metribolone and Prostatic-Neoplasms--Castration-Resistant

The androgen receptor (AR) plays a key role in the maintenance of muscle and bone and the support of male sexual-related functions, as well as in the progression of prostate cancer. Accordingly, AR-targeted therapies have been developed for the treatment of related human diseases and conditions. AR agonists are an important class of drugs in the treatment of bone loss and muscle atrophy. AR antagonists have also been developed for the treatment of prostate cancer, including metastatic castration-resistant prostate cancer (mCRPC). Additionally, selective AR degraders (SARDs) have been reported. More recently, heterobifunctional degrader molecules of AR have been developed, and four such compounds are now in clinical development for the treatment of human prostate cancer. This review attempts to summarize the different types of compounds designed to target AR and the current frontiers of research on this important therapeutic target.

Topics: Androgen Antagonists; Androgen Receptor Antagonists; Humans; Male; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen

Prostate cancer (PC) is the second most common malignancy in men worldwide. Among current therapies, two antiandrogens, Abiraterone Acetate and Enzalutamide (Enza) have become the standard of care for patients with metastatic castration-resistant prostate cancer (mCRPC). Here, we designed and synthesized a new series of nonsteroidal compounds deriving from the hybridization of Abiraterone (Abi) and Enzalutamide, among which compound 4a featuring the diphenylamine scaffold was identified as a potent and cell selective androgen receptor (AR) antagonist. In cell proliferation assays, compound 4a exhibited better antiproliferative activities than Enzalutamide against AR-overexpressing VCaP cells and 22Rv1 cells bearing H874Y-mutated AR. In addition, 4a suppressed the activity of AR-F876L mutant that confers resistance to Enzalutamide and efficiently blocked R1881-induced PSA and FKBP5 gene expression. In competitive binding assay, compound 4a displayed higher binding affinity to AR than Enzalutamide. These results suggest compound 4a as a potential candidate to treat Enza-resistant CRPC.

Topics: Androgen Receptor Antagonists; Antineoplastic Agents; Cell Proliferation; Dose-Response Relationship, Drug; Drug Discovery; Drug Screening Assays, Antitumor; Humans; Male; Models, Molecular; Molecular Structure; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Structure-Activity Relationship; Tumor Cells, Cultured

3βHSD1 enzymatic activity is essential for synthesis of potent androgens from adrenal precursor steroids in prostate cancer. A germline variant in HSD3B1, the gene that encodes 3βHSD1, encodes for a stable enzyme, regulates adrenal androgen dependence, and is a predictive biomarker of poor clinical outcomes after gonadal testosterone deprivation therapy. However, little is known about HSD3B1 transcriptional regulation. Generally, it is thought that intratumoral androgen synthesis is upregulated after gonadal testosterone deprivation, enabling development of castration-resistant prostate cancer. Given its critical role in extragonadal androgen synthesis, we sought to directly interrogate the transcriptional regulation of HSD3B1 in multiple metastatic prostate cancer cell models. Surprisingly, we found that VCaP, CWR22Rv1, LNCaP, and LAPC4 models demonstrate induction of HSD3B1 upon androgen stimulation for approximately 72 hours, followed by attenuation around 120 hours. 3βHSD1 protein levels mirrored transcriptional changes in models harboring variant (LNCaP) and wild-type (LAPC4) HSD3B1, and in these models androgen induction of HSD3B1 is abrogated via enzalutamide treatment. Androgen treatment increased flux from [3H]-dehydroepiandrosterone to androstenedione and other downstream metabolites. HSD3B1 expression was reduced 72 hours after castration in the VCaP xenograft mouse model, suggesting androgen receptor (AR) regulation of HSD3B1 also occurs in vivo. Overall, these data suggest that HSD3B1 is unexpectedly positively regulated by androgens and ARs. These data may have implications for the development of treatment strategies tailored to HSD3B1 genotype status.

