistant to ER antagonists fulvestrant and tamoxifen (right pane) compared to wt-ER-oc (left pane).
  • ER-a from HCI-13 was cloned into pCR3.l vector. Wildtype ER-a and HCI-13 ER-a, ERE-LUC, and CMV-LUC were transfected into COS-l cells using lipofectamine. Cells were treated 24 hours after transfection with vehicle, 0.1 nM estradiol, 10 nM fulvestrant or 1 mM tamoxifen in combination with 0.1 nM estradiol. Twenty four hours after treatment cells were harvested and luciferase assay was performed. ER antagonists in wt-ER-oc were significantly different than vehicle-treated wt-ER-oc as depicted by * p ⁇ 0.05.
  • AR-androgen receptor GFP-green fluorescent protein
  • DHT-5a-dihydrotestosterone E2- 17 b-estrad io I
  • ER-estrogen receptor SARM- selective androgen receptor modulator
  • Figure 35A- Figure 35D depict that AR agonists inhibited proliferation and growth of wildtype and mutant ER and AR -positive xenografts.
  • Figure 35A depicts that protein from HCI PDX (HCI-7, 9, or 13) tumor fragments was extracted and fractionated on a SDS-PAGE, and Western blotted for the AR. AR was also quantified at mRNA level and expressed as fold change from LNCaP prostate cancer cell AR (numbers provided under the blot).
  • Figures 35B (same as Figure 32) and Figure 35C depict that Formula IX inhibited HCI-7 tumor growth.
  • vehicle DMSO:PEG-300 (l5%:85%)
  • Formula IX (10 mpk p.o.
  • enzalutamide (30 mpk p.o.
  • Figure 36A- Figure 36K depict that AR agonists inhibited proliferation and growth of mutant ER and AR-positive xenografts.
  • Figure 36A depicts that the growth of HCI- 13 PDX was not dependent on circulating estrogens.
  • Figure 36B and Figure 36C depict that AR agonist (Formula IX) inhibited growth of HCI- 13 PDX.
  • Figure 36D- Figure 36G depict that AR agonists, but not AR- or ER- antagonists, inhibited ER-target genes in HCI- 13 ex vivo sponge culture.
  • Tissues were treated with vehicle, 1 mM Formula IX, or 100 nM fulvestrant for three days.
  • RNA was extracted from the tissues and expression of genes was measured by real time PCR and normalized to GAPDH.
  • Figure 37A- Figure 37H depict a gene expression study in HCI- 13 PDX that indicated the inhibition of the ER pathway by an AR agonist.
  • Genes that were different in Formula IX treated group (q ⁇ 0.05) are represented in the heatmap (upper 1/5 of the left column (vehicle-treated) of the heatmap is predominantly upregulated (originally red) whereas lowered 4/5 of heatmap is predominantly downregulated (originally green); in contrast, the Formula IX treated column is just the opposite (green at top and red at bottom).) (Figure 37 A).
  • Figure 37H depicts that the GSEA KEGG pathway analysis provided ERBB2 (ERBB is abbreviated from erythroblastic oncogene B; also frequently called HER2 (from human epidermal growth factor receptor 2) or HER2/neu) pathway as one of the highly correlated pathway with Formula IX treatment (bottom four rows in the left column (vehicle treated) are downregulated genes (blue in the original color) whereas most of the rows are upregulated genes (red in the original color); in contrast, Formula IX treated column (right) is just the opposite).
  • * q ⁇ 0.05; ER-estrogen receptor; AR-androgen receptor; PDX-patient-derived xenograft; GSEA-gene set enrichment analysis; KEGG- Kyoto encyclopedia of genes and genomes.
  • Figure 38A- Figure 38H depict that ChIP-Sequencing showed rearrangement of ER and AR binding to the DNA.
  • Next-generation sequencing was performed to determine the genome-wide binding of ER and AR to the DNA. Heatmap of significantly different peaks (q ⁇ 0.05 for ER and corresponding AR peaks) is shown. The top enriched motifs are shown in Figure 38H.
  • Figure 38B shows representative peaks from KFK3 regulatory regions from ER and AR ChIP-Seq.
  • Figure 38C shows Principal Component Analysis (PCA) plot of vehicle- and Formula IX -treated samples that corresponds to ER-ChIP peaks.
  • Figure 38D depicts that ChIP assay was performed with AR or ER antibody in HCI-13 specimens treated with vehicle or Formula IX and real time PCR was performed with the primers and Taqman probe to the specified regions.
  • Figure 38E depicts pie charts showing the distribution of ER enrichment in Formula IX - treated HCI-13 samples. For downregulated sites (left pie),‘distal regulatory regions’ represent 56%, introns 38%, exons 5%, and promoters 2%. For enriched sites (right pie),‘distal regulatory proteins’ represent 53%, introns 36%, exons 8%, and promoters 3%.
  • PCA Principal Component Analysis
  • Figure 38F depicts Venn diagrams showing the overlap between depleted FOXA1RE and ERE regions and enriched ARE, GRE, and FOXA1RE.
  • Figure 38G depicts that SRC-l interacted with both AR and ER in response to Formula IX. Protein extracts from HCI-13 tumor samples treated with vehicle or Formula IX were immunoprecipitated with AR or ER antibodies and Western blot for SRC-l was performed.
  • AR-androgen receptor AR-androgen receptor
  • ER-estrogen receptor ChIP- chromatin immunoprecipitation
  • ARE-androgen response elements ERE-estrogen response element
  • GRE-glucocorticoid response elements SRC-l- steroid receptor coactivator- 1, FOXAlRE-Forkhead box Al response element.
  • Figure 38H depicts up-regulated motifs (ER).
  • Figure 39 depicts colocalization of AR and ER-oc in luminal B breast cancer specimens.
  • Figure 40 depicts representative ChIP Seq peaks in the regulated regions of genes.
  • the peaks are color coded with the top panel being predominantly upregulated (red), whereas the 2 nd from top panel is downregulated (blue), 3 rd panel from top (CERS3) is downregulated except for the last line (IX (AR)), and bottom panel (miR447l) is also downregulated except for the last line (IX (AR)).
  • Figure 41A- Figure 41E depict a phospho-proteome analysis of HCI-13 PDX.
  • Figure 4lD- Figure 41E depict that activation of PKC overcame inhibition by Formula IX.
  • PMA-phorbol l2-myristate 13- acetate EGF-epidermal growth factor
  • Figure 42 shows a model depicting the regulation of ER function by AR agonist.
  • this invention relates to the treatment of androgen receptor-positive breast cancer in a subject. Accordingly, this invention provides methods of: a) treating a subject suffering from breast cancer; b) treating a subject suffering from metastatic breast cancer; c) treating a subject suffering from refractory breast cancer; d) treating a subject suffering from AR-positive breast cancer; e) treating a subject suffering from AR-positive refractory breast cancer; f) treating a subject suffering from AR-positive metastatic breast cancer; g) treating a subject suffering from AR-positive and ER-positive breast cancer; h) treating a subject suffering from AR- positive breast cancer with or without expression of ER, PR, and/or HER2; i) treating a subject suffering from triple negative breast cancer; j) treating a subject suffering from advanced breast cancer; k) treating a subject suffering from breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonado
  • SERM selective estrogen receptor
  • a method for treating a subject suffering from breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, A-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat breast cancer in the subject.
  • the subject is a female subject. In another embodiment, the subject is a male subject.
  • a method for treating a subject suffering from metastatic breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, /V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat metastatic breast cancer in the subject.
  • the subject is a female subject. In another embodiment, the subject is a male subject.
  • a method for treating a subject suffering from refractory breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat refractory breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from AR-positive breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat AR-positive breast cancer in the subject.
  • the subject is a female subject. In another embodiment, the subject is a male subject.
  • the AR-positive breast cancer is ER, PR and HER2- positive. In another embodiment, the AR-positive breast cancer is ER, PR and HER2- negative. In one embodiment, the AR-positive breast cancer is ER-positive, and PR and HER2-negative. In another embodiment, the AR-positive breast cancer is ER and PR- positive, and HER2-negative. In yet another embodiment, the AR-positive breast cancer is ER and HER2 -positive, and PR-negative. In still another embodiment, the AR- positive breast cancer is ER-negative, and PR and HER2 -positive. In a further embodiment, the AR-positive breast cancer is ER and PR-negative, and HER2-positive.
  • the AR-positive breast cancer is ER and HER2-negative, and PR-positive. In one embodiment, the AR-positive breast cancer is ER-negative. In another embodiment, the AR-positive breast cancer is ER-positive.
  • a method for treating a subject suffering from AR-positive refractory breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, /V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat AR-positive refractory breast cancer in the subject.
  • the subject is a female subject. In another embodiment, the subject is a male subject.
  • a method for treating a subject suffering from AR-positive metastatic breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat AR-positive metastatic breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from AR-positive and ER-positive breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat AR-positive metastatic breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from ER-positive breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat ER-positive breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • the ER-positive breast cancer is AR-positive.
  • the ER-positive breast cancer is AR-negative.
  • ER- positive breast cancer is triple positive (ER, PR, HER2) breast cancer.
  • ER-positive breast cancer is not triple positive breast cancer.
  • a method for treating a subject suffering from triple negative breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, A-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat triple negative breast cancer in the subject.
  • the subject is a female subject. In another embodiment, the subject is a male subject.
  • a method for treating a subject suffering from AR-positive triple negative breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, A-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to AR-positive treat triple negative breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from advanced breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, A-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat advanced breast cancer in the subject.
  • the subject is a female subject. In another embodiment, the subject is a male subject.
  • a method for treating a subject suffering from breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, exemestane), cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio)), mTOR inhibitor (everolimus), trastuzumab (Herceptin, ado-trastuzumab emtansine), pertuzumab (Perjeta), lapatinib, neratinib (Nerlynx), olaparib (Lynparza) (an inhibitor of the enzyme poly ADP ribose poly
  • this invention provides a method for treating a subject suffering from HER2-positive breast cancer, comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat HER2-positive breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • the HER2-positive breast cancer is HER2-positive refractory breast cancer. In another embodiment, the HER2 -positive breast cancer is HER2 -positive metastatic breast cancer. In one embodiment, the HER2-positive breast cancer is ER-negative. In another embodiment, the HER2 -positive breast cancer is ER-positive. In one embodiment, the HER2 -positive breast cancer is PR- positive. In another embodiment, the HER2-positive breast cancer is PR-negative. In one embodiment, the HER2-positive breast cancer is AR-positive. In another embodiment, the HER2 -positive breast cancer is AR-negative.
  • the HER2 -positive breast cancer is ER-positive, PR-positive, and AR-positive. In another embodiment, the HER2 -positive breast cancer is ER-positive, PR-negative, and AR-positive. In another embodiment, the HER2 -positive breast cancer is ER-positive, PR-negative, and AR-negative. In other embodiment, the HER2 -positive breast cancer is ER-positive, PR-positive, and AR- negative. In another embodiment, the HER2 -positive breast cancer is ER-negative, PR-negative, and AR-positive. In another embodiment, the HER2 -positive breast cancer is ER-negative, PR-positive, and AR-positive. In another embodiment, the HER2 -positive breast cancer is ER-negative, PR-positive, and AR-positive.
  • the HER2 -positive breast cancer is ER-negative, PR-positive, and AR-negative. In certain embodiment, the HER2-positive breast cancer is ER-negative, PR-negative, and AR-negative. In certain embodiment, the HER2 -positive breast cancer is triple positive HER2 breast cancer.
  • this invention provides a method for treating a subject suffering from ER mutant expressing breast cancer, comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, A-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat ER mutant expressing breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • the ER mutant expressing breast cancer is Y537S mutation expressing breast cancer.
  • the ER mutant expressing breast cancer is D351Y mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is E380Q mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is V422del mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is S432L mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is G442A mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is S463P mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is L469V mutation expressing breast cancer.
  • the ER mutant expressing breast cancer is L536R mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is L536H mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is L536P mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is L536Q mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is Y537N mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is Y537C mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is Y537D mutation expressing breast cancer.
  • the ER mutant expressing breast cancer is D538G mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is E542G mutation expressing breast cancer. In one embodiment, ER mutant expressing breast cancer refers to mutants of ER-alpha.
  • the ER mutant expressing breast cancer is as described in Cancer Cell 2018, 33, 173-186; or in Nat Rev Cancer. 2018 Jun;l8(6):377-388, which are incorporated herein by reference.
  • the ER mutant expressing breast cancer is as described in Cancer Cell 2018, 33, 173-186; or in Nat Rev Cancer. 2018 Jun;l8(6):377-388, which are incorporated herein by reference.
  • ER mutant expressing breast cancer refers to mutants of ER-alpha.
  • the term “treating” may refer to treating, delaying the progression, preventing the recurrence or treating the recurrence. In one embodiment, the term “treating” refers to a reduction in morbidity, mortality, or a combination thereof, in association with breast cancer.
  • the term“preventing” may refer to preventing the initial occurance of a disorder, reducing risk factors, minimize the disability or potential health threat of a disorder.
  • breast cancer may refer to breast cancer; advanced breast cancer; metastatic breast cancer; AR-positive breast cancer; ER-positive breast cancer; AR-positive breast cancer with or without expression of ER, PR and/or HER2; triple-positive breast cancer (ER, PR and HER2-positive), AR-positive breast cancer with or without expression of ER; ER-positive breast cancer with or without expression of AR; AR-positive and ER-positive breast cancer; refractory breast cancer; AR-positive refractory breast cancer; ER-positive refractory breast cancer; AR-positive metastatic breast cancer; ER-positive metastatic breast cancer; breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, exemestane), cyclin-dependent kina
  • SERM selective estrogen receptor modulator
  • breast cancer refers to a condition characterized by anomalous rapid proliferation of abnormal cells in one or both breasts of a subject.
  • the abnormal cells often are referred to as“neoplastic cells,” which refers to, in some embodiments, transformed cells that can form a solid tumor.
  • tumor in some embodiments, refers to an abnormal mass or population of cells (i.e. two or more cells) that result from excessive or abnormal cell division, whether malignant or benign, and pre-cancerous and cancerous cells.
  • Malignant tumors are distinguished from benign growths or tumors in that, in addition to uncontrolled cellular proliferation, they can invade surrounding tissues and can metastasize.
  • neoplastic cells may be identified in one or both breasts only and not in another tissue or organ, in one or both breasts and one or more adjacent tissues or organs (e.g. lymph node), or in a breast and one or more non-adjacent tissues or organs to which the breast cancer cells have metastasized.
  • adjacent tissues or organs e.g. lymph node
  • the term“metastasis”, in some embodiments, refers to a process in which cancer cells travel from one organ or tissue to another non-adjacent organ or tissue. Cancer cells in the breast(s) can spread to tissues and organs of a subject, and conversely, cancer cells from other organs or tissue can invade or metastasize to a breast. Cancerous cells from the breast(s) may invade or metastasize to any other organ or tissue of the body. Breast cancer cells often invade lymph node cells and/or metastasize to the liver, brain and/or bone and spread cancer in these tissues and organs.
  • the term “invasion”, in some embodiments, refers to the spread of cancerous cells to adjacent surrounding tissues.
  • breast cancer refers to cancer that has spread to other places in the body and usually cannot be cured or controlled with current treatment.
  • AR-positive breast cancer may refer to breast cancer wherein at least a portion of the cancer cells express at least the androgen receptor (AR).
  • ER-positive breast cancer may refer to breast cancer wherein at least a portion of the cancer cells express at least the estrogen receptor (ER).
  • triple negative breast cancer may refer to breast cancer cells that do not have estrogen receptors (ER), progesterone receptors (PR), or large amounts of HER2/neu protein.
  • ER estrogen receptors
  • PR progesterone receptors
  • Triple negative breast cancer may also be referred to herein as "ER-negative PR-negative HER2/neu -negative breast cancer”.
  • triple positive breast cancer may refer to breast cancer cells that express estrogen receptors (ER), progesterone receptors (PR), and large amounts of HER2/neu (HER2) protein.
  • ER estrogen receptors
  • PR progesterone receptors
  • HER2 HER2/neu protein.
  • Triple positive breast cancer may also be referred to herein as "ER-positive PR-positive HER2/neu -positive breast cancer” or“ER, PR, and HER2 breast cancer”.
  • the term "refractory” may refer to breast cancer that does not respond to treatment.
  • the breast cancer may be resistant at the beginning of treatment or it may become resistant during treatment.
  • "Refractory breast cancer” may also be referred to herein as "resistant cancer”.
  • HER2 -positive breast cancer may refer to breast cancers wherein at least a portion of the cancer cells express elevated levels of HER2 protein (HER2 (from human epidermal growth factor receptor 2) or HER2/neu) which promotes rapid growth of cells.
  • HER2 from human epidermal growth factor receptor 2
  • HER2/neu human epidermal growth factor receptor 2
  • the term“ER mutant expressing breast cancer” may refer to breast cancers that express estrogen receptor alpha (ER-oc) with therapy resistance conferring mutations. Often these mutations are located within the ligand binding domain of ER-oc, are treatment emergent, and/or confer resistance to certain or all endocrine therapies such as SERMs, AIs, SERDs, and/or GnRH agonists.
  • the term“Y537S ER mutant expressing breast cancer” may refer to breast cancers that express estrogen receptor alpha (ER-oc) with the point mutation Y537S.
  • a method for treating, preventing, suppressing or inhibiting metastasis in a subject suffering from breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, A-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat, prevent, suppress or inhibit metastasis in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for prolonging the survival of a subject with breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, A-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to prolong the survival of a subject with breast cancer.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for slowing the progression of breast cancer in a subject comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, A-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to slow the progression of breast cancer in the subject.
  • the subject is a female subject. In another embodiment, the subject is a male subject.
  • a method for prolonging progression- free survival of a subject with breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, /V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to prolong progression-free survival of a subject with breast cancer.
  • the subject is a female subject.
  • the subject is a male subject.
  • breast cancer of this invention refers to in one embodiment to ER-positive metastatic breast cancer; In another embodiment to ER-positive refractory breast cancer; In another embodiment to ER-positive PR-positive HER2- negative breast cancer; In another embodiment to AR-positive ER-positive breast cancer; In another embodiment to AR-positive ER-positive refractory breast cancer; In another embodiment to AR-positive ER-positive metastatic breast cancer; In another embodiment to triple positive breast cancer; In another embodiment to advanced ER- positive breast cancer; In another embodiment to AR-positive; In another embodiment to ER-positive breast cancer; and in another embodiment to breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, exemestane), cyclin-dependent kinase 4/6 (CDK 4/
  • SERM selective estrogen receptor
  • a method for lowering biomarker levels in a subject with breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, N- oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to lower the biomarker level in said subject.
  • the method comprises administering a compound of Formulae I-XIV of this invention.
  • the term“biomarker” may refer to a substance used as an indicator of a process, event, or condition.
  • a biomarker can be a biomolecule such as a nucleic acid molecule (e.g. microRNA, genomic DNA, etc.), a protein, a polysaccharide, and the like. Biomarkers include tumor antigens and tumor markers. In one embodiment, a biomarker indicates the presence of cancer, e.g., breast cancer. In one embodiment, a bio marker may be used to determine the efficacy of treatment. In one embodiment, a biomarker may be used to determine the progression of a condition, e.g., breast cancer.
  • CA 27.29 is a cancer antigen highly associated with breast cancer.
  • CA27.29 biomarker refers to a biomarker for breast cancer.
  • CA27.29 is a biomarker for advanced breast cancer.
  • PSA prote-specific antigen
  • CTX biomarker and “NTX biomarker” are the C-telopeptide and N- telopeptide of collagen type I, respectively, which are used as biomarkers of bone turnover. NTX and CTX biomarkers may be sensitive indicators of the presence of bone metastases in breast cancer patients.
  • a method of this invention lowers CA27.29 biomarker in a subject. In one embodiment, a method of this invention lowers PSA in a subject. In one embodiment, a method of this invention lowers CTX biomarker in a subject. In one embodiment of this invention, a method of this invention lowers NTX biomarker in a subject. In another embodiment, a method of this invention maintains the level of CA27.29 in a subject. In another embodiment, a method of this invention maintains the level of PSA in a subject. In another embodiment, a method of this invention maintains the level of CTX biomarker in a subject. In another embodiment, a method of this invention maintains the level of NTX biomarker.
  • the subject has breast cancer. In one embodiment, the subject has advanced breast cancer. In another embodiment, the subject has refractory breast cancer. In yet another embodiment, the subject has AR-positive breast cancer. In still another embodiment, the subject has ER- positive breast cancer.
  • the compound of this invention is an antagonist. In another embodiment, the compound of this invention is an agonist. In yet another embodiment, the compound of this invention is a partial agonist/partial antagonist. In one embodiment, a compound of this invention is an AR agonist. In another embodiment, a compound is an AR antagonist. In yet another embodiment, a compound is a partial AR agonist and AR antagonist. In one embodiment, a compound of this invention is a PR agonist. In another embodiment, a compound is a PR antagonist. In yet another embodiment, a compound is a partial PR agonist and PR antagonist.
  • a compound of this invention is an AR agonist and a PR antagonist.
  • the SARM compounds of this invention may be useful, in some embodiments, for: a) treatment, prevention, delaying onset of, increasing time to first skeletal related event (SRE), suppression or inhibition of, or the reduction of the risk of developing a skeletal-related event (SRE), such as pathological bone fractures, surgery of the bone, radiation of the bone, spinal cord compression, new bone metastasis, and/or bone loss in a subject; b) treatment, prevention, suppression or inhibition of, or the reduction of the risk of developing a variety of hormone-related conditions in a subject, for example for increasing libido; and/or for c) improving quality of life in a subject.
  • SRE first skeletal related event
  • SRE skeletal-related event
  • Osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.
  • the condition affects more than 25 million people and causes more than 1.3 million fractures each year, including 500,000 spine, 250,000 hip and 240,000 wrist fractures annually.
  • Hip fractures are the most serious consequence of osteoporosis, with 5-20% of patients dying within one year, and over 50% of survivors being incapacitated.
  • the elderly are at greatest risk of osteoporosis, and the problem is therefore predicted to increase significantly with the aging of the population.
  • Worldwide fracture incidence is forecasted to increase three-fold over the next 60 years, and one study estimated that there will be 4.5 million hip fractures worldwide in 2050.
  • this invention provides for the use of a compound as herein described, or its prodmg, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, /V-oxide, hydrate or any combination thereof, for: a) treating a bone related disorder; b) preventing a bone related disorder; c) suppressing a bone related disorder; d) inhibiting a bone related disorder; e) increasing a strength of a bone of a subject; f) increasing a bone mass in a subject; g) use for osteoclastogenesis inhibition; and/or h) use for osteoblastogenesis stimulation.
  • this invention provides for the use of a compound as herein described, or its prodmg, analog, isomer, metabolite, derivative, pharmaceutically acceptable salt, pharmaceutical product, polymorph, crystal, impurity, /V-oxide, hydrate or any combination thereof, for: a) accelerating bone repair; b) - treating bone disorders; c) treating bone density loss; d) treating low bone mineral density (BMD); e) treating reduced bone mass; f) treating metabolic bone disease; g) promoting bone growth or regrowth; h) promoting bone restoration; i) promoting bone fracture repair; j) promoting bone remodeling; k) treating bone damage following reconstructive surgery including of the face, hip, or joints; 1) enhancing of bone strength and function; m) increasing cortical bone mass; n) increasing trabecular connectivity; o) preventing, inhibiting or delaying metastasis to the bone; and/or p) preventing, inhibiting or delaying the growth of metastatic tumors
  • the bone related disorder is a genetic disorder, or in another embodiment, is induced as a result of a treatment regimen for a given disease.
  • the compounds as herein described are useful in treating a bone-related disorder that arises as a result of cancer metastasis to bone, or in another embodiment, as a result of androgen-deprivation therapy, for example, given in response to prostate carcinogenesis in the subject.
  • estrogen-deprivation therapy may refer to therapy which is given in response to breast cancer in a subject.
  • treatments include treatment with GnRH agonists, SERMs, SERDs, or aromatase inhibitors (AI).
  • the compounds as herein described are useful in treating a bone-related disorder that arises as a result of cancer metastasis to bone, or in another embodiment, as a result of estrogen-deprivation therapy, for example, given in response to breast cancer in the subject.
  • Menopause can also be induced using GnRH agonists such as gosarelin (Zoladex) which maintains endogeneous estrogens at low levels via inhibition of the hypothalamus-pituitary-gonadal axis.
  • the bone-related disorder is a loss of bone mineral density (BMD).
  • the bone-related disorder is osteoporosis.
  • the bone-related disorder is osteopenia.
  • the bone-related disorder is increased bone resorption.
  • the bone-related disorder is bone fracture.
  • the bone-related disorder is bone frailty.
  • the bone-related disorder is any combination of osteoporosis, osteopenia, increased bone resorption, bone fracture, bone frailty and loss of BMD.
  • Each disorder represents a separate embodiment of the present invention.
  • osteoporosis refers, in one embodiment, to a thinning of the bones with reduction in bone mass due to depletion of calcium and bone protein.
  • osteoporosis is a systemic skeletal disease, characterized by low bone mass and deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture.
  • bone strength is abnormal, in one embodiment, with a resulting increase in the risk of fracture.
  • osteoporosis depletes both the calcium and the protein collagen normally found in the bone, in one embodiment, resulting in either abnormal bone quality or decreased bone density.
  • bones that are affected by osteoporosis can fracture with only a minor fall or injury that normally would not cause a bone fracture.
  • the fracture can be, in one embodiment, either in the form of cracking (as in a hip fracture) or collapsing (as in a compression fracture of the spine).
  • the spine, hips, and wrists are common areas of osteoporosis-induced bone fractures, although fractures can also occur in other skeletal areas.
  • Unchecked osteoporosis can lead, in another embodiment, to changes in posture, physical abnormality, and decreased mobility.
  • the osteoporosis results from androgen deprivation. In another embodiment, the osteoporosis follows androgen deprivation. In another embodiment, the osteoporosis results from estrogen-deprivation therapy. In another embodiment, the osteoporosis follows estrogen-deprivation therapy. In another embodiment, the osteoporosis is primary osteoporosis. In another embodiment, the osteoporosis is secondary osteoporosis. In another embodiment, the osteoporosis is postmenopausal osteoporosis. In another embodiment, the osteoporosis is juvenile osteoporosis. In another embodiment, the osteoporosis is idiopathic osteoporosis.
  • the osteoporosis is senile osteoporosis.
  • osteoporosis can predispose a breast cancer patient to metastasis to the bones and/or predispose the patients toward the development of a skeletally related event.
  • the primary osteoporosis is type I primary osteoporosis. In another embodiment, the primary osteoporosis is type II primary osteoporosis. Each type of osteoporosis represents a separate embodiment of the present invention.
  • the bone- related disorder is treated with a compound as herein described, or a combination thereof.
  • other bone-stimulating compounds can be provided to the subject, prior to, concurrent with or following administration of a compound or compounds as herein described.
  • such a bone stimulating compound may comprise natural or synthetic materials.
  • the bone stimulating compound may comprise a bone morphogenetic protein (BMP), a growth factor, such as epidermal growth factor (EGF), a fibroblast growth factor (FGF), a transforming growth factor (TGF, an insulin growth factor (IGF), a platelet-derived growth factor (PDGF) hedgehog proteins such as sonic, indian and desert hedgehog, a hormone such as follicle stimulating hormone, parathyroid hormone, parathyroid hormone related peptide, activins, inhibins, follistatin, frizzled, frzb or frazzled proteins, BMP binding proteins such as chordin and fetuin, a cytokine such as IF-3, IF-7, GM-CSF, a chemokine, such as eotaxin, a collagen, osteocalcin, osteonectin and others, as will be appreciated by one skilled in the art.
  • BMP bone morphogenetic protein
  • a growth factor such as epidermal growth factor (EGF), a fibro
  • compositions for use in treating a bone disorder of this invention may comprise a compound or compounds as herein described, an additional bone stimulating compound, or compounds, and osteogenic cells.
  • an osteogenic cell may be a stem cell or progenitor cell, which may be induced to differentiate into an osteoblast.
  • the cell may be an osteoblast.
  • nucleic acids which encode bone-stimulating compounds may be administered to the subject, which is to be considered as part of this invention.
  • this invention provides for the treatment, prevention, suppression or inhibition of, or the reduction of the risk of developing a skeletal-related event (SRE), such as bone fractures, surgery of the bone, radiation of the bone, spinal cord compression, new bone metastasis, bone loss, or a combination thereof in a subject with cancer, comprising administering a compound as herein described and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, /V-oxide, or any combination thereof.
  • SRE skeletal-related event
  • the invention relates, inter alia, to treatment of an SRE with the compound of Formulae I-XIV of this invention: (a) in a subject with prostate cancer undergoing or having undergone androgen deprivation therapy (ADT); or (b) in a subject with breast cancer undergoing or having undergone estrogen-deprivation therapy.
  • ADT androgen deprivation therapy
  • the skeletal-related events treated using the methods provided herein and/or utilizing the compositions provided herein are fractures, which in one embodiment, are pathological fractures, non-traumatic fractures, vertebral fracture, non-vertebral fractures, morphometric fractures, or a combination thereof.
  • fractures may be simple, compound, transverse, greenstick, or comminuted fractures.
  • fractures may be to any bone in the body, which in one embodiment, is a fracture in any one or more bones of the arm, wrist, hand, finger, leg, ankle, foot, toe, hip, collar bone, or a combination thereof. In breast cancer, metastasis occurs most often to the hip and vertebrae.
  • the skeletal- related is fractures to the hip and/or vertebrae.
  • the methods and/or compositions provided herein are effective in treatment, prevention, suppression, inhibition or reduction of the risk of skeletal-related events such as pathologic fractures, spinal cord compression, hypercalcemia, bone-related pain, or their combination.
  • the skeletal-related events sought to be treated using the methods provided herein and/or utilizing the compositions provided herein comprise the necessity for bone surgery and/or bone radiation, which in some embodiments, is for the treatment of pain resulting in one embodiment from bone damage, or nerve compression.
  • the skeletal-related events sought to be treated using the methods provided herein and/or utilizing the compositions provided herein comprise spinal cord compression, or the necessity for changes in antineoplastic therapy, including changes in hormonal therapy, in a subject.
  • skeletal- related events sought to be treated using the methods provided herein and/or utilizing the compositions provided herein comprise treating, suppressing, preventing, reducing the incidence of, or delaying progression or severity of bone metastases, or bone loss.
  • bone loss may comprise osteoporosis, osteopenia, or a combination thereof.
  • skeletal-related events may comprise any combination of the embodiments listed herein.
  • the methods provided herein and/or utilizing the compositions provided herein are effective in reducing metastases to the bone, such as in terms of number of foci, the size of foci, or a combination thereof.
  • a method of preventing or inhibiting cancer metastasis to bone in a subject comprising the step of administering to the subject a composition comprising toremifene, raloxifene, tamoxifen or an analogue, functional derivative, metabolite or a combination thereof, or a pharmaceutically acceptable salt thereof.
  • metabolites may comprise ospemifene, fispemifene or their combination.
  • the cancer is prostate cancer. In one embodiment, the cancer is breast cancer.
  • the skeletal-related events are a result of cancer therapy.
  • the skeletal-related events are a result of hormone deprivation therapy, while in another embodiment, they are a product of androgen deprivation therapy (ADT), and in another embodiment they are a product of estrogen-deprivation therapy
  • the term“libido”, may refer to sexual desire, or as defined in Example 9.
  • the term "quality of life” may refer to the focuses on the health and life of a subject suffering from a condition or disease, for example suffering from breast cancer, post treatment until the end of life. It covers the physical, psychosocial, and economic issues faced by the subject, beyond the diagnosis and treatment phases.
  • the term "quality of life” may also be referred to herein as "survivorship”.
  • survivorship includes issues related to the ability to get health care and follow-up treatment, late effects of treatment, second cancers, and quality of life. Family members, friends, and caregivers are also considered part of the survivorship experience.
  • the methods of this invention are useful to a subject, which is a human.
  • the subject is male.
  • the subject is female.
  • the methods as described herein may be useful for treating either males or females, females may respond more advantageously to administration of certain compounds, for certain methods.
  • males may respond more advantageously to administration of certain compounds, for certain methods.
  • the compound of this invention which is effective at: a) treating a subject suffering from breast cancer; b) treating a subject suffering from metastatic breast cancer; c) treating a subject suffering from refractory breast cancer; d) treating a subject suffering from AR-positive breast cancer; e) treating a subject suffering from AR-positive refractory breast cancer; f) treating a subject suffering from AR-positive metastatic breast cancer; g) treating a subject suffering from AR-positive and ER-positive breast cancer; h) treating a subject suffering from AR-positive breast cancer with or without expression of ER, PR, and/or HER2; i) treating a subject suffering from triple negative breast cancer; j) treating a subject suffering from advanced breast cancer; k) treating a subject suffering from breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin releasing hormone (GnRH) agonist (goserelin
  • SERM selective estrogen receptor modul
  • X is a bond, O, CH 2 , NH, S, Se, PR, NO or NR;
  • G is O or S
  • T is OH, OR, -NHCOCHs, or NHCOR;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHFT, CF 3 , CF2CF3, aryl, phenyl, halogen, alkenyl or OH;
  • Ri is CHs, CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R 2 is H, F, Cl, Br, I, CH 3 , CF 3 , OH, CN, N0 2 , NHCOCHs, NHCOCFs, NHCOR, alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , or SR;
  • R 3 is H, F, Cl, Br, I, CN, N0 2 , COR, COOH, CONHR, CF 3 , Sn(R) 3 , or R 3 together with the benzene ring to which it is attached forms a fused ring system represented by the structure:
  • Z is N0 2 , CN, COR, COOH, or CONHR;
  • Y is CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;
  • Q is CN, alkyl, halogen, N(R) 2 , NHCOCH 3 , NHCOCFs, NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHS0 2 CH 3 , NHS0 2 R, OR, COR, OCOR,
  • n is an integer of 1-4;
  • n is an integer of 1-3.
  • this invention relates to the treatment of androgen receptor-positive breast cancer in a subject, for example a female subject. Accordingly, this invention provides methods for: a) treating AR-positive breast cancer in a subject; b) treating metastatic AR-positive breast cancer, or advanced AR-positive breast cancer; c) treating refractory AR-positive breast cancer; d) treating, preventing, suppressing or inhibiting metastasis in a subject suffering from breast cancer; e) prolonging progression-free survival of a subject suffering from breast cancer; f) treating a subject suffering from ER-positive breast cancer; g) treating a subject suffering from metastatic ER-positive breast cancer; h) treating a subject suffering from refractory ER-positive breast cancer; i) treating a subject suffering from AR-positive ER-positive breast cancer; j) treating a subject suffering from AR-positive ER-positive refractory breast cancer; k) treating a subject suffering from AR-positive ER-positive metastatic breast cancer; 1)
  • X is a bond, O, CH 2 , NH, S, Se, PR, NO or NR;
  • G is O or S ;
  • T is OH, OR, -NHCOCHs, or NHCOR;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F,
  • Ri is CHs, CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • R 2 is H, F, Cl, Br, I, CH 3 , CF 3 , OH, CN, N0 2 ,
  • NHCOCHs NHCOCFs
  • NHCOR alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , or SR;
  • R 3 is H, F, Cl, Br, I, CN, N0 2 , COR, COOH,
  • Z is NO2, CN, COR, COOH, or CONHR;
  • Y is CFs, F, Br, Cl, I, CN, or Sn(R) 3 ;
  • Q is CN, alkyl, halogen, N(R) 2 , NHCOCH 3 ,
  • NHCSR NHCSR, NHS0 2 CH 3 , NHS0 2 R, OR, COR, OCOR,
  • n is an integer of 1-4;
  • n is an integer of 1-3; and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, A-oxide, crystal, polymorph, prodmg or any combination thereof, as described herein.
  • the subject is a female subject. In one embodiment, the subject is a male subject.