Topics: Androgens; Androstenedione; Animals; Antineoplastic Agents, Hormonal; Benzamides; Cell Line, Tumor; Dehydroepiandrosterone; Gene Expression Regulation, Neoplastic; Humans; Male; Metribolone; Mice; Multienzyme Complexes; Neoplasm Transplantation; Nitriles; Orchiectomy; Phenylthiohydantoin; Progesterone Reductase; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Steroid Isomerases; Testosterone; Testosterone Congeners; Up-Regulation

The clinical utility of inhibiting cytochrome P450 17A1 (CYP17), a cytochrome p450 enzyme that is required for the production of androgens, has been exemplified by the approval of abiraterone for the treatment of castration-resistant prostate cancer (CRPC). Recently, however, it has been reported that CYP17 inhibitors can interact directly with the androgen receptor (AR). A phase I study recently reported that seviteronel, a CYP17 lyase-selective inhibitor, ædemonstrated a sustained reduction in prostate-specific antigen in a patient with CRPC, and another study showed seviteronel's direct effects on AR function. This suggested that seviteronel may have therapeutically relevant activities in addition to its ability to inhibit androgen production. Here, we have demonstrated that CYP17 inhibitors, with the exception of orteronel, can function as competitive AR antagonists. Conformational profiling revealed that the CYP17 inhibitor-bound AR adopted a conformation that resembled the unliganded AR (apo-AR), precluding nuclear localization and DNA binding. Further, we observed that seviteronel and abiraterone inhibited the growth of tumor xenografts expressing the clinically relevant mutation AR-F876L and that this activity could be attributed entirely to competitive AR antagonism. The results of this study suggest that the ability of CYP17 inhibitors to directly antagonize the AR may contribute to their clinical efficacy in CRPC.

Topics: Active Transport, Cell Nucleus; Androgen Receptor Antagonists; Animals; Antineoplastic Agents, Hormonal; Benzamides; Cell Line, Tumor; Cell Proliferation; Drug Resistance, Neoplasm; Drug Synergism; HEK293 Cells; Humans; Inhibitory Concentration 50; Male; Metribolone; Mice, Inbred NOD; Mice, SCID; Nitriles; Phenylthiohydantoin; Prostatic Neoplasms, Castration-Resistant; Protein Binding; Receptors, Androgen; Steroid 17-alpha-Hydroxylase; Testosterone; Transcriptional Activation; Xenograft Model Antitumor Assays

Anabolic signals such as androgens and the growth hormone/insulin-like growth factor 1 (GH/IGF-1) axis play an essential role in the normal development of the prostate but also in its malignant transformation. In this study, we investigated the role of suppressor of cytokine signaling 2 (SOCS2) as mediator of the cross talk between androgens and GH signals in the prostate and its potential role as tumor suppressor in prostate cancer (PCa). We observed that SOCS2 protein levels assayed by immunohistochemistry are elevated in hormone therapy-naive localized prostatic adenocarcinoma in comparison with benign tissue. In contrast, however, castration-resistant bone metastases exhibit reduced levels of SOCS2 in comparison with localized or hormone naive, untreated metastatic tumors. In PCa cells, SOCS2 expression is induced by androgens through a mechanism that requires signal transducer and activator of transcription 5 protein (STAT5) and androgen receptor-dependent transcription. Consequentially, SOCS2 inhibits GH activation of Janus kinase 2, Src and STAT5 as well as both cell invasion and cell proliferation in vitro. In vivo, SOCS2 limits proliferation and production of IGF-1 in the prostate in response to GH. Our results suggest that the use of GH-signaling inhibitors could be of value as a complementary treatment for castration-resistant PCa.. Androgen induced SOCS2 ubiquitin ligase expression and inhibited GH signaling as well as cell proliferation and invasion in PCa, whereas reduced SOCS2 was present in castration-resistant cases. GH-signaling inhibitors might be a complementary therapeutic option for advanced PCa.

Topics: Adenocarcinoma; Aged; Androgens; Animals; Cell Line, Tumor; Cell Proliferation; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Metribolone; Mice, Inbred C57BL; Mice, Mutant Strains; Middle Aged; Predictive Value of Tests; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Receptors, Androgen; Signal Transduction; STAT5 Transcription Factor; Suppressor of Cytokine Signaling Proteins