  • this invention provides methods for: a) treating a subject suffering from HER2-positive breast cancer; b) treating a subject suffering from HER2 -positive refractory breast cancer; c) treating a subject suffering from HER2- positive metastatic breast cancer; d) treating a subject suffering from HER2-positive and ER-negative breast cancer; e) treating a subject suffering from HER2-positive and ER- positive breast cancer; f) treating a subject suffering from HER2 -positive and PR- positive breast cancer; g) treating a subject suffering from HER2-positive and PR- negative breast cancer; h) treating a subject suffering from HER2-positive and AR- positive breast cancer; i) treating a subject suffering from HER2-positive and AR- negative breast cancer; j) treating a subject suffering from HER2 -positive, ER-positive, PR-positive, and AR-positive breast cancer; k) treating a subject suffering from HER2- positive, ER-positive, PR-negative, and AR-positive breast cancer;
  • X is a bond, O, CH 2 , NH, S, Se, PR, NO or NR;
  • G is O or S
  • T is OH, OR, -NHCOCH 3 , or NHCOR;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, C3 ⁇ 4F, CHF2, CF3, CF2CF3,
  • Ri is CH 3 , CH 2 F, CHF 2 , CF 3 , CH2CH3, or CF2CF3;
  • R 2 is H, F, Cl, Br, I, CH 3 , CF 3 , OH, CN, N0 2 , NHCOCH3, NHCOCF3,
  • NHCOR alkyl, arylalkyl, OR, NH 2 , NHR, N(R) 2 , or SR;
  • R 3 is H, F, Cl, Br, I, CN, N0 2 , COR, COOH, CONHR, CF 3 , Sn(R) 3 , or
  • Z is N0 2 , CN, COR, COOH, or CONHR;
  • Y is CF 3 , F, Br, Cl, I, CN, or Sn(R) 3 ;
  • Q is CN, alkyl, halogen, N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR,
  • n is an integer of 1-4;
  • n is an integer of 1-3; and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, /V-oxide, crystal, polymorph, prodmg or any combination thereof, as described herein.
  • the subject is a female subject. In one embodiment, the subject is a male subject.
  • G in Formula I is O.
  • X in Formula I is O.
  • T in Formula I is OH.
  • Ri in Formula I is CH3 ⁇ 4.
  • Z in Formula I is N0 2 .
  • Z in Formula I is CN.
  • Y in Formula I is CF3.
  • Y in Formula I is Cl.
  • Q in Formula I is CN.
  • Q in Formula I is halogen.
  • Q in Formula I is F.
  • Q in Formula I is Cl.
  • Q in Formula I is NHCOCH3.
  • Q in Formula I is CN and R 2 is F.
  • Q in Formula I is Cl and R 2 is F.
  • Q in Formula I is in the para position.
  • Z in Formula I is in the para position.
  • Y in Formula I is in the meta position.
  • the substituents Z, Y and R3 ⁇ 4 can be in any position of the ring carrying these substituents (hereinafter“A ring”).
  • the substituent Z is in the para position of the A ring.
  • the substituent Y is in the meta position of the A ring.
  • the substituent Z is in the para position of the A ring and substituent Y is in the meta position of the A ring.
  • the substituents Q and R 2 can be in any position of the ring carrying these substituents (hereinafter“B ring”).
  • the substituent Q is in the para position of the B ring.
  • the substituent R 2 is in the meta position of the B ring.
  • the substituent Q is CN and is in the para position of the B ring.
  • the compound of this invention which is effective at: a) treating a subject suffering from breast cancer; b) treating a subject suffering from metastatic breast cancer; c) treating a subject suffering from refractory breast cancer; d) treating a subject suffering from AR-positive breast cancer; e) treating a subject suffering from AR-positive refractory breast cancer; f) treating a subject suffering from AR-positive metastatic breast cancer; g) treating a subject suffering from AR-positive and ER-positive breast cancer; h) treating a subject suffering from AR-positive breast cancer with or without expression of ER, PR, and/or HER2; i) treating a subject suffering from triple negative breast cancer; j) treating a subject suffering from advanced breast cancer; k) treating a subject suffering from breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin releasing hormone (GnRH) agonist (goserelin),
  • SERM selective estrogen receptor
  • X is a bond, O, CH 2 , NH, Se, PR, or NR;
  • G is O or S
  • T is OH, OR, -NHCOCHs, or NHCOR;
  • Z is N0 2 , CN, COR, COOH or CONHR;
  • Y is I, CF 3 , Br, Cl, or Sn(R) 3 ;
  • Q is CN, alkyl, halogen, N(R) 2 , NHCOCH 3 ,
  • NHCSR NHCSR, NHS0 2 CH 3 , NHS0 2 R, OR, COR,
  • R is a C1-C4 alkyl, aryl, phenyl, alkenyl, hydroxyl, a C1-C4 haloalkyl, halogen, or haloalkenyl;
  • Ri is CH 3 , CF 3 , CH2CH 3 , or CF2CF 3 .
  • this invention relates to the treatment of androgen receptor-positive breast cancer in a subject, for example a female subject. Accordingly, this invention provides methods for: a) treating AR-positive breast cancer in a subject; b) treating metastatic AR-positive breast cancer, or advanced AR-positive breast cancer; c) treating refractory AR-positive breast cancer; d) treating, preventing, suppressing or inhibiting metastasis in a subject suffering from breast cancer; e) prolonging progression-free survival of a subject suffering from breast cancer; f) treating a subject suffering from ER-positive breast cancer; g) treating a subject suffering from metastatic ER-positive breast cancer; h) treating a subject suffering from refractory ER-positive breast cancer; i) treating a subject suffering from AR-positive ER-positive breast cancer; j) treating a subject suffering from AR-positive ER-positive refractory breast cancer; k) treating a subject suffering from AR-positive ER-positive metastatic breast cancer; 1)
  • X is a bond, O, CH2, NH, Se, PR, or NR;
  • G is O or S ;
  • T is OH, OR, -NHCOCH 3 , or NHCOR;
  • Z is N0 2 , CN, COR, COOH or CONHR;
  • Y is I, CF 3 , Br, Cl, or Sn(R)3;
  • Q is CN, alkyl, halogen, N(R) 2 , NHCOCH3,
  • NHCSR NHCSR, NHSO2CH3, NHSO2R, OR, COR,
  • R is a C1-C4 alkyl, aryl, phenyl, alkenyl, hydroxyl, a C1-C4 haloalkyl, halogen, or haloalkenyl;
  • Ri is CH 3 , CF 3 , CH2CH 3 , or CF2CF 3 ; and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, /V-oxide, crystal, polymorph, prodmg or any combination thereof, as described herein.
  • the subject is a female subject. In one embodiment, the subject is a male subject.
  • this invention provides methods for: a) treating a subject suffering from HER2-positive breast cancer; b) treating a subject suffering from HER2 -positive refractory breast cancer; c) treating a subject suffering from HER2- positive metastatic breast cancer; d) treating a subject suffering from HER2-positive and ER-negative breast cancer; e) treating a subject suffering from HER2-positive and ER- positive breast cancer; f) treating a subject suffering from HER2 -positive and PR- positive breast cancer; g) treating a subject suffering from HER2-positive and PR- negative breast cancer; h) treating a subject suffering from HER2-positive and AR- positive breast cancer; i) treating a subject suffering from HER2-positive and AR- negative breast cancer; j) treating a subject suffering from HER2 -positive, ER-positive, PR-positive, and AR-positive breast cancer; k) treating a subject suffering from HER2- positive, ER-positive, PR-negative, and AR-positive breast cancer;
  • X is a bond, O, CH 2 , NH, Se, PR, or NR;
  • G is O or S
  • T is OH, OR, -NHCOCH 3 , or NHCOR;
  • Z is N0 2 , CN, COR, COOH or CONHR;
  • Y is I, CF 3 , Br, Cl, or Sn(R)3;
  • Q is CN, alkyl, halogen, N(R) 2 , NHCOCH3,
  • NHCSR NHCSR, NHSO2CH3, NHSO2R, OR, COR,
  • R is a C 1 -C 4 alkyl, aryl, phenyl, alkenyl, hydroxyl, a C 1 -C 4 haloalkyl, halogen, or haloalkenyl;
  • Ri is CH 3 , CF 3 , CH2CH 3 , or CF2CF 3 ; and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, /V-oxide, crystal, polymorph, prodmg or any combination thereof, as described herein.
  • the subject is a female subject. In one embodiment, the subject is a male subject.
  • G in Formula II is O.
  • X in Formula II is O.
  • T in Formula II is OH.
  • Ri in Formula II is CH3.
  • Z in Formula II is NO2.
  • Z in Formula II is CN.
  • Y in Formula II is CF3.
  • Y in Formula II is halogen.
  • Y in Formula II is Cl.
  • Q in Formula II is CN.
  • Q in Formula II is halogen.
  • Q in Formula II is Cl.
  • Q in Formula II is F.
  • Q in Formula II is NHCOCH3.
  • Q in Formula II is in the para position.
  • Z in Formula II is in the para position.
  • Y in Formula II is in the meta position.
  • G in Formula II is O, T is OH, Ri is CH3, X is O, Z is CN, Y is CF3 or halogen and Q is CN or F.
  • G in Formula II is O, T is OH, Ri is CH3, X is O, Z is NO2, Y is CF3 and Q is NHCOCH3, F or Cl.
  • the substituents Z and Y can be in any position of the ring carrying these substituents (hereinafter“A ring”).
  • the substituent Z is in the para position of the A ring.
  • the substituent Y is in the meta position of the A ring.
  • the substituent Z is in the para position of the A ring and substituent Y is in the meta position of the A ring.
  • the substituent Q can be in any position of the ring carrying this substituent (hereinafter“B ring”). In one embodiment, the substituent Q is in the para position of the B ring. In another embodiment, the substituent Q is CN and is in the para position of the B ring.
  • the compound of this invention which is effective at: a) treating a subject suffering from breast cancer; b) treating a subject suffering from metastatic breast cancer; c) treating a subject suffering from refractory breast cancer; d) treating a subject suffering from AR-positive breast cancer; e) treating a subject suffering from AR-positive refractory breast cancer; f) treating a subject suffering from AR-positive metastatic breast cancer; g) treating a subject suffering from AR-positive and ER-positive breast cancer; h) treating a subject suffering from AR-positive breast cancer with or without expression of ER, PR, and/or HER2; i) treating a subject suffering from triple negative breast cancer; j) treating a subject suffering from advanced breast cancer; k) treating a subject suffering from breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin releasing hormone (GnRH) agonist (goserelin),
  • SERM selective estrogen receptor
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CFs, F, I, Br, Cl, CN, C(R) 3 or Sn(R) 3 ;
  • Q is CN, alkyl, halogen, N(R) 2 , NHCOCH 3 ,
  • NHCSR NHCSR, NHS0 2 CH , NHS0 2 R, OR, COR,
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH.
  • this invention relates to the treatment of androgen receptor-positive breast cancer in a subject, for example a female subject. Accordingly, this invention provides methods for: a) treating AR-positive breast cancer in a subject; b) treating metastatic AR-positive breast cancer, or advanced AR-positive breast cancer; c) treating refractory AR-positive breast cancer; d) treating, preventing, suppressing or inhibiting metastasis in a subject suffering from breast cancer; e) prolonging progression-free survival of a subject suffering from breast cancer; f) treating a subject suffering from ER-positive breast cancer; g) treating a subject suffering from metastatic ER-positive breast cancer; h) treating a subject suffering from refractory ER-positive breast cancer; i) treating a subject suffering from AR-positive ER-positive breast cancer; j) treating a subject suffering from AR-positive ER-positive refractory breast cancer; k) treating a subject suffering from AR-positive ER-positive metastatic breast cancer; 1)
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CFs, F, I, Br, Cl, CN, C(R) 3 or Sn(R) 3 ;
  • Q is CN, alkyl, halogen, N(R) 2 , NHCOCH ,
  • NHCSR NHCSR, NHS0 2 CH 3 , NHS0 2 R, OR, COR,
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH;
  • the subject is a female subject. In one embodiment, the subject is a male subject.
  • this invention provides methods for: a) treating a subject suffering from HER2-positive breast cancer; b) treating a subject suffering from HER2 -positive refractory breast cancer; c) treating a subject suffering from HER2- positive metastatic breast cancer; d) treating a subject suffering from HER2-positive and ER-negative breast cancer; e) treating a subject suffering from HER2-positive and ER- positive breast cancer; f) treating a subject suffering from HER2 -positive and PR- positive breast cancer; g) treating a subject suffering from HER2-positive and PR- negative breast cancer; h) treating a subject suffering from HER2-positive and AR- positive breast cancer; i) treating a subject suffering from HER2-positive and AR- negative breast cancer; j) treating a subject suffering from HER2 -positive, ER-positive, PR-positive, and AR-positive breast cancer; k) treating a subject suffering from HER2- positive, ER-positive, PR-negative, and AR-positive breast cancer;
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CFs, F, I, Br, Cl, CN, C(R) 3 or Sn(R) 3 ;
  • Q is CN, alkyl, halogen, N(R) 2 , NHCOCH 3 ,
  • NHCSR NHCSR, NHS0 2 CH 3 , NHS0 2 R, OR, COR,
  • fused ring system represented by structure A, B or C:
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF3 ⁇ 4, CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH;
  • the subject is a female subject. In one embodiment, the subject is a male subject.
  • Z in Formula III is N0 2 . In another embodiment, Z in
  • Formula III is CN. In another embodiment, Y in Formula III is CF3 ⁇ 4. In another embodiment, Y in Formula III is Cl. In another embodiment, Y in Formula III is halogen. In another embodiment, Q in Formula III is CN. In another embodiment, Q in Formula III is halogen. In another embodiment, Q in Formula III is F. In another embodiment, Q in Formula III is Cl. In another embodiment, Q in Formula III is NHCOCH 3 . In another embodiment, Z is CN, Y is CF 3 or halogen, and Q is CN or F. In another embodiment, Z is N0 2 , Y is CF 3 , and Q is NHCOCH 3 , F or Cl.
  • the compound of this invention which is effective at: a) treating a subject suffering from breast cancer; b) treating a subject suffering from metastatic breast cancer; c) treating a subject suffering from refractory breast cancer; d) treating a subject suffering from AR-positive breast cancer; e) treating a subject suffering from AR-positive refractory breast cancer; f) treating a subject suffering from AR-positive metastatic breast cancer; g) treating a subject suffering from AR-positive and ER-positive breast cancer; h) treating a subject suffering from AR-positive breast cancer with or without expression of ER, PR, and/or HER2; i) treating a subject suffering from triple negative breast cancer; j) treating a subject suffering from advanced breast cancer; k) treating a subject suffering from breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin releasing hormone (GnRH) agonist (goserelin),
  • SERM selective estrogen receptor
  • X is a bond, O, CH 2 , NH, S, Se, PR, NO or NR;
  • G is O or S
  • Ri is CHs, CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • T is OH, OR, -NHCOCH 3 , or NHCOR;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F,
  • A is a ring selected from: wherein A and B cannot simultaneously be a benzene ring;
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CFs, F, I, Br, Cl, CN, C(R) 3 or Sn(R) 3 ;
  • Qi and Q 2 are independently hydrogen, alkyl, halogen, CF , CN, C(R) 3 , Sn(R) , N(R) 3 ⁇ 4 NHCOCH , NHCOCF , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, 0S0 2 R, S0 2 R, SR, or
  • Q 3 and Q 4 are independently of each other a hydrogen, alkyl, halogen, CF 3 , CN, C(R) 3 , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHS0 2 CH 3 , NHS0 2 R, OR, COR, OCOR, 0S0 2 R, S0 2 R or SR; Wi is O, NH, NR, NO or S; and
  • W 2 is N or NO.
  • this invention relates to the treatment of androgen receptor-positive breast cancer in a subject, for example a female subject. Accordingly, this invention provides methods for: a) treating AR-positive breast cancer in a subject; b) treating metastatic AR-positive breast cancer, or advanced AR-positive breast cancer; c) treating refractory AR-positive breast cancer; d) treating, preventing, suppressing or inhibiting metastasis in a subject suffering from breast cancer; e) prolonging progression-free survival of a subject suffering from breast cancer; f) treating a subject suffering from ER-positive breast cancer; g) treating a subject suffering from metastatic ER-positive breast cancer; h) treating a subject suffering from refractory ER-positive breast cancer; i) treating a subject suffering from AR-positive ER-positive breast cancer; j) treating a subject suffering from AR-positive ER-positive refractory breast cancer; k) treating a subject suffering from AR-positive ER-positive metastatic breast cancer; 1)
  • X is a bond, O, CH 2 , NH, S, Se, PR, NO or NR;
  • G is O or S
  • Ri is CHs, CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • T is OH, OR, -NHCOCH 3 , or NHCOR;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F,
  • A is a ring selected from:
  • B is a ring selected from:
  • a and B cannot simultaneously be a benzene ring
  • Z is NO2, CN, COOH, COR, NHCOR or CONHR;
  • Y is CFs, F, I, Br, Cl, CN, C(R) 3 or Sn(R) 3 ;
  • Qi and Q 2 are independently hydrogen, alkyl, halogen,
  • CF 3 CN, C(R) , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHS0 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO2R, SO2R, SR, or
  • Q 3 and Q 4 are independently of each other a
  • Wi O, NH, NR, NO or S;
  • W 2 is N or NO; and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, /V-oxide, crystal, polymorph, prodmg or any combination thereof, as described herein.
  • the subject is a female subject. In one embodiment, the subject is a male subject.
  • this invention provides methods for: a) treating a subject suffering from HER2-positive breast cancer; b) treating a subject suffering from HER2 -positive refractory breast cancer; c) treating a subject suffering from HER2- positive metastatic breast cancer; d) treating a subject suffering from HER2-positive and ER-negative breast cancer; e) treating a subject suffering from HER2-positive and ER- positive breast cancer; f) treating a subject suffering from HER2 -positive and PR- positive breast cancer; g) treating a subject suffering from HER2-positive and PR- negative breast cancer; h) treating a subject suffering from HER2-positive and AR- positive breast cancer; i) treating a subject suffering from HER2-positive and AR- negative breast cancer; j) treating a subject suffering from HER2 -positive, ER-positive, PR-positive, and AR-positive breast cancer; k) treating a subject suffering from HER2- positive, ER-positive, PR-negative, and AR-positive breast cancer;
  • X is a bond, O, CH2, NH, S, Se, PR, NO or NR;
  • G is O or S
  • Ri is CHs, CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 , or CF 2 CF 3 ;
  • T is OH, OR, -NHCOCH 3 , or NHCOR;
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F, CHF 2 , CF 3 , CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH;
  • A is a ring selected from:
  • a and B cannot simultaneously be a benzene ring
  • Z is N0 2 , CN, COOH, COR, NHCOR or CONHR;
  • Y is CF , F, I, Br, Cl, CN, C(R) 3 or Sn(R) ;
  • Qi and Q 2 are independently hydrogen, alkyl, halogen, CF 3 , CN, C(R) , Sn(R) 3 , N(R) 2 , NHCOCH 3 , NHCOCF 3 , NHCOR, NHCONHR, NHCOOR, OCONHR, CONHR, NHCSCH 3 , NHCSCF 3 , NHCSR, NHSO 2 CH 3 , NHSO 2 R, OR, COR, OCOR, OSO2R, SO2R, SR, or
  • Q 3 and Q 4 are independently of each other a
  • NHCSR NHCSR, NHSO2CH3, NHSO2R, OR, COR, OCOR,
  • Wi is O, NH, NR, NO or S; and W2 is N or NO; and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, /V-oxide, crystal, polymorph, prodmg or any combination thereof, as described herein.
  • the subject is a female subject.
  • the subject is a male subject.
  • G in Formula IV is O.
  • Formula IV is O. In another embodiment, T in Formula IV is OH. In another embodiment, Ri in Formula IV is CH 3 . In another embodiment, Z in Formula IV is NO 2 . In another embodiment, Z in Formula IV is CN. In another embodiment, Y in Formula IV is CF 3 . In another embodiment, Y in Formula IV is halogen. In another embodiment, Y in Formula IV is Cl. In another embodiment, Qi in Formula II is CN. In another embodiment, Qi in Formula IV is F. In another embodiment, Qi in Formula IV is Cl. In another embodiment, Qi in Formula II is NHCOCH 3 . In another embodiment, Qi in Formula IV is in the para position. In another embodiment, Z in Formula IV is in the para position.
  • Y in Formula IV is in the meta position.
  • G in Formula IV is O
  • T is OH
  • Ri is CH 3
  • X is O
  • Z is NO 2 or CN
  • Y is CF 3 or halogen
  • Qi is CN, F, Cl, or NHCOCH 3 .
  • the substituents Z and Y can be in any position of the ring carrying these substituents (hereinafter“A ring”).
  • the substituent Z is in the para position of the A ring.
  • the substituent Y is in the meta position of the A ring.
  • the substituent Z is in the para position of the A ring and substituent Y is in the meta position of the A ring.
  • the substituents Qi and Q 2 can be in any position of the ring carrying these substituents (hereinafter“B ring”).
  • the substituent Qi is in the para position of the B ring.
  • the substituent is Q 2 is H.
  • the substituent Qi is in the para position of the B ring and the substituent is Q 2 is H.
  • the substituent Qi is CN and is in the para position of the B ring, and the substituent is Q 2 is H.
  • NHCSCFs NHCSR, NHSO2CH3, NHSO2R, OR,
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CH 2 F,
  • this invention relates to the treatment of androgen receptor-positive breast cancer in a subject, for example a female subject. Accordingly, this invention provides methods for: a) treating AR-positive breast cancer in a subject; b) treating metastatic AR-positive breast cancer, or advanced AR-positive breast cancer; c) treating refractory AR-positive breast cancer; d) treating, preventing, suppressing or inhibiting metastasis in a subject suffering from breast cancer; e) prolonging progression-free survival of a subject suffering from breast cancer; f) treating a subject suffering from ER-positive breast cancer; g) treating a subject suffering from metastatic ER-positive breast cancer; h) treating a subject suffering from refractory ER-positive breast cancer; i) treating a subject suffering from AR-positive ER-positive breast cancer; j) treating a subject suffering from AR-positive ER-positive refractory breast cancer; k) treating a subject suffering from AR-positive ER-positive metastatic breast cancer; 1)
  • R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, C3 ⁇ 4F, CHF 2 , CF3 ⁇ 4, CF 2 CF 3 , aryl, phenyl, halogen, alkenyl or OH; and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, /V-oxide, crystal, polymorph, prodmg or any combination thereof, as described herein.
  • the subject is a female subject. In one embodiment, the subject is a male subject.
  • this invention provides methods for: a) treating a subject suffering from HER2-positive breast cancer; b) treating a subject suffering from HER2 -positive refractory breast cancer; c) treating a subject suffering from HER2- positive metastatic breast cancer; d) treating a subject suffering from HER2-positive and ER-negative breast cancer; e) treating a subject suffering from HER2-positive and ER- positive breast cancer; f) treating a subject suffering from HER2 -positive and PR- positive breast cancer; g) treating a subject suffering from HER2-positive and PR- negative breast cancer; h) treating a subject suffering from HER2-positive and AR- positive breast cancer; i) treating a subject suffering from HER2-positive and AR- negative breast cancer; j) treating a subject suffering from HER2 -positive, ER-positive, PR-positive, and AR-positive breast cancer; k) treating a subject suffering from HER2- positive, ER-positive, PR-negative, and AR-positive breast cancer;
  • a B C; and R is alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, C3 ⁇ 4F, CHF 2 , CF3 ⁇ 4, CF2CF3, aryl, phenyl, halogen, alkenyl or OH; and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, as described herein.
  • the subject is a female subject. In one embodiment, the subject is a male subject.
  • Q in Formula V or VI is CN. In one embodiment, Q in Formula V or VI is halogen. In one embodiment, Q in Formula V or VI is F. In one embodiment, Q in Formula V or VI is Cl. In one embodiment, Q in Formula V or VI is NHCOCH3.
  • the compound of this invention which is effective at: a) treating a subject suffering from breast cancer; b) treating a subject suffering from metastatic breast cancer; c) treating a subject suffering from refractory breast cancer; d) treating a subject suffering from AR-positive breast cancer; e) treating a subject suffering from AR-positive refractory breast cancer; f) treating a subject suffering from AR-positive metastatic breast cancer; g) treating a subject suffering from AR-positive and ER-positive breast cancer; h) treating a subject suffering from AR-positive breast cancer with or without expression of ER, PR, and/or HER2; i) treating a subject suffering from triple negative breast cancer; j) treating a subject suffering from advanced breast cancer; k) treating a subject suffering from breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin releasing hormone (GnRH) agonist (goserelin
  • SERM selective estrogen receptor modul
  • this invention relates to the treatment of androgen receptor-positive breast cancer in a subject, for example a female subject. Accordingly, this invention provides methods for: a) treating AR-positive breast cancer in a subject; b) treating metastatic AR-positive breast cancer, or advanced AR-positive breast cancer; c) treating refractory AR-positive breast cancer; d) treating, preventing, suppressing or inhibiting metastasis in a subject suffering from breast cancer; e) prolonging progression-free survival of a subject suffering from breast cancer; f) treating a subject suffering from ER-positive breast cancer; g) treating a subject suffering from metastatic ER-positive breast cancer; h) treating a subject suffering from refractory ER-positive breast cancer; i) treating a subject suffering from AR-positive ER-positive breast cancer; j) treating a subject suffering from AR-positive ER-positive refractory breast cancer; k) treating a subject suffering from AR-positive ER-positive metastatic breast cancer;
  • the subject is a female subject. In one embodiment, the subject is a male subject
  • this invention provides methods for: a) treating a subject suffering from HER2-positive breast cancer; b) treating a subject suffering from HER2 -positive refractory breast cancer; c) treating a subject suffering from HER2- positive metastatic breast cancer; d) treating a subject suffering from HER2-positive and ER-negative breast cancer; e) treating a subject suffering from HER2-positive and ER- positive breast cancer; f) treating a subject suffering from HER2 -positive and PR- positive breast cancer; g) treating a subject suffering from HER2-positive and PR- negative breast cancer; h) treating a subject suffering from HER2-positive and AR- positive breast cancer; i) treating a subject suffering from HER2-positive and AR- negative breast cancer; j) treating a subject suffering from HER2 -positive, ER-positive, PR-positive, and AR-positive breast cancer; k) treating a subject suffering from HER2- positive, ER-positive, PR-negative, and AR-positive breast cancer;
  • the subject is a female subject. In one embodiment, the subject is a male subject.
  • SERM selective estrogen receptor modul
  • SERM selective estrogen receptor modul
  • SERM selective estrogen receptor modul
  • SERM selective estrogen receptor modul
  • SERM selective estrogen receptor modul
  • SERM selective estrogen receptor modulator
  • SERM selective estrogen receptor modulator
  • this invention relates to the treatment of androgen receptor-positive breast cancer in a subject, for example a female subject. Accordingly, this invention provides methods for: a) treating AR-positive breast cancer in a subject; b) treating metastatic AR-positive breast cancer, or advanced AR-positive breast cancer; c) treating refractory AR-positive breast cancer; d) treating, preventing, suppressing or inhibiting metastasis in a subject suffering from breast cancer; e) prolonging progression-free survival of a subject suffering from breast cancer; f) treating a subject suffering from ER-positive breast cancer; g) treating a subject suffering from metastatic ER-positive breast cancer; h) treating a subject suffering from refractory ER-positive breast cancer; i) treating a subject suffering from AR-positive ER-positive breast cancer; j) treating a subject suffering from AR-positive ER-positive refractory breast cancer; k) treating a subject suffering from AR-positive ER-positive metastatic breast cancer; 1)
  • the subject is a female subject. In one embodiment, the subject is a male subject.
  • this invention provides methods for: a) treating a subject suffering from HER2-positive breast cancer; b) treating a subject suffering from HER2 -positive refractory breast cancer; c) treating a subject suffering from HER2- positive metastatic breast cancer; d) treating a subject suffering from HER2-positive and ER-negative breast cancer; e) treating a subject suffering from HER2-positive and ER- positive breast cancer; f) treating a subject suffering from HER2 -positive and PR- positive breast cancer; g) treating a subject suffering from HER2-positive and PR- negative breast cancer; h) treating a subject suffering from HER2-positive and AR- positive breast cancer; i) treating a subject suffering from HER2-positive and AR- negative breast cancer; j) treating a subject suffering from HER2 -positive, ER-positive, PR-positive, and AR-positive breast cancer; k) treating a subject suffering from HER2- positive, ER-positive, PR-negative, and AR-positive breast cancer;
  • the methods of this invention make use of a compound of Formula VIII. In one embodiment, the methods of this invention make use of a compound of Formula IX. In one embodiment, the methods of this invention make use of a compound of Formula X. In one embodiment, the methods of this invention make use of a compound of Formula XI. In one embodiment, the methods of this invention make use of a compound of Formula XII. In one embodiment, the methods of this invention make use of a compound of Formula XIII. In one embodiment, the methods of this invention make use of a compound of Formula XIV. [000175] In one embodiment, the methods of the present invention comprise administering an analog of the compound of Formulae I-XIV.
  • the methods of the present invention comprise administering a derivative of the compound of Formulae I-XIV. In another embodiment, the methods of the present invention comprise administering an isomer of the compound of Formulae I-XIV. In another embodiment, the methods of the present invention comprise administering a metabolite of the compound of Formulae I-XIV. In another embodiment, the methods of the present invention comprise administering a pharmaceutically acceptable salt of the compound of Formulae I-XIV. In another embodiment, the methods of the present invention comprise administering a pharmaceutical product of the compound of Formulae I-XIV. In another embodiment, the methods of the present invention comprise administering a hydrate of the compound of Formulae I-XIV.
  • the methods of the present invention comprise administering an V-oxide of the compound of Formulae I-XIV. In another embodiment, the methods of the present invention comprise administering a polymorph of the compound of Formulae I-XIV. In another embodiment, the methods of the present invention comprise administering a crystal of the compound of Formulae I-XIV. In another embodiment, the methods of the present invention comprise administering a prodrug of the compound of Formulae I- XIV. In another embodiment, the methods of the present invention comprise administering a combination of any of an analog, derivative, metabolite, isomer, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, polymorph, crystal or prodmg of the compound of Formulae I-XIV.
  • the methods of this invention comprise administering a compound of Formulae I-XIV. In another embodiment, the methods of this invention comprise administering a compound of Formula I. In another embodiment, the methods of this invention comprise administering a compound of Formula II. In another embodiment, the methods of this invention comprise administering a compound of Formula III. In another embodiment, the methods of this invention comprise administering a compound of Formula IV. In another embodiment, the methods of this invention comprise administering a compound of Formula V. In another embodiment, the methods of this invention comprise administering a compound of Formula VI. In another embodiment, the methods of this invention comprise administering a compound of Formula VII. In another embodiment, the methods of this invention comprise administering a compound of Formula VIII.
  • the methods of this invention comprise administering a compound of Formula IX. In another embodiment, the methods of this invention comprise administering a compound of Formula X. In another embodiment, the methods of this invention comprise administering a compound of Formula XI. In another embodiment, the methods of this invention comprise administering a compound of Formula XII. In another embodiment, the methods of this invention comprise administering a compound of Formula XIII. In another embodiment, the methods of this invention comprise administering a compound of Formula XIV.
  • the compounds of the present invention are useful for: a) treating a subject suffering from breast cancer; b) treating a subject suffering from metastatic breast cancer; c) treating a subject suffering from refractory breast cancer; d) treating a subject suffering from AR-positive breast cancer; e) treating a subject suffering from AR-positive refractory breast cancer; f) treating a subject suffering from AR-positive metastatic breast cancer; g) treating a subject suffering from AR-positive and ER-positive breast cancer; h) treating a subject suffering from AR-positive breast cancer with or without expression of ER, PR, and/or HER2; i) treating a subject suffering from triple negative breast cancer; j) treating a subject suffering from advanced breast cancer; k) treating a subject suffering from breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (
  • SERM selective estrogen receptor modulator
  • the compounds of the present invention offer a significant advance over steroidal androgen treatment since treatment of breast cancer with these compounds will not be accompanied by serious side effects, inconvenient modes of administration, or high costs and still have the advantages of oral bio availability, lack of cross-reactivity with other steroid receptors, lack of aromatizability, and long biological half-lives.
  • this invention relates to the treatment of androgen receptor-positive breast cancer in a subject. Accordingly, this invention provides methods of: a) treating a subject suffering from breast cancer; b) treating a subject suffering from metastatic breast cancer; c) treating a subject suffering from refractory breast cancer; d) treating a subject suffering from AR-positive breast cancer; e) treating a subject suffering from AR-positive refractory breast cancer; f) treating a subject suffering from AR-positive metastatic breast cancer; g) treating a subject suffering from AR-positive and ER-positive breast cancer; h) treating a subject suffering from AR- positive breast cancer with or without expression of ER, PR, and/or HER2; i) treating a subject suffering from triple negative breast cancer; j) treating a subject suffering from advanced breast cancer; k) treating a subject suffering from breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonado
  • SERM selective estrogen receptor
  • the term“isomer” includes, but is not limited to, optical isomers and analogs, structural isomers and analogs, conformational isomers and analogs, and the like. As used herein, the term “isomer” may also be referred to herein as an "enantiomer” having all of the qualities and properties of an "isomer”. [000181] In one embodiment, this invention encompasses the use of various optical isomers of the selective androgen receptor modulator. It will be appreciated by those skilled in the art that the selective androgen receptor modulators of the present invention contain at least one chiral center.
  • the selective androgen receptor modulators used in the methods of the present invention may exist in, and be isolated in, optically-active or racemic forms. Some compounds may also exhibit polymorphism. It is to be understood that the present invention encompasses any racemic, optically-active, polymorphic, or stereoisomeric form, or any combination thereof, which form possesses properties useful in the treatment of androgen-related conditions described herein.
  • the selective androgen receptor modulators are the pure ( ?)-isomers.
  • the selective androgen receptor modulators are the pure (S)- isomers.
  • the selective androgen receptor modulators are a mixture of the (R) and the ( S ) isomers.
  • the selective androgen receptor modulators are a racemic mixture comprising an equal amount of the (R) and the ( S ) isomers. It is well known in the art how to prepare optically-active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis from optically-active starting materials, by chiral synthesis, or by chromatographic separation using a chiral stationary phase).
  • the invention includes“pharmaceutically acceptable salts” of the compounds of this invention, which may be produced, by reaction of a compound of this invention with an acid or base.
  • the invention includes pharmaceutically acceptable salts of amino- substituted compounds with organic and inorganic acids, for example, citric acid and hydrochloric acid.
  • the invention also includes A-oxides of the amino substituents of the compounds described herein.
  • Pharmaceutically acceptable salts can also be prepared from the phenolic compounds by treatment with inorganic bases, for example, sodium hydroxide.
  • esters of the phenolic compounds can be made with aliphatic and aromatic carboxylic acids, for example, acetic acid and benzoic acid esters.
  • Suitable pharmaceutically acceptable salts of the compounds of Formulae I- XIV may be prepared from an inorganic acid or from an organic acid.
  • examples of inorganic salts of the compounds of this invention are bisulfates, borates, bromides, chlorides, hemisulfates, hydrobromates, hydrochlorates, 2- hydroxyethylsulfonates (hydroxyethanesulfonates), iodates, iodides, isothionates, nitrates, persulfates, phosphate, sulfates, sulfamates, sulfanilates, sulfonic acids (alkylsulfonates, arylsulfonates, halogen substituted alkylsulfonates, halogen substituted arylsulfonates), sulfonates and thiocyanates.
  • examples of organic salts of the compounds of this invention may be selected from aliphatic, cycloaliphatic, aromatic, araliphatic, heterocyclic, carboxylic and sulfonic classes of organic acids, examples of which are acetates, arginines, aspartates, ascorbates, adipates, anthranilates, algenates, alkane carboxylates, substituted alkane carboxylates, alginates, benzenesulfonates, benzoates, bisulfates, butyrates, bicarbonates, bitartrates, citrates, camphorates, camphorsulfonates, cyclohexylsulfamates, cyclopentanepropionates, calcium edetates, camsylates, carbonates, clavulanates, cinnamates, dicarboxylates, digluconates, dodecylsulfonates, dihydrochlorides, decano
  • the salts may be formed by conventional means, such as by reacting the free base or free acid form of the product with one or more equivalents of the appropriate acid or base in a solvent or medium in which the salt is insoluble or in a solvent such as water, which is removed in vacuo or by freeze drying or by exchanging the ions of a existing salt for another ion or suitable ion-exchange resin.