We show that HEXIM1 (hexamethylene bis-acetamide inducible 1) functions as an AR (androgen receptor) co-repressor as it physically interacts with the AR and is required for the ability of anti-androgens to inhibit androgen-induced target gene expression and cell proliferation. Oncomine™ database and IHC (immunohistochemistry) analyses of human prostate tissues revealed that expression of HEXIM1 mRNA and protein are down-regulated during the development and progression of prostate cancer. Enforced down-regulation of HEXIM1 in parental hormone-dependent LNCaP cells results in resistance to the inhibitory action of anti-androgens. Conversely, ectopic expression of HEXIM1 in the CRPC (castration-resistant prostate cancer) cell line, C4-2, enhances their sensitivity to the repressive effects of the anti-androgen bicalutamide. Novel insight into the mechanistic basis for HEXIM1 inhibition of AR activity is provided by the present studies showing that HEXIM1 induces expression of the histone demethylase KDM5B (lysine-specific demethylase 5B) and inhibits histone methylation, resulting in the inhibition of FOXA1 (forkhead box A1) licensing activity. This is a new mechanism of action attributed to HEXIM1, and distinct from what has been reported so far to be involved in HEXIM1 regulation of other nuclear hormone receptors, including the oestrogen receptor.

Topics: Androgen Antagonists; Anilides; Cell Line, Tumor; Enhancer Elements, Genetic; Epithelial Cells; Gene Expression; Histones; Humans; Jumonji Domain-Containing Histone Demethylases; Male; Metribolone; Nitriles; Nuclear Proteins; Prostate; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Protein Transport; Receptors, Androgen; Repressor Proteins; RNA-Binding Proteins; Tosyl Compounds; Transcription Factors; Transcriptional Elongation Factors

Prostate cancer (PCA) kills thousands of men every year, demanding additional approaches to better understand and target this malignancy. Recently, critical role of aberrant lipogenesis is highlighted in prostate carcinogenesis, offering a unique opportunity to target it to reduce PCA. Here, we evaluated efficacy and associated mechanisms of silibinin in inhibiting lipid metabolism in PCA cells. At physiologically achievable levels in human, silibinin strongly reduced lipid and cholesterol accumulation specifically in human PCA cells but not in non-neoplastic prostate epithelial PWR-1E cells. Silibinin also decreased nuclear protein levels of sterol regulatory element binding protein 1 and 2 (SREBP1/2) and their target genes only in PCA cells. Mechanistically, silibinin activated AMPK, thereby increasing SREBP1 phosphorylation and inhibiting its nuclear translocation; AMPK inhibition reversed silibinin-mediated decrease in nuclear SREBP1 and lipid accumulation. Additionally, specific SREBP inhibitor fatostatin and stable overexpression of SREBP1 further confirmed the central role of SREBP1 in silibinin-mediated inhibition of PCA cell proliferation and lipid accumulation and cell cycle arrest. Importantly, silibinin also inhibited synthetic androgen R1881-induced lipid accumulation and completely abrogated the development of androgen-independent LNCaP cell clones via targeting SREBP1/2. Together, these mechanistic studies suggest that silibinin would be effective against PCA by targeting critical aberrant lipogenesis.

Topics: Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Humans; Lipid Metabolism; Male; Metribolone; Molecular Targeted Therapy; Phosphorylation; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Pyridines; Silybin; Silymarin; Sterol Regulatory Element Binding Protein 1; Sterol Regulatory Element Binding Protein 2; Thiazoles; Transfection

We demonstrate that the androgen receptor (AR) regulates a transcriptional program of DNA repair genes that promotes prostate cancer radioresistance, providing a potential mechanism by which androgen deprivation therapy synergizes with ionizing radiation. Using a model of castration-resistant prostate cancer, we show that second-generation antiandrogen therapy results in downregulation of DNA repair genes. Next, we demonstrate that primary prostate cancers display a significant spectrum of AR transcriptional output, which correlates with expression of a set of DNA repair genes. Using RNA-seq and ChIP-seq, we define which of these DNA repair genes are both induced by androgen and represent direct AR targets. We establish that prostate cancer cells treated with ionizing radiation plus androgen demonstrate enhanced DNA repair and decreased DNA damage and furthermore that antiandrogen treatment causes increased DNA damage and decreased clonogenic survival. Finally, we demonstrate that antiandrogen treatment results in decreased classical nonhomologous end-joining.. We demonstrate that the AR regulates a network of DNA repair genes, providing a potential mechanism by which androgen deprivation synergizes with radiotherapy for prostate cancer.

Topics: Androgen Antagonists; Animals; Antineoplastic Agents, Hormonal; Cell Line, Tumor; Disease Models, Animal; DNA Damage; DNA Repair; Gene Expression Regulation, Neoplastic; Humans; Male; Metribolone; Mice; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Radiation, Ionizing; Receptors, Androgen; Signal Transduction; Xenograft Model Antitumor Assays