  • This invention further includes derivatives of the selective androgen receptor modulators.
  • derivatives includes but is not limited to ether derivatives, acid derivatives, amide derivatives, ester derivatives and the like.
  • this invention further includes hydrates of the selective androgen receptor modulators.
  • hydrate includes but is not limited to hemihydrate, monohydrate, dihydrate, trihydrate and the like.
  • This invention further includes metabolites of the selective androgen receptor modulators.
  • metabolite means any substance produced from another substance by metabolism or a metabolic process.
  • This invention further includes pharmaceutical products of the selective androgen receptor modulators.
  • pharmaceutical product means a composition suitable for pharmaceutical use (pharmaceutical composition), as defined herein.
  • This invention further includes prodmgs of the selective androgen receptor modulators.
  • prodrug means a substance which can be converted in vivo into a biologically active agent by such reactions as hydrolysis, esterification, de esterification, activation, salt formation and the like.
  • This invention further includes crystals of the selective androgen receptor modulators. Furthermore, this invention provides polymorphs of the selective androgen receptor modulators.
  • the term“crystal” means a substance in a crystalline state.
  • the term“polymorph” refers to a particular crystalline state of a substance, having particular physical properties such as X-ray diffraction, IR spectra, melting point, and the like.
  • a method for treating a subject suffering from breast cancer comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, /V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from metastatic breast cancer comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, /V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat metastatic breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from refractory breast cancer comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat refractory breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from AR-positive breast cancer comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat AR-positive breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • the AR-positive breast cancer is ER, PR and HER2- positive. In another embodiment, the AR-positive breast cancer is ER, PR and HER2- negative. In one embodiment, the AR-positive breast cancer is ER-positive, and PR and HER2-negative. In another embodiment, the AR-positive breast cancer is ER and PR- positive, and HER2-negative. In yet another embodiment, the AR-positive breast cancer is ER and HER2 -positive, and PR-negative. In still another embodiment, the AR- positive breast cancer is ER-negative, and PR and HER2 -positive. In a further embodiment, the AR-positive breast cancer is ER and PR-negative, and HER2-positive. In still a further embodiment, the AR-positive breast cancer is ER and HER2-negative, and PR-positive. In one embodiment, the AR-positive breast cancer is ER-negative. In another embodiment, the AR-positive breast cancer is ER-positive.
  • a method for treating a subject suffering from AR-positive refractory breast cancer comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, A-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat AR- positive refractory breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from AR-positive metastatic breast cancer comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, A-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat AR- positive metastatic breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from ER-positive breast cancer comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, A-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat ER-positive breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from AR-positive and ER-positive breast cancer comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, /V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat AR- positive metastatic breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from ER-positive refractory breast cancer comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat ER- positive refractory breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from ER-positive metastatic breast cancer comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat ER- positive metastatic breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • an ER-positive breast cancer is AR-positive. In another embodiment, an ER-positive breast cancer is AR-negative.
  • a method for treating a subject suffering from advanced breast cancer comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat advanced breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from AR-positive and ER-positive breast cancer comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, /V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat AR- positive and ER-positive refractory breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from AR-positive and ER-negative breast cancer comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat AR- positive and ER-negative metastatic breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from triple negative breast cancer comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat triple negative breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, exemestane), cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio)), mTOR inhibitor (everolimus), trastuzumab (Herceptin, ado-trastuzumab emtansine), pertuzumab (Perjeta), lapatinib, neratinib (Nerlynx), olaparib (Lynparza) (an inhibitor of the enzyme poly ADP ribose poly
  • a method for treating, preventing, suppressing or inhibiting metastasis in a subject suffering from breast cancer comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat, prevent, suppress or inhibit metastasis in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating and/or preventing skeletal related events in a subject suffering comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, /V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat and/or prevent skeletal related events in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for improving libido in a subject comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to improve libido in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for improving quality of life in a subject comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to quality of life in the subject.
  • the subject is a female subject. In another embodiment, the subject is a male subject.
  • a method for treating, preventing, suppressing or inhibiting metastasis in a subject suffering from breast cancer comprising the step of administering to the subject a selective androgen receptor modulator of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, V-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat, prevent, suppress or inhibit metastasis in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • a method for treating a subject suffering from HER2-positive breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, A-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat HER2-positive breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • the HER2-positive breast cancer is HER2-positive refractory breast cancer.
  • the HER2 -positive breast cancer is HER2 -positive metastatic breast cancer.
  • the HER2-positive breast cancer is ER-negative.
  • the HER2 -positive breast cancer is ER-positive.
  • the HER2 -positive breast cancer is PR- positive.
  • the HER2-positive breast cancer is PR-negative.
  • the HER2-positive breast cancer is AR-positive. In another embodiment, the HER2 -positive breast cancer is AR-negative.
  • the HER2 -positive breast cancer is ER-positive, PR-positive, and AR-positive. In another embodiment, the HER2 -positive breast cancer is ER-positive, PR-negative, and AR-positive. In another embodiment, the HER2 -positive breast cancer is ER-positive, PR-negative, and AR-negative. In other embodiment, the HER2 -positive breast cancer is ER-positive, PR-positive, and AR- negative. In another embodiment, the HER2 -positive breast cancer is ER-negative, PR-negative, and AR-positive. In another embodiment, the HER2 -positive breast cancer is ER-negative, PR-positive, and AR-positive. In other embodiment, the HER2 -positive breast cancer is ER-negative, PR-positive, and AR-negative. In certain embodiment, the HER2-positive breast cancer is ER-negative, PR-negative, and AR-negative.
  • a method for treating a subject suffering from ER mutant expressing breast cancer comprising the step of administering to the subject a compound of Formulae I-XIV of this invention and/or its analog, derivative, isomer, metabolite, pharmaceutically acceptable salt, pharmaceutical product, hydrate, A-oxide, crystal, polymorph, prodmg or any combination thereof, in an amount effective to treat ER mutant expressing breast cancer in the subject.
  • the subject is a female subject.
  • the subject is a male subject.
  • the ER mutant expressing breast cancer is Y537S mutation expressing breast cancer.
  • the ER mutant expressing breast cancer is D351Y mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is E380Q mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is V422del mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is S432L mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is G442A mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is S463P mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is L469V mutation expressing breast cancer.
  • the ER mutant expressing breast cancer is L536R mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is L536H mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is L536P mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is L536Q mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is Y537N mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is Y537C mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is Y537D mutation expressing breast cancer.
  • the ER mutant expressing breast cancer is D538G mutation expressing breast cancer. In a certain embodiment, the ER mutant expressing breast cancer is E542G mutation expressing breast cancer. In one embodiment, ER mutant expressing breast cancer refers to mutants of ER-alpha.
  • the ER mutant expressing breast cancer is as described in Cancer Cell 2018, 33, 173-186; or in Nat Rev Cancer. 2018 Jun;l8(6):377-388, which are incorporated herein by reference.
  • the ER mutant expressing breast cancer is as described in Cancer Cell 2018, 33, 173-186; or in Nat Rev Cancer. 2018 Jun;l8(6):377-388, which are incorporated herein by reference.
  • ER mutant expressing breast cancer refers to mutants of ER-alpha.
  • the substituent R is defined herein as an alkyl, haloalkyl, dihaloalkyl, trihaloalkyl, CfTF, CHF 2 , CF 3 , CF 2 CF 3 ; aryl, phenyl, halogen, alkenyl, or hydroxyl (OH).
  • An “alkyl” group refers to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain and cyclic alkyl groups. In one embodiment, the alkyl group has 1-12 carbons. In another embodiment, the alkyl group has 1-7 carbons. In another embodiment, the alkyl group has 1-6 carbons. In another embodiment, the alkyl group has 1-4 carbons.
  • the alkyl group may be unsubstituted or substituted by one or more groups selected from halogen, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxyl, thio and thioalkyl.
  • A“haloalkyl” group refers to an alkyl group as defined above, which is substituted by one or more halogen atoms, e.g. by F, Cl, Br or I.
  • An“aryl” group refers to an aromatic group having at least one carbocyclic aromatic group or heterocyclic aromatic group, which may be unsubstituted or substituted by one or more groups selected from halogen, haloalkyl, hydroxy, alkoxy carbonyl, amido, alkylamido, dialkylamido, nitro, amino, alkylamino, dialkylamino, carboxy or thio or thioalkyl.
  • Nonlimiting examples of aryl rings are phenyl, naphthyl, pyranyl, pyrrolyl, pyrazinyl, pyrimidinyl, pyrazolyl, pyridinyl, furanyl, thiophenyl, thiazolyl, imidazolyl, isoxazolyl, and the like.
  • A“hydroxyl” group refers to an OH group.
  • An“alkenyl” group refers to a group having at least one carbon to carbon double bond.
  • a halo group refers to F, Cl, Br or I.
  • An“arylalkyl” group refers to an alkyl bound to an aryl, wherein alkyl and aryl are as defined above.
  • An example of an aralkyl group is a benzyl group.
  • the selective androgen receptor modulators provided herein are a new class of compounds, which suppress growth of AR-positive breast cancers.
  • the compounds of this invention have a tissue-selective myoanabolic activity profile of a nonsteroidal ligand for the androgen receptor.
  • compounds of the present invention are non-aromatizable, non- virilizing, and are not commonly cross-reactive with ER and PR.
  • the selective androgen receptor modulators (S ARMs) of the present invention are beneficial to refractory breast cancer patients undergoing chemotherapy due to anabolism.
  • the appropriately substituted selective androgen receptor modulators of the present invention are useful for: a) treating a subject suffering from breast cancer; b) treating a subject suffering from metastatic breast cancer; c) treating a subject suffering from refractory breast cancer; d) treating a subject suffering from AR-positive breast cancer; e) treating a subject suffering from AR- positive refractory breast cancer; f) treating a subject suffering from AR-positive metastatic breast cancer; g) treating a subject suffering from AR-positive and ER- positive breast cancer; h) treating a subject suffering from AR-positive breast cancer with or without expression of ER, PR, and/or HER2; i) treating a subject suffering from triple negative breast cancer; j) treating a subject suffering from advanced breast cancer; k) treating a subject suffering from breast cancer that has failed selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin-releasing hormone (GSM) (tamoxifen, tore
  • a“refractory breast cancer” is a breast cancer that has not responded to treatment.
  • a“refractory breast cancer” is a breast cancer resistant to treatment.
  • refractory breast cancer is refractory metastatic breast cancer.
  • refractory breast cancer has not responded to treatment with anthracyclines, taxanes, capecitabine, ixabepilone, selective estrogen receptor modulator (SERM) (tamoxifen, toremifene, raloxifene), gonadotropin- releasing hormone (GnRH) agonist (goserelin), aromatase inhibitor (AI) (letrozole, anastrozole, exemestane), cyclin-dependent kinase 4/6 (CDK 4/6) inhibitor (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio)), mTOR inhibitor (everolimus), trastuzumab (Herceptin, ado-trastuzumab emtansine), pertuzumab (Perjeta), lapatinib, neratinib (Nerlynx), olaparib (Lynparza) (an inhibitor
  • a“triple negative breast cancer” is defined by lack of expression of estrogen, progesterone, and ErbB2 (also known as human epidermal growth factor receptor 2 (HER2)) receptors. This subgroup accounts for 15% of all types of breast cancer. This subtype of breast cancer is clinically characterized as more aggressive and less responsive to standard treatment and associated with poorer overall patient prognosis.
  • the methods of this invention are directed to treating a subject suffering from AR-positive breast cancer, regardless of grade, stage or prior treatments.
  • the methods of this invention are directed to treating a subject suffering from HER2-positive breast cancer, regardless of grade, stage or prior treatments.
  • the methods of this invention are first, second, third, or fourth line therapies for breast cancer.
  • a first line therapy refers to a medical therapy recommended for the initial treatment of a disease, sign or symptom.
  • a second line therapy therapy is given when initial treatment (first-line therapy) does not work, or stops working.
  • Third line therapy is given when both initial treatment (first-line therapy) and subsequent treatment (second-line therapy) does not work, or stop working, etc.
  • kinases are a group of enzymes that catalyze the transfer of a phosphate group from a donor, such as ADP or ATP, to an acceptor.
  • phosphorylation results in a functional change of the target protein (substrate) by changing enzyme activity, cellular location, or association with other protein kinases.
  • Kinases regulate the majority of cellular pathways, especially those involved in signal transduction.
  • deregulated kinase activity is a frequent cause of disease, in particular cancer, wherein kinases regulate many aspects that control cell growth, movement and death.
  • dmgs that inhibit specific kinases are used to treat kinase-related diseases, including cancer.
  • HER2 -positive breast cancers are susceptible to HER2 kinase inhibitors (e.g., trastuzumab and lapatinib) and are generally used in metastatic disease. However, some breast cancers are refractory to HER2 kinase inhibitor treatment.
  • HER2 kinase inhibitors e.g., trastuzumab and lapatinib
  • some breast cancers are refractory to HER2 kinase inhibitor treatment.
  • cell signaling receptors receptors for extracellular signaling molecules are collectively referred to as "cell signaling receptors".
  • Many cell signaling receptors are transmembrane proteins on a cell surface; when they bind an extracellular signaling molecule (i.e., a ligand), they become activated so as to generate a cascade of intracellular signals that alter the behavior of the cell.
  • the receptors are inside the cell and the signaling ligand has to enter the cell to activate them; these signaling molecules therefore must be sufficiently small and hydrophobic to diffuse across the plasma membrane of the cell.
  • Steroid hormones are one example of small hydrophobic molecules that diffuse directly across the plasma membrane of target cells and bind to intracellular cell signaling receptors. These receptors are stmcturally related and constitute the intracellular receptor superfamily (or steroid-hormone receptor superfamily). Steroid hormone receptors include but are not limited to progesterone receptors, estrogen receptors, androgen receptors, glucocorticoid receptors, and mineralocorticoid receptors. In one embodiment, the present invention is directed to androgen receptors. In one embodiment, the present invention is directed to androgen receptor agonists. In one embodiment, the present invention is directed to progesterone receptors. In one embodiment, the present invention is directed to progesterone receptor antagonists.
  • the receptors can be blocked to prevent ligand binding.
  • affinity If the affinity of a substance is greater than the original hormone, it will compete with the hormone and bind the binding site more frequently.
  • signals may be sent through the receptor into the cells, causing the cell to respond in some fashion. This is called activation. On activation, the activated receptor then directly regulates the transcription of specific genes.
  • the substance and the receptor may have certain attributes, other than affinity, in order to activate the cell. Chemical bonds between atoms of the substance and the atoms of the receptors may form. In some cases, this leads to a change in the configuration of the receptor, which is enough to begin the activation process (called signal transduction).
  • the compounds of this invention inhibit the intratumoral expression of genes and pathways that promote breast cancer development through their actions on the AR.
  • a compound of this invention inhibits intratumoral expression of Mucl, SLUG, VCAM1, SPARC or MMP2, or any combination thereof.
  • Formula VIII inhibits gene expression that promotes breast cancer.
  • a receptor antagonist is a substance which binds receptors and inactivates them.
  • a selective androgen receptor modulator is a molecule that exhibits in vivo tissue selectivity, activating signaling activity of the androgen receptor (AR) in anabolic (muscle, bone, etc.) tissues to a greater extent than in the androgenic tissues.
  • the selective androgen receptor modulators of the present invention are useful in binding to and activating steroidal hormone receptors.
  • the SARM compound of the present invention is an agonist which binds the androgen receptor.
  • the compound has high affinity for the androgen receptor.
  • AR agonistic activity can be determined by monitoring the ability of the selective androgen receptor modulators to maintain and/or stimulate the growth of AR containing androgenic tissue such as prostate and seminal vesicles, as measured by weight, in castrated animals.
  • AR antagonistic activity can be determined by monitoring the ability of the selective androgen receptor modulators to inhibit the growth of AR containing tissue in intact animals or counter the effects of testosterone in castrated animals.
  • An androgen receptor is an androgen receptor of any species, for example a mammal.
  • the androgen receptor is an androgen receptor of a human.
  • the selective androgen receptor modulators bind reversibly to an androgen receptor of a human.
  • the selective androgen receptor modulators bind reversibly to an androgen receptor of a mammal.
  • the term“selective androgen receptor modulator” refers to, in one embodiment, a molecule that exhibits in vivo tissue selectivity, activating signaling activity of the androgen receptor in anabolic (muscle, bone, etc.) tissues to a greater extent than in the androgenic tissues.
  • a selective androgen receptor modulator selectively binds the androgen receptor.
  • a selective androgen receptor modulator selectively affects signaling through the androgen receptor.
  • the SARM is a partial agonist.
  • the SARM is a tissue-selective agonist, or in some embodiments, a tissue-selective antagonist.
  • a SARM of this invention exerts its effects on the androgen receptor in a tissue-dependent manner.
  • a SARM of this invention will have an IC50 or EC50 with respect to AR, as determined using AR transactivation assays, as known in the art, or, in other embodiments, as described herein.
  • IC50 refers, in some embodiments, to a concentration of the SARM which reduces the activity of a target (e.g., AR) to half-maximal level.
  • EC50 refers, in some embodiments, to a concentration of the SARM that produces a half-maximal effect.
  • Figure 5 shows that compounds of this invention exhibit AR agonist activity in MDA-MB-231 cells transfected with AR.
  • “contacting” means that the selective androgen receptor modulators of the present invention are introduced into a sample containing the receptor in a test tube, flask, tissue culture, chip, array, plate, microplate, capillary, or the like, and incubated at a temperature and time sufficient to permit binding of the selective androgen receptor modulators to the receptor.
  • Methods for contacting the samples with the selective androgen receptor modulators or other specific binding components are known to those skilled in the art and may be selected depending on the type of assay protocol to be run. Incubation methods are also standard and are known to those skilled in the art.
  • the term “contacting” means that the selective androgen receptor modulators of the present invention are introduced into a subject receiving treatment, and the selective androgen receptor modulator is allowed to come in contact with the androgen receptor in vivo.
  • the term“treating” includes disorder remitative treatment.
  • the terms“reducing”,“suppressing” and“inhibiting” have their commonly understood meaning of lessening or decreasing.
  • the term“progression” means increasing in scope or severity, advancing, growing or becoming worse.
  • the term“recurrence” means the return of a disease after a remission.
  • the term“delaying” means stopping, hindering, slowing down, postponing, holding up or setting back.
  • the term“metastasis” refers to the transfer of a disease from one organ or part thereof to another not directly connected with it. Metastasis can occur for example as a result of transfer of malignant cells from one organ (for example breast) to other organs.
  • treating refers to reducing tumor growth by 75%, as demonstrated in, e.g., Example 8.
  • treating refers to reducing tumor growth by at least 75%.
  • treating refers to reducing tumor growth by at least 50%.
  • treating refers to reducing tumor growth by at least 25%.
  • treating refers to reducing tumor growth by 50- 100%.
  • treating refers to reducing tumor growth by 70-80%.
  • treating refers to reducing tumor growth by 25-125%.
  • treating refers to reducing tumor weight by 50%, as demonstrated in, e.g., Example 8.
  • treating refers to reducing tumor weight by at least 50%.
  • treating refers to reducing tumor weight by at least 40%.
  • treating refers to reducing tumor weight by at least 30%.
  • treating refers to reducing tumor weight by at least 20%.
  • treating refers to reducing tumor weight by 25-75%.
  • treating refers to reducing tumor weight by 25-100%.
  • administering refers to bringing a subject in contact with a compound of the present invention.
  • administration can be accomplished in vitro, i.e. in a test tube, or in vivo, i.e. in cells or tissues of living organisms, for example humans.
  • the present invention encompasses administering the compounds of the present invention to a subject.
  • a compound of the present invention is administered to a subject once a week. In another embodiment, a compound of the present invention is administered to a subject twice a week. In another embodiment, a compound of the present invention is administered to a subject three times a week. In another embodiment, a compound of the present invention is administered to a subject four times a week. In another embodiment, a compound of the present invention is administered to a subject five times a week. In another embodiment, a compound of the present invention is administered to a subject daily. In another embodiment, a compound of the present invention is administered to a subject weekly. In another embodiment, a compound of the present invention is administered to a subject bi-weekly. In another embodiment, a compound of the present invention is administered to a subject monthly.
  • the methods of the present invention comprise administering a selective androgen receptor modulator as the sole active ingredient.
  • methods for hormone therapy, for treating breast cancer, for delaying the progression of breast cancer, and for preventing and treating the recurrence of breast cancer and/or breast cancer metastasis which comprise administering the selective androgen receptor modulators in combination with one or more therapeutic agents.
  • SARM selective estrogen receptor modulator
  • GnRH gonadotropin-releasing hormone
  • AI aromatase inhibitor
  • PEG 4/6 cyclin-dependent kinase 4/6
  • mTOR inhibitor mTOR inhibitor
  • trastuzumab Herceptin, ado-trastuzumab emtansine
  • pertuzumab Perjeta
  • lapatinib neratinib
  • neratinib Neerlynx
  • olaparib (Lynparza) (an inhibitor of the enzyme poly ADP ribose polymerase (PARP)
  • PARP poly ADP ribose polymerase
  • Additional therapeutic agents that may be administered in combination with a selective androgen receptor modulator compound of this invention include, but are not limited to: abemaciclib, Abitrexate ® (methotrexate), Abraxane® (paclitaxel albumin- stabilized nanoparticle formulation), ado-trastuzumab emtansine, adriamycin PFS (doxombicin hydrochloride), adriamycin RDF (doxombicin hydrochloride), Admcil® (fluorouracil), Afinitor® (everolimus), alpelisib, anastrozole, Arimidex® (anastrozole), Aromasin® (exemestane), velumab, atezolizumb, bicalutamide, buparlisib, Caelyx® (pegylated liposomal doxombicin), capecitabine, carboplatin, cisplatin, Clafen® (cyclopho
  • the methods of the present invention comprise administering the selective androgen receptor modulator, in combination with a selective estrogen receptor modulator.
  • the methods of the present invention comprise administering the selective androgen receptor modulator, in combination with a selective estrogen receptor degrader (fulvestrant).
  • the methods of the present invention comprise administering the selective androgen receptor modulator, in combination with a CDK4/6 inhibitor (palbociclib, ribociclib, abemaciclib).
  • the methods of the present invention comprise administering the selective androgen receptor modulator, in combination with a HER2 inhibitor (lapatinib, trastuzumab, neratinib).
  • the methods of the present invention comprise administering the selective androgen receptor modulator, in combination with a VEGF-A inhibitor (bevacizumab).
  • the methods of the present invention comprise administering the selective androgen receptor modulator, in combination with a chemotherapeutic agent.
  • the chemotherapeutic agent is a taxane.
  • the chemotherapeutic agent is an anthracycline.
  • the chemotherapeutic agent is an epothilone (ixabepilone).
  • the methods of the present invention comprise administering the selective androgen receptor modulator, in combination with an LHRH analog.
  • the methods of the present invention comprise administering a selective androgen receptor modulator, in combination with a reversible antiandrogen. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator, in combination with an antiestrogen. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator, in combination with an anticancer dmg. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator, in combination with a 5-alpha reductase inhibitor. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with an aromatase inhibitor.
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with a progestin. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with an agent acting through other nuclear hormone receptors. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with a selective estrogen receptor modulators (SERM). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with a progestin or anti progestin. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator, in combination with an estrogen.
  • SERM selective estrogen receptor modulators
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with a PDE5 inhibitor. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with apomorphine. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with a bisphosphonate (pamidronate, zoledronic acid). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with a denosumab (Xgeva®).
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with a growth factor inhibitor. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with one or more additional selective androgen receptor modulators (SARMs).
  • SARMs selective androgen receptor modulators
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Abitrexate® (methotrexate). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Abraxane® (paclitaxel albumin-stabilized nanoparticle formulation). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with ado-trastuzumab emtansine. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Adriamycin PFS® (doxombicin hydrochloride). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with
  • Adriamycin RDF ® (doxombicin hydrochloride).
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Admcil® (fluorouracil).
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Afinitor® (everolimus).
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with anastrozole.
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Arimidex® (anastrozole).
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Aromasin® (exemestane). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with capecitabine. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Clafen® (cyclophosphamide). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with cyclophosphamide.
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Cytoxan® (cyclophosphamide). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with docetaxel. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with doxombicin hydrochloride. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Efudex® (fluorouracil).
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Ellence® (epimbicin hydrochloride). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with epirubicin hydrochloride. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with everolimus. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with exemestane. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Fareston® (toremifene).
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Evista® (raloxifene). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Faslodex® (fulvestrant). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Femara® (letrozole).
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Fluoroplex® (5-fluorouracil). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with fluorouracil. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Folex® (methotrexate). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Folex PFS® (methotrexate).
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with fulvestrant. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with gemcitabine hydrochloride. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Gemzar® (gemcitabine hydrochloride). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Herceptin® (trastuzumab). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Ibrance (palbociclib).
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with ixabepilone. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Ixempra® (ixabepilone). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with lapatinib ditosylate. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with letrozole. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with methotrexate.
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with methotrexate LPF (methotrexate). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Mexate® (methotrexate). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Mexate-AQ® (methotrexate). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Neosar® (cyclophosphamide).
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Nolvadex® (tamoxifen citrate). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with paclitaxel. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with paclitaxel albumin-stabilized nanoparticle formulation. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Perjeta® (pertuzumab).
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with pertuzumab. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with tamoxifen citrate. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Taxol® (paclitaxel). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Taxotere® (docetaxel). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with trastuzumab.
  • the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with oremifene. In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Tykerb® (lapatinib ditosylate). In another embodiment, the methods of the present invention comprise administering a selective androgen receptor modulator of this invention, in combination with Xeloda® (capecitabine).
  • the methods of the present invention comprise administering a pharmaceutical composition (or pharmaceutical preparation, used herein interchangeably) comprising the selective androgen receptor modulator of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceutical product, hydrate, /V-oxide, polymorph, crystal, prodmg or any combination thereof; and a suitable carrier or diluent.
  • a pharmaceutical composition or pharmaceutical preparation, used herein interchangeably
  • pharmaceutical compositions comprising the selective androgen receptor modulator of the present invention and/or its analog, derivative, isomer, metabolite, pharmaceutical product, hydrate, /V-oxide, polymorph, crystal, prodmg or any combination thereof.
  • pharmaceutical composition means therapeutically effective amounts of the selective androgen receptor modulator together with suitable diluents, preservatives, solubilizers, emulsifiers, adjuvant and/or carriers.
  • a “therapeutically effective amount” as used herein refers to that amount which provides a therapeutic effect for a given condition and administration regimen.
  • compositions are liquids or lyophilized or otherwise dried formulations and include diluents of various buffer content (e.g., Tris-HCl, acetate, phosphate), pH and ionic strength, additives such as albumin or gelatin to prevent absorption to surfaces, detergents (e.g., Tween 20®, Tween 80®, Pluronic F68®, bile acid salts), solubilizing agents (e.g., glycerol, polyethylene glycerol), anti-oxidants (e.g., ascorbic acid, sodium metabisulfite), preservatives (e.g., Thimerosal ®, benzyl alcohol, parabens), bulking substances or tonicity modifiers (e.g., lactose, mannitol), covalent attachment of polymers such as polyethylene glycol to the protein, complexation with metal ions, or incorporation of the material into or onto particulate preparations of polymeric compounds such as polylactic acid, pol
  • the pharmaceutical compositions comprising the compounds of this invention make use in the methods of this inventionof a dosage of between 1 and 50 mg of a compound of this invention. In another embodiment, the dosage is 1 mg, 3 mg, 9 mg, 10 mg, 18 mg or 30 mg of the compound of this invention. In another embodiment, the pharmaceutical compositions comprising the compounds of this invention make use in the methods of this invention of a dosage of 1 mg of a compound of this invention. In another embodiment, the pharmaceutical compositions comprising the compounds of this invention make use in the methods of this invention of a dosage of 3 mg of a compound of this invention. In another embodiment, the pharmaceutical compositions comprising the compounds of this invention make use in the methods of this invention of a dosage of 9 mg of a compound of this invention.
  • the pharmaceutical compositions comprising the compounds of this invention make use in the methods of this invention of a dosage of 10 mg of a compound of this invention. In another embodiment, the pharmaceutical compositions comprising the compounds of this invention make use in the methods of this invention of a dosage of 18 mg of a compound of this invention. In another embodiment, the pharmaceutical compositions comprising the compounds of this invention make use in the methods of this invention of a dosage of 30 mg of a compound of this invention.
  • compositions coated with polymers e.g., poloxamers or poloxamines.
  • Other embodiments of the compositions of the invention incorporate particulate forms protective coatings, protease inhibitors or permeation enhancers for various routes of administration, including parenteral, pulmonary, nasal and oral.
  • the pharmaceutical composition is administered parenterally, paracancerally, transmucosally, transdermally, intramuscularly, intravenously, intradermally, subcutaneously, intraperitoneally, intraventricularly, intravaginally, intracranially and intratumorally.
  • pharmaceutically acceptable carriers are well known to those skilled in the art and include, but are not limited to, 0.01-0.1 M and preferably 0.05 M phosphate buffer or about 0.8% saline. Additionally, such pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's and fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers such as those based on Ringer's dextrose, and the like. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, collating agents, inert gases and the like.
  • Controlled or sustained release compositions include formulation in lipophilic depots (e.g. fatty acids, waxes, oils). Also comprehended by the invention are particulate compositions coated with polymers (e.g. poloxamers or poloxamines) and the compound coupled to antibodies directed against tissue-specific receptors, ligands or antigens or coupled to ligands of tissue-specific receptors.
  • lipophilic depots e.g. fatty acids, waxes, oils.
  • particulate compositions coated with polymers e.g. poloxamers or poloxamines
  • compositions of the invention incorporate particulate forms, protective coatings, protease inhibitors or permeation enhancers for various routes of administration, including parenteral, pulmonary, nasal and oral.
  • the pharmaceutical composition can be delivered in a controlled release system.
  • the agent may be administered using intravenous infusion, an implantable osmotic pump, a transdermal patch, liposomes, or other modes of administration.
  • a pump may be used (see Langer, supra Sefton, CRC Crit. Ref. Biomed. Eng. 14:201 (1987); Buchwald et al, Surgery 88:507 (1980); Saudek et al, N. Engl. J. Med. 321:574 (1989).
  • polymeric materials can be used.
  • a controlled release system can be placed in proximity to the therapeutic target, i.e., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol. 2, pp. 115-138 (1984). Other controlled release systems are discussed in the review by Langer (Science 249:1527-1533 (1990).
  • the pharmaceutical preparation can comprise the selective androgen receptor modulator alone, or can further include a pharmaceutically acceptable carrier, and can be in solid or liquid form such as tablets, powders, capsules, pellets, solutions, suspensions, elixirs, emulsions, gels, creams, or suppositories, including rectal and urethral suppositories.
  • Pharmaceutically acceptable carriers include gums, starches, sugars, cellulosic materials, and mixtures thereof.
  • the pharmaceutical preparation containing the selective androgen receptor modulator can be administered to a subject by, for example, subcutaneous implantation of a pellet; in a further embodiment, the pellet provides for controlled release of selective androgen receptor modulator over a period of time.
  • the preparation can also be administered by intravenous, intraarterial, or intramuscular injection of a liquid preparation, oral administration of a liquid or solid preparation, or by topical application. Administration can also be accomplished by use of a rectal suppository or a urethral suppository.
  • the pharmaceutical preparations of the invention can be prepared by known dissolving, mixing, granulating, or tablet-forming processes.
  • the selective androgen receptor modulators or their physiologically tolerated derivatives such as salts, esters, A-oxides, and the like are mixed with additives customary for this purpose, such as vehicles, stabilizers, or inert diluents, and converted by customary methods into suitable forms for administration, such as tablets, coated tablets, hard or soft gelatin capsules, aqueous, alcoholic or oily solutions.
  • suitable inert vehicles are conventional tablet bases such as lactose, sucrose, or cornstarch in combination with binders such as acacia, cornstarch, gelatin, with disintegrating agents such as cornstarch, potato starch, alginic acid, or with a lubricant such as stearic acid or magnesium stearate.
  • binders such as acacia, cornstarch, gelatin
  • disintegrating agents such as cornstarch, potato starch, alginic acid, or with a lubricant such as stearic acid or magnesium stearate.
  • suitable oily vehicles or solvents are vegetable or animal oils such as sunflower oil or fish-liver oil. Preparations can be effected both as dry and as wet granules.
  • the selective androgen receptor modulators or their physiologically tolerated derivatives such as salts, esters, A-oxides, and the like are converted into a solution, suspension, or emulsion, if desired with the substances customary and suitable for this purpose, for example, solubilizers or other auxiliaries.
  • sterile liquids such as water and oils, with or without the addition of a surfactant and other pharmaceutically acceptable adjuvants.
  • Illustrative oils are those of petroleum, animal, vegetable, or synthetic origin, for example, peanut oil, soybean oil, or mineral oil.
  • water, saline, aqueous dextrose and related sugar solutions, and glycols such as propylene glycols or polyethylene glycol are preferred liquid carriers, particularly for injectable solutions.
  • compositions which contain an active component are well understood in the art.
  • Such compositions can be prepared as aerosols of the active component delivered to the nasopharynx or as injectables, either as liquid solutions or suspensions; however, solid forms suitable for solution in, or suspension in, liquid prior to injection can also be prepared.
  • the preparation can also be emulsified.
  • the active therapeutic ingredient is often mixed with excipients which are pharmaceutically acceptable and compatible with the active ingredient. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol, or the like or any combination thereof.
  • composition can contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents which enhance the effectiveness of the active ingredient.
  • An active component can be formulated into the composition as neutralized pharmaceutically acceptable salt forms.
  • Pharmaceutically acceptable salts include the acid addition salts (formed with the free amino groups of the polypeptide or antibody molecule), which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric, mandelic, and the like. Salts formed from the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, 2-ethylamino ethanol, histidine, procaine, and the like.
  • the selective androgen receptor modulators or their physiologically tolerated derivatives such as salts, esters, A-oxides, and the like are prepared and applied as solutions, suspensions, or emulsions in a physiologically acceptable diluent with or without a pharmaceutical carrier.
  • the active compound can be delivered in a vesicle, in particular a liposome (see Langer, Science 249:1527-1533 (1990); Treat et al, in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez- Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid).
  • a liposome see Langer, Science 249:1527-1533 (1990); Treat et al, in Liposomes in the Therapy of Infectious Disease and Cancer, Lopez- Berestein and Fidler (eds.), Liss, New York, pp. 353-365 (1989); Lopez-Berestein, ibid., pp. 317-327; see generally ibid).
  • the salts of the selective androgen receptor modulator will be pharmaceutically acceptable salts.
  • Other salts may, however, be useful in the preparation of the compounds of the invention or of their pharmaceutically acceptable salts.
  • Suitable pharmaceutically acceptable salts of the compounds of this invention include acid addition salts which may, for example, be formed by mixing a solution of the compound of the invention with a solution of a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • a pharmaceutically acceptable acid such as hydrochloric acid, sulphuric acid, methanesulphonic acid, fumaric acid, maleic acid, succinic acid, acetic acid, benzoic acid, oxalic acid, citric acid, tartaric acid, carbonic acid or phosphoric acid.
  • the term“about”, refers to a deviance of between 0.0001-5% from the indicated number or range of numbers. In one embodiment, the term“about”, refers to a deviance of between 1-10% from the indicated number or range of numbers. In one embodiment, the term“about”, refers to a deviance of up to 25% from the indicated number or range of numbers.
  • the term“comprise” or grammatical forms thereof refers to the inclusion of the indicated active agent, such as the compound of this invention, as well as inclusion of other active agents, and pharmaceutically acceptable carriers, excipients, emollients, stabilizers, etc., as are known in the pharmaceutical industry.
  • the term “consisting essentially of’ refers to a composition, whose only active ingredient is the indicated active ingredient, however, other compounds may be included which are for stabilizing, preserving, etc. the formulation, but are not involved directly in the therapeutic effect of the indicated active ingredient.
  • the term“consisting essentially of’ may refer to components, which exert a therapeutic effect via a mechanism distinct from that of the indicated active ingredient. In some embodiments, the term“consisting essentially of’ may refer to components, which exert a therapeutic effect and belong to a class of compounds distinct from that of the indicated active ingredient. In some embodiments, the term“consisting essentially of’ may refer to components, which exert a therapeutic effect and belong to a class of compounds distinct from that of the indicated active ingredient, by acting via a different mechanism of action, for example, and representing an embodiment of this invention, polypeptides comprising T cell epitopes present in a composition may be specifically combined with polypeptides comprising B cell epitopes.
  • the term“consisting essentially of’ may refer to components which facilitate the release of the active ingredient.
  • the term“consisting” refers to a composition, which contains the active ingredient and a pharmaceutically acceptable carrier or excipient.
  • the term“comprising” is intended to mean that the system includes the recited elements, but not excluding others which may be optional.
  • the phrase“consisting essentially of’ it is meant a method that includes the recited elements but exclude other elements that may have an essential significant effect on the performance of the method.“Consisting of’ shall thus mean excluding more than traces of other elements. Embodiments defined by each of these transition terms are within the scope of this invention.
  • the present invention provides combined preparations.
  • a combined preparation defines especially a "kit of parts" in the sense that the combination partners as defined above can be dosed independently or by use of different fixed combinations with distinguished amounts of the combination partners i.e., simultaneously, concurrently, separately or sequentially.
  • the parts of the kit of parts can then, e.g., be administered simultaneously or chronologically staggered, that is at different time points and with equal or different time intervals for any part of the kit of parts.
  • the ratio of the total amounts of the combination partners in some embodiments, can be administered in the combined preparation.
  • the combined preparation can be varied, e.g., in order to cope with the needs of a patient subpopulation to be treated or the needs of the single patient which different needs can be due to a particular disease, severity of a disease, age, sex, or body weight as can be readily made by a person skilled in the art.
  • the term“a” or“one” or“an” refers to at least one.
  • the phrase“two or more” may be of any denomination, which will suit a particular purpose.
  • “about” may comprise a deviance from the indicated term of + 1%, or in some embodiments, - 1%, or in some embodiments, ⁇ 2.5%, or in some embodiments, ⁇ 5%, or in some embodiments, ⁇ 7.5%, or in some embodiments, ⁇ 10%, or in some embodiments, ⁇ 15%, or in some embodiments, ⁇ 20%, or in some embodiments, ⁇ 25%.
  • MB-231 cells were grown in RPMI-1640 medium containing 2 mM L-glutamine supplemented with 10% fetal bovine serum (FBS). Cells were maintained in a 5% CO2/95 % air humidified atmosphere at 37°C. MCF-7 cells were grown in Minimum Essential Medium supplemented with 10% FBS.
  • FBS fetal bovine serum
  • MCF-7 cells were grown in Minimum Essential Medium supplemented with 10% FBS.
  • the SRB assay was used to determine cell number during cytotoxocity experiments. The following protocol was used: 1. Cells were detached with 0.25% trypsin.
  • Experimental cultures were cultured in 96-well microtiter plates (200 uL growth medium per well; 1,000-200,000 cells per well).
  • the cellular protein-bound SRB was dissolved with 200 uL unbuffered Tris base (10 mM, pH 10.5) for 30 minutes on a rocking platform shaker.
  • MDA-MB-231 and HCC-38 triple negative breast cancer cells were used to analyze growth effects of various compounds.
  • MDA-MB-231 and HCC-38 triple negative breast cancer cells were infected with 200 pL or 500 pL adenovirus containing LacZ (negative control) or AR, and were treated with various AR ligands (agonists: DHT and Formula IX, and antagonist: bicalutamide) or a non-AR binder that is structurally similar to Formula IX, R- enantiomer of Formula IX.
  • MDA-MB-231 cells were infected with adenovirus containing LacZ (negative control) or AR and were treated with AR agonists, DHT or Formula IX, in the presence or absence of the AR antagonist, bicalutamide.
  • Cells were treated in charcoal stripped FBS ( Figures 3A and 3C or full serum ( Figures 3B and 3D for 3 days, fixed and stained with sulforhodamine blue (SRB) to measure cell viability. IC 50 values were calculated. Results:
  • MDA-MB-231 cells were infected with adenovirus containing LacZ or AR and were treated with various AR ligands (agonists: DHT, Formula VIII, Formula IX, Formula X, Formula XIII, Formula XIV; antagonist: bicalutamide) and a non-AR- binder: / ⁇ -enantiomer of Formula IX.
  • MDA-MB-231 cells were transfected using lipofectamine with AR, GRE-LUC and CMV-LUC as normalization control. The cells were treated 24 h after transfection and luciferase assay performed 48 h after transfection.
  • Figure 5 shows that all AR ligands that elicited anti-proliferative activity are agonists in MDA-MB-231 cells transfected with AR and their agonist and growth inhibitory properties compare well.
  • growth inhibitory ligands are AR agonists in MDA-MB-231 cells transfected with AR.
  • MDA-MB-231 triple negative breast cancer cells were infected with ER-a or ER-b adenovirus constructs and were treated with ER agonist: 17 b-estradiol (E2) or ER antagonist: ICI 182,780 (ICI) in charcoal stripped semm (Figure 6C)
  • Figures 6A-6B show the presence or absence of ERa or ER in MDA-MB- 231 cells following transfection. These results show that the anti-proliferative effects observed with androgens is unique to ligand activated AR and not an artifact of adenovirus.
  • Figures 6C-6E show that over-expression of ER-a or ER-b in MDA-MB- 231 cells failed to promote growth inhibition either in the presence of ER agonists or antagonists. Thus, the observed growth inhibitory effects in MDA-MB-231 cells are selective to the presence of the AR and AR agonists.
  • MDA-MB-231 cells were stably transfected with AR using lentivirus. Following transfection, cells were treated for 3 days with the indicated concentrations of DHT or bicalutamide. Live cells were visualized using a light-microscope and photographed. The cells were imaged at the same magnification and under the same microscopic conditions.
  • FIG. 7 shows that DHT altered the morphology of MDA-MB-231 cells into more anchorage dependent and differentiated cells, indicating that AR agonist-bound AR expressing breast cancer cells will have less invasive and migratory properties (e.g., less likely to metastasize).
  • MDA-MB-231 cells were stably transfected with AR using lentivirus and were treated with vehicle or AR agonists at the indicated concentrations. At the end of 3 days of incubation, the cells were imaged under a microscope (40X).
  • DHT and SARMs but not the AR antagonist, bicalutamide (data not shown), or the inactive isomer of Formula IX, altered the morphology of the cells into a more anchorage-dependent phenotype ( Figure 12).
  • Rat GR, MR, PR, ER-oc and ER-b were individually cloned into a pCR3.l vector backbone. Sequencing was performed to verify the absence of any mutations.
  • HEK-293 cells were plated at 90,000 cells per well of a 24 well plate in Dulbecco’s Minimal Essential Media supplemented with 5% charcoal-stripped FBS.
  • the cells were transfected using Lipofectamine (Invitrogen, Carlsbad, CA) with 0.25 pg GRE-LUC for GR, MR and PR and ERE-LUC for ER-cc and ER-b, 0.5 ng CMV-LUC (renilla luciferase) and 12.5-25 ng of the respective expression vector for each receptor.
  • the cells were treated 24 h after transfection with Formula VIII in the absence (agonist mode) and presence (antagonist mode) of known agonists (17b-b8 ⁇ o1 for ER; dexamethasone for GR; aldosterone for MR; progesterone for PR) as controls.
  • Luciferase assays were performed 48 h after transfection. Transcriptional activation values are represented as firefly luciferase normalized to renilla luciferase.
  • a compound of Formula VIII at all the tested concentrations did not induce GR- or MR-mediated transactivation, whereas the known ligands (dexamethasone and aldosterone) induced the activities of GR or MR by 70- and 60-fold, respectively, at a concentration of 1 nM.
  • a compound of Formula VIII increased the transactivation of PR at 1 mM and 10 mM by 3 and 8 fold, respectively.
  • Progesterone activated PR by 23 fold at a 1 nM concentration, indicating that a compound of Formula VIII is greater than 10,000-fold weaker than the endogenous agonist for PR.
  • a dose response curve for a compound of Formula VIII in antagonist mode demonstrated potent partial inhibition of PR activity (Figure 9).
  • Formula VIII is was 10-times more potent, and lOO-times more potent than / ⁇ -enantiomer of Formula IX.
  • Formula VIII was about 1,000 fold weaker as a PR antagonist, than RU486.
  • Compounds of Formulae VIII and IX are specific for the AR and do not stimulate or inhibit receptor-mediated transactivation of ERa, ERb, GR, or MR. Unexpectedly, Formula VIII exhibited moderate potency partial agonist activity for PR, and potent PR partial antagonism (see Figure 9). Combined AR-agonism and PR- antagonism will be beneficial in certain breast cancers (e.g., PR-positive breast cancers).
  • Formula VIII significantly reduced the tumor growth with TGI of -75% (Figure 10B). Tumor weights were also reduced by more than 50% by Formula VIII treatment (Figure 11, right panel) as were tumor size ( Figure 11, left panel (mm 3 ) and middle panel (% change)). Formula VIII elicited these results without any associated toxicity or changes in body weight ( Figure 10A). Uterus weight also increased in response to Formula VIII treatment (not shown), indicative of in vivo androgenic response.
  • the Formula VIII SARM is extremely effective in regressing the growth of AR expressing triple negative breast cancer xenografts in mice, and is likely to be effective in a wide variety of AR-positive breast cancers in humans, as described supra and infra.
  • CBR clinical benefit response
  • Serum prostate specific antigen was evaluated as a biomarker of AR activity.
  • subjects To be eligible for participation in this study, subjects must meet all of the following criteria, including give voluntary, signed informed consent in accordance with institutional policies; be a woman that has been diagnosed with ER-positive metastatic breast cancer; and be clinically confirmed as postmenopausal. Subjects must have undergone the onset of spontaneous, medical or surgical menopause prior to the start of this study. (Spontaneous menopause is defined as the natural cessation of ovarian function as indicated by being amenorrheic for at least 12 months.
  • the subject has been amenorrheic for > 6 months but ⁇ 12 months they must have a serum FSH concentration of > 50 mlU/mL and an 17 b-estrad io I concentration of ⁇ 25 pg/mL; medical menopause is defined as treatment with a luteinizing hormone receptor hormone agonist; and surgical menopause is defined as bilateral oophorectomy).
  • Subjects with any of the following exclusion criteria will NOT be eligible for enrollment in this study: have triple negative breast cancer; have, in the judgment of the Investigator, a clinically significant concurrent illness or psychological, familial, sociological, geographical or other concomitant condition that would not permit adequate follow-up and compliance with the study protocol; have uncontrolled hypertension, congestive heart failure or angina; have Stage 4 chronic obstmctive pulmonary disease (COPD); have positive screen for hepatitis B consisting of HBsAg (Hepatitis B Surface Antigen), unless subject was diagnosed > 10 years prior to enrollment and no evidence of active liver disease; have ALT/SGOT or AST/SGPT above 1.5 times the upper limit of normal (ULN); have positive screen for hepatitis A antibody IgM or HIV; have received chemotherapy for metastatic breast cancer within the 3 months prior to enrollment in the study or be expected to receive chemotherapy for metastatic breast cancer during the study; be currently taking testosterone, methyltestosterone, oxandrolone (Oxandrin®
  • Androgen receptor (AR) status was assessed in all subjects from primary and/or metastatic lesions after enrollment. It was observed that the majority (17/19) of subjects with ER-positive breast cancer also expressed AR) in their primary tumor samples, which correlated well with previous literature which predicted 70-95% would be AR-positive (Niemeier LA, et.al. Androgen receptor in breast cancer: expression in estrogen receptor-positive tumors and in estrogen-negative tumors with apocrine differentiation. Modern Pathology 23:205-212, 2010; Narita D, el al.
  • Table 2 Table of Subjects Assessed as Having Clinical Benefit as Best Response
  • Table 3 Table of Subjects Assessed as Having Clinical Benefit at 6 Months
  • Table 4 Table of Subjects Assessed as Having Progressive Disease at 6 Months or Prior
  • PFS progression free survival
  • the primary efficacy analysis was the clinical benefit in subjects with AR- positive breast cancer at 6 months as measured by a modified Response Evaluation Criteria In Solid Tumors (RECIST 1.1) classification.
  • RECIST 1.1 modified Response Evaluation Criteria In Solid Tumors
  • Key secondary endpoints of clinical benefit in all subjects and AR-negative subjects, as well as objective response rate, progression free survival, time to progression, duration of response, incidence of SREs, and time to first SRE in subsets based on AR status i.e., all subjects, AR-positive subjects, and AR-negative subjects
  • Effects on CA 27-29, PSA, bone turnover markers, QOL, and libido were assessed as tertiary endpoints.
  • Clinical benefit in a subject is defined as a complete response [CR], a partial response [PR] or stable disease [SD] as measured by modified RECIST 1.1 , which is described in detail below.
  • modified RECIST 1.1 Clinical benefit in a subject is defined as a complete response [CR], a partial response [PR] or stable disease [SD] as measured by modified RECIST 1.1 , which is described in detail below.
  • the secondary efficacy endpoints include:
  • SD was defined as those with non-CR/non-PD combined response.
  • Objective response rate is defined as the proportion of subjects with a
  • ORR is defined as the proportion of subjects with a CR at 6 months as measured by modified RECIST 1.1.
  • PFS progression free survival
  • Time to progression is defined as the time elapsed between treatment initiation and tumor progression as measured by modified RECIST 1.1.
  • ⁇ To assess duration of response in subjects with breast cancer treated with
  • liver enzymes ALT, AST and bilirubin
  • ALT, AST and bilirubin returned to baseline with no interruption of therapy and no increase in total bilirubin.
  • a measurable lesion is defined as one lesion whose longest diameter (LD) can be accurately measured as > 10 mm CT or MRI technique by using a 5 mm contiguous reconstruction algorithm.
  • Measurable lesions must be at least 2 times the slice thickness or at least two times the size of the CT scan interval cut.
  • a lymph node To be considered pathologically enlarged and measurable, a lymph node must be > 15 mm in short axis when assessed by CT scan (CT scan slice thickness recommended to be no greater than 5 mm). At baseline and in follow-up, only the short axis will be measured and followed. [000348] Measurable disease is defined as the presence of at least one measurable lesion.
  • Non-measurable lesions are defined as any lesion(s) that are smaller than the criteria for measurable lesions stated above (non-nodal lesions with longest diameter ⁇ lOmm or pathological lymph nodes with > 10 mm to ⁇ 15 mm in short axis) or tmly non measurable lesions (or sites of disease).
  • Lesions considered to be tmly non-measurable are bone lesions (lytic lesions or mixed lytic-blastic lesions without identifiable soft tissue components, and blastic lesions), leptomeningeal disease, ascites, pleural/pericardial effusions, lymphangitis cutis/pulmonis, inflammatory breast disease, abdominal masses not confirmed by imaging techniques, and cystic lesions.
  • Target lesions must be measurable lesions.
  • Target lesions should be selected on the basis of their size (lesions with the longest diameter) and their suitability for accurate repetitive measurements by CT/MRI imaging techniques and be most representative of the subject’s tumor burden.
  • Target lesions will be measured in one dimension by the size estimation of their diameter. A sum of the diameters (longest for non-nodal lesions and shortest for nodal lesions) for all target lesions will be calculated and reported for each time point. The baseline sum of diameters will be used as reference to further characterize the objective tumor response of the measurable dimension of the disease.
  • New lesions will be called at follow-up visits regardless of whether they occur in anatomic regions that were routinely subjected to follow-up, or in regions without disease at baseline and for which a follow-up scan is performed for clinical suspicion of new disease.
  • New lymph nodes need to have a minimum size of 10 mm in their shortest axis.
  • New non-nodal lesions need not to be measurable or to have a minimum size. Measurements of new lesions may be performed.
  • CR Complete Response
  • Partial Response At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of the diameters.
  • Stable Disease SD: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD taking as reference the smallest sum of diameters (nadir).
  • Progressive Disease At least a 20% increase in the sum of the diameters of target lesions taking as reference the smallest sum of diameters (nadir) recorded since the treatment started. In addition to the relative increase of 20%, the sum of diameters must also demonstrate an absolute increase of at least 5 mm.
  • Not evaluable (NE) NE can be applied if repeated measurements cannot be assessed for reasons such as inadequate or missing imaging.
  • Non-Target Lesion Response Criteria [000364] Complete Response (CR): Disappearance of all non-target lesions. All lymph nodes must be non-pathological in size ( ⁇ 10 mm short axis). Disappearance of bone lesions identified on bone scintigraphy.
  • Non-CR/Non-PD Persistence of one or more non-target lesions. Stability, decrease, or mild increase in uptake of bone lesions on bone scintigraphy.
  • Progressive Disease Unequivocal progression of existing non-target lesions. A perceived increase in bone disease in a preexisting area will not be considered progression.
  • PD Progressive Disease
  • Not Evaluable (NE) NE can be applied if repeated evaluations cannot be assessed for reasons such as inadequate or missing imaging.
  • Table C2 Summary of Definitions of Response for Patients with Non- Measurable (Non-Target) Disease only at Baseline
  • This oil was purified by column chromatography using CH2Ck/EtOAc (80:20) to give an oil which was crystallized from CH2Cl2/hexane to give 33.2 g (59.9%) of (S)-N-( 4- cyano-3-(trifluoromethyl)phenyl)-3-(4-cyanophenoxy)-2-hydroxy-2-methylpropanamide as a colorless solid (a cotton type).
  • HEK-293 or MDA-MB-231 cells were transfected with 0.25 pg GRE-LUC, 10 ng CMV-renilla LUC, and 25 ng CMV-hAR using lipofectamine. Twenty four hours after transfection, the cells were treated with DHT, compound of Formula VIII or compound of Formula IX and luciferase assay was performed 48 hrs after transfection.
  • DHT, compound of Formula VIII and Formula IX are agonists of AR in breast cancer cells as presented in Figure 13A-13C (HEK-293 cells in Figure 13A and MDA-MB-231 cells in Figures 13B-13C).
  • the relative binding affinities (RBAs) for AR of DHT, Formula IX, Formula VIII, and bicalutamide were 1.0, 0.330, 0.314, and 0.016, respectively, demonstrating high affinity AR binding for the SARM compounds of this invention (data not shown).
  • AR agonists differentially regulate genes in ER-positive and ER-negative breast cancer cells.
  • MDA-MB-231 and MCF-7 cells infected with AR or GFP containing adenovirus were maintained in charcoal stripped serum containing medium for 3 days and were treated with DHT or Formula VIII. After overnight treatment, the cells were harvested, RNA isolated and real-time PCR for the indicated genes were performed. The expression of various genes in response to either DHT or Formula VIII were measured and normalized to GAPDH, and are presented as composite data (same effects for DHT and Formula VIII) in Table 6.
  • SPARC Secreted protein acidic and rich in cysteine (aka Osteonectin) - extracellular glycoprotein important for angiogenesis.
  • MMP2 matrix metalloproteinase-2 - gene that is activated by cell-cell clustering.
  • RNA was extracted from MDA-MB-231-AR tumors (n 5/group) treated with vehicle or compound of Formula VIII. RNA was pooled and Affymetrix microarray was performed to determine the change in expression of gene signature.
  • 231-AR xenografts suppressed the expression of more genes than it induced in these tumors. This pattern is unique in breast cancer cells and is different from gene expression results observed in prostate cancer cells, where more genes are induced than repressed (data not shown).
  • Figure 15 by analyzing selected genes using realtime PCR TaqMan primers and probe in ABI 7900.
  • the graph presented in Figure 17 demonstrates inhibition of triple-positive breast cancer (ER, PR, and HER2) using Formula VIII.
  • the results show that Formula VIII inhibited the growth of MCF-7 breast cancer cell xenografts by greater than 50%.
  • Protein from MCF-7 -AR tumors that were treated with vehicle or compound of Formula VIII were extracted and incubated with phospho MAPK array to determine the effect of compound of Formula VIII on phosphorylation of various kinases.
  • JNK phosphorylation is upregulated in MCF-7-AR tumors by treatment with compound of Formula VIII.
  • JNK plays a critical role in death receptor-mediated intrinsic and extrinsic apoptotic pathways. JNK activates apoptotic signaling by up-regulating pro-apoptotic genes.
  • the observed phosphorylation of the pro-apoptotic kinase, JNK may be suggestive of a possible mechanistic explanation of the anti-proliferation.
  • Microarray Analysis was performed on RNA from MDA-MB-231-AR and MCF-7-AR tumors in order to identify and compare changes in gene expression in ER- negative (MDA-MB-231-AR; triple negative) an ER-positive (MCF-7-AR; triple positive) breast cancer tumors treated with a compound of Formula VIII (30 mg/kg/day p.o. for 4 weeks).
  • Affymetrix analysis of the xenografts was done on pooled samples of the xenografts. The analysis included -70,000 sequences with -30,000 genes and variations thereof represented, as well as microRNA’s.
  • RNA was isolated and expression of genes was evaluated using microarray (Affymetrix Human Gene ST 2.0 array). Expression of genes in compound of Formula VUI-treated samples was compared with the expression in vehicle-treated samples. Genes that were up- or down- regulated by more than 2 fold were considered differentially regulated by compound of Formula VIII.
  • Table 7 below presents the sum totals of up-regulated and down-regulated genes in MDA-MB-231-AR and MCF-7-AR tumors.
  • Tables 8 and 9 below present genes involved in mammary tumorigenesis that were differentially regulated (by at least 2 fold) by Formula VIII in MDA-MB-231-AR tumors (Table 8) and MCF-7-AR tumors (Table 9). Indications of up-regulation or down-regulation are presented in the right-most column.
  • mice obtained from JAX labs were housed with five animals per cage and were allowed free access to tap water and commercial rat chow (Harlan Teklad 22/5 rodent diet - 8640). During the course of the study, the animals were maintained on a 12 hr light:dark cycle. Animals were anesthetized and BR-0001 TNBC fragments of 1 mm 3 (approximately) were implanted subcutaneously in NSG mice.
  • tumor size reached 100-200 mm 3
  • Tumor volume was measured thrice weekly. Tumor volume was calculated using the formula lengthxwidthxwidthxO.5236.
  • Formula IX (lower trace) produced some tumor growth inhibition of this AR-positive TNBC tumor in each experiment whereas enzalutamide was indistinguishable from vehicle treatment ( Figures 26A and 26B).
  • Formula IX reduced tumor weight in experiment 2 by -40%.
  • Figures 28A-28B demonstrated an approximately 50% reduction in Ki-67 staining in 2 weeks of treatment. Tumors from replicate experiment 2 (Figure 27B) were fixed in formalin and paraffin embedded. Slides were cut and stained with Ki-67 antibody. Ki-67 positive cells (total 200 cells were counted in each slide) in each slide were counted and represented as % stained cells, as shown in Figure 28B. Ki-67 staining was reduced in tumors of the animals treated with Formula IX.
  • Chromatin Immunoprecipitation Assay (ChIP). Proteins were cross-linked by incubation with 1% formaldehyde (final concentration) at 37°C for 10 min. Tumors were homogenized using a probe hand-held homogenizer.
  • the cells were washed with lx PBS twice, scraped in 1 mL of PBS containing protease inhibitors ([1 mg each of aprotinin, leupeptin, antipain, benzamidine HC1, and pepstatin/ml], 0.2 mM phenylmethylsulfonyl fluoride, and 1 mM sodium vanadate), pelleted, and resuspended in SDS lysis buffer (1% SDS, 10 mM EDTA, 50 mM Tris-HCl [pH 8.1]).
  • the cell extract was sonicated (Branson sonifier 250) in a cold room eight times for 10 s each at constant duty cycle, with an output of 3 and with incubation on ice after every sonication.
  • the debris was pelleted at 13,000 rpm for 10 min at 4°C, and the supernatant was diluted lO-fold with ChIP dilution buffer (0.01% SDS, 1.1% Triton X-100, 1.2 mM EDTA, 16.7 mM Tris HC1 [pH 8.1], 167 mM NaCl).
  • ChIP dilution buffer 0.01% SDS, 1.1% Triton X-100, 1.2 mM EDTA, 16.7 mM Tris HC1 [pH 8.1], 167 mM NaCl.
  • the proteins were precleared with 50 pL of 1:1 protein A-Sepharose beads in TE.
  • the protein-DNA-antibody complex was precipitated by incubating with 100 pL of 1 :1 protein A-Sepharose beads and 2 pg of salmon sperm DNA at 4°C for 2 h.
  • the beads were pelleted and washed three times with low-salt wash buffer (0.1% sodium dodecyl sulfate [SDS], 1% Triton X-100, 2 mM EDTA, 20 mM Tris HC1 [pH 8.1], 0.15 M NaCl), and twice with lx TE (10 mM Tris HC1, 1 mM EDTA; pH 8.0).
  • DNA-protein complexes were obtained by extracting the beads with 50 pL of freshly prepared extraction buffer (1% SDS, 0.1 M NaHCCh) three times. Cross-linking of the DNA protein complexes was reversed by incubating at 65 °C for 6 h. The DNA was extracted with a QIAquick PCR purification kit (QIAGEN, Valencia, Calif.) in 25 pL final volume of TE. The purified DNA was given to University of Tennessee Health Science Center Molecular Resource Center (UTHSC MRC) for next generation sequencing using ion proton sequencer.
  • extraction buffer 1% SDS, 0.1 M NaHCCh
  • RNA Analysis and microarray Tumors were homogenized, RNA isolated, purified and submitted to the UTHSC MRC core facility for microarray analysis (ST2.0 array from Affymetrix).
  • Chrin immunoprecipitation was performed in untreated BR-0001 specimen and the DNA immunoprecipitated with AR antibody was sequenced using ion torrent next-generation sequencer. It was shown that -20% of AR-occupied promoters (-5kb to +1 kb) were activated by androgen (mRNA increased by >1.5 fold) (data not shown). Androgen treatment primarily affected cell cycle and metabolic process according to gene set enrichment analysis (GSEA) ( Figure 31). Expression of TNBC subtype markers in Figures 30A and 30B show that in the SARM-treated tumors, gene markers for LAR and MSL subtypes are highly expressed.
  • GSEA gene set enrichment analysis
  • TNBC Triple-negative breast cancer
  • BL1 and BL2 2 basal-like (BL1 and BL2)
  • IM immunomodulatory
  • M mesenchymal
  • MSL mesenchymal stem-like
  • LAR luminal androgen receptor
  • Figure 31 demonstrates that in BR-0001 tumors Formula IX up-regulated gene expression. Approximately 4200 genes were up-regulated by Formula IX compared to vehicle, while approximately 1170 genes were down-regulated by Formula IX compared to vehicle. Formula IX recmited AR to 176 promoters (-5 kb to +1 kb). 20% of the promoters occupied by the AR in response to Formula IX also had the gene up-regulated by Formula IX. This showed that these genes were direct targets of the AR rather than an indirect effect.
  • the Ingenuity Pathway Analysis http://www.ingenuity.com/; QIAGEN, Redwood City, California suggests that genes involved in cell cycle were altered by Formula IX.
  • Study design This is an open label, multicenter, multinational, randomized, parallel design Phase 2 study, and is to assess the efficacy and safety of Formula IX in postmenopausal subjects with ER+/AR+ BC. Subjects will be randomized to receive either Formula IX 9 mg or 18 mg given PO daily for up to 24 months. Each dose arm will be treated independently and each assessed for efficacy using Simon’s two-stage (optimal) design (Simon R. Optimal two-stage designs for Phase 2 clinical trials. Controlled Clinical Trials 1989; 10: 1-10). Subjects will be randomized in a 1:1 fashion to one of the two dose arms.
  • Randomization will be stratified by subjects presenting with bone only metastases and all other subjects, and further by setting of immediately preceding therapy (adjuvant setting or metastatic setting) in order to balance the proportion of subjects with these presenting features in each dose arm.
  • immediately preceding therapy adjuvant setting or metastatic setting
  • CBR clinical benefit response
  • evaluable subjects i.e., subjects with centrally confirmed AR+ and who receive at least one dose of study dmg
  • CR, PR, or SD by RECIST 1.1 at week 24, consistent with 30% while maintaining an acceptable safety profile.
  • Subjects on the 18 mg treatment arm who experience an adverse event (AE) with Grade > 3 intensity may have a dose reduction from 18 mg to 9 mg per day or a dmg interruption based on the medical judgment of the Investigator and after confirmation by the study Medical Monitor.
  • the dmg interruption may last for a period of up to 5 days after which the subject must be rechallenged with study dmg (18 mg or 9 mg) or discontinued from the study.
  • a dose reduction once the AE has resolved or reduced in intensity to Grade 1, the subject may be rechallenged with 18 mg or maintained at 9 mg at the discretion of the Investigator.
  • Subjects on the 9 mg treatment arm who experience an AE with Grade > 3 intensity (NCI-CTCAE 4.0) and/or intolerance may have a dmg intermption based on the medical judgment of the Investigator and after confirmation by the study Medical Monitor.
  • the dmg intermption may last for a period of up to 5 days after which the subject must be rechallenged with study dmg (9 mg) or discontinued from the study.
  • Target Population Adult postmenopausal women with metastatic or recurrent locally advanced ER+/AR+ BC.
  • Study Duration The study duration is estimated at 3 years.
  • Preclinical data with Formula IX suggests that it is also anabolic in bone and decreases bone turn over markers.
  • Treatment with Formula IX may decrease bone turn over as compared with other hormonal therapies for the treatment of hormone receptor positive BC. Stronger bone microenvironment may decrease metastases to bone or delay time to skeletal related events.
  • the primary efficacy objective of this trial is to estimate the CBR at 24 weeks (defined as complete response [CR], partial response [PR], or SD) (by RECIST 1.1) of Formula IX 9 mg and of Formula IX 18 mg given PO daily in subjects with estrogen receptor positive and androgen receptor positive (ER+/AR+) BC who have centrally confirmed AR+ status.
  • the secondary efficacy objectives are to estimate the CBR at 24 weeks (by RECIST 1.1) of Formula IX 9 mg and 18 mg in all subjects randomized who receive at least one dose of study medication (the full analysis set [FAS]) regardless of AR status as determined by the central laboratory.
  • the additional secondary efficacy objectives apply to both centrally confirmed AR+ subjects (the evaluable subset of the FAS) as well as to all subjects in the FAS: (a) Estimate the objective response rate (ORR; defined as CR or PR) (by RECIST 1.1) of Formula IX 9 mg and 18 mg at 24 weeks; (b) Estimate the best overall response rate (BOR) of Formula IX 9 mg and 18 mg; (c) Estimate the progression free survival (PFS) of subjects receiving Formula IX 9 mg and 18 mg; (d) Estimate the TTP of subjects receiving Formula IX 9 mg and 18 mg; and (e) Estimate duration of response (time from documentation of tumor response to disease progression or death) of subjects receiving Formula IX 9 mg and 18 mg.
  • ORR objective response rate
  • BOR Best overall response rate
  • PFS progression free survival
  • TTP of subjects receiving Formula IX 9 mg and 18 mg
  • Estimate duration of response time from documentation of tumor response to disease progression or death
  • the tertiary objectives apply to both centrally confirmed AR+ subjects (the evaluable subset of the FAS) as well as to all subjects in the FAS (a) Assess the effect of Formula IX 9 mg and 18 mg on serum PSA; (b) Assess the effect of Formula IX 9 mg and 18 mg on Quality of Life (QoL) as measured by EQ-5D-5L; (c) Assess the effect of Formula IX 9 mg and 18 mg on circulating tumor cells (CTCs); (d) Assess the impact of duration of prior CB on outcome; (e) Assess the impact of time from diagnosis of metastases to randomization on outcome; (f) Describe the effect of Formula IX 9 mg and 18 mg on tumor volumetries; (g) Assess the effect of plasma concentrations of Formula IX and Formula IX glucuronide on CBR at 24 weeks.
  • the safety objective is to describe the safety profile of Formula IX 9 mg and 18 mg PO daily in subjects with ER+/AR+ BC with centrally confirmed AR+ as well as in all subjects randomized and treated.
  • Formula IX 3.0 mg Softgels will be supplied as opaque, white to off-white, size 5, oval Softgel capsules containing 3.0 mg of Formula IX.
  • the liquid Softgel fill is composed of Formula IX dissolved in polyethylene glycol 400.
  • Formula IX 3.0 mg Softgels will be packaged in blister packs. Each blister pack will contain sufficient study dmg for one (1) week of dosing. At randomization (Visit 2) and at Visits 3, 4, and 5), subjects will be provided with a carton of study drug containing 7 blister packs, equivalent to 7 weeks of dosing.
  • Each blister pack will be comprised of an appropriate number of blister strips (1 blister for the 9 mg treatment arm and 2 blisters for the 18 mg treatment arm) encased in a child-resistant heat-sealed card.
  • the blister strips are composed of a PVC/ACLAR base and an aluminum foil/PVC/PVAC copolymer and polymethacrylate (product contact) lidding. Perforations on the back of the heat-seal card overlay the foil lidding. To remove the study dmg, subjects will release the appropriate perforation by depressing a release button on the inside of the card. Once released, the perforation can be removed and the study dmg pushed through the foil.

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Abstract

La présente invention concerne le traitement du cancer du sein chez un sujet, par exemple un sujet féminin. L'invention comprend des méthodes de traitement de : cancer du sein métastatique; cancer du sein réfractaire; cancer du sein AR positif; cancer du sein réfractaire AR positif; cancer du sein métastatique AR positif; cancer du sein AR positif et ER positif; cancer du sein triple négatif; cancer du sein avancé; cancer du sein pour lequel le traitement par un modulateur sélectif du récepteur des œstrogènes (SERM) (tamoxifène, torémifène, raloxifène), un agoniste de l'hormone de libération de la gonadotropine (GnRH) (goséréline), un inhibiteur de l'aromatase (AI) (létrozole, anastrozole, exémestane), un inhibiteur de la kinase 4/6 dépendant de la cycline (CDK 4/6) (palbociclib (Ibrance), ribociclib (Kisqali), abemaciclib (Vorzenio)), un inhibiteur de mTOR (évérolimus), le trastuzumab (Herceptine, ado-trastuzumab emtansine), le pertuzumab (Perjeta), le lapatinib, le nératinib (Nerlynx), l'olaparib (Lynparza) (un inhibiteur de l'enzyme poly ADP ribose polymérase (PARP)) le bevacizumab (Avastin), et/ou le fulvestrant a échoué; la métastase chez un sujet souffrant d'un cancer du sein; HER2 positif; et/ou de traitement d'un sujet souffrant d'un cancer du sein exprimant un mutant ER, comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un composé modulateur sélectif du récepteur des androgènes (SARM).
PCT/US2019/044550 2018-07-31 2019-07-31 Méthode de traitement de cancers du sein exprimant un mutant er avec des modulateurs sélectifs du récepteur des androgènes (sarm) WO2020028593A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022020605A1 (fr) * 2020-07-23 2022-01-27 The Board Of Trustees Of The University Of Illinois Traitement du cancer du sein positif aux récepteurs des œstrogènes metastasé

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100144871A1 (en) * 2001-12-06 2010-06-10 Steiner Mitchell S Treating muscle wasting with selective androgen receptor modulators
WO2012139093A2 (fr) * 2011-04-08 2012-10-11 University Of Tennessee Research Foundation Modulateurs sélectifs des récepteurs des androgènes pour le traitement du diabète

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100144871A1 (en) * 2001-12-06 2010-06-10 Steiner Mitchell S Treating muscle wasting with selective androgen receptor modulators
WO2012139093A2 (fr) * 2011-04-08 2012-10-11 University Of Tennessee Research Foundation Modulateurs sélectifs des récepteurs des androgènes pour le traitement du diabète

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
FUQUA ET AL., BREAST CANCER RES. TREAT., vol. 144, no. 1, 2014, pages 1 - 17 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022020605A1 (fr) * 2020-07-23 2022-01-27 The Board Of Trustees Of The University Of Illinois Traitement du cancer du sein positif aux récepteurs des œstrogènes metastasé

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