Enzyme In Androgen Biosynthesis Research Articles

AKR1C3 in carcinomas: from multifaceted roles to therapeutic strategies.

Aldo-Keto Reductase Family 1 Member C3 (AKR1C3), also known as type 5 17β-hydroxysteroid dehydrogenase (17β-HSD5) or prostaglandin F (PGF) synthase, functions as a pivotal enzyme in androgen biosynthesis. It catalyzes the conversion of weak androgens, estrone (a weak estrogen), and PGD2 into potent androgens (testosterone and 5α-dihydrotestosterone), 17β-estradiol (a potent estrogen), and 11β-PGF2α, respectively. Elevated levels of AKR1C3 activate androgen receptor (AR) signaling pathway, contributing to tumor recurrence and imparting resistance to cancer therapies. The overexpression of AKR1C3 serves as an oncogenic factor, promoting carcinoma cell proliferation, invasion, and metastasis, and is correlated with unfavorable prognosis and overall survival in carcinoma patients. Inhibiting AKR1C3 has demonstrated potent efficacy in suppressing tumor progression and overcoming treatment resistance. As a result, the development and design of AKR1C3 inhibitors have garnered increasing interest among researchers, with significant progress witnessed in recent years. Novel AKR1C3 inhibitors, including natural products and analogues of existing drugs designed based on their structures and frameworks, continue to be discovered and developed in laboratories worldwide. The AKR1C3 enzyme has emerged as a key player in carcinoma progression and therapeutic resistance, posing challenges in cancer treatment. This review aims to provide a comprehensive analysis of AKR1C3's role in carcinoma development, its implications in therapeutic resistance, and recent advancements in the development of AKR1C3 inhibitors for tumor therapies.

A Phase II Study Evaluating Orteronel, an Inhibitor of Androgen Biosynthesis, in Patients With Androgen Receptor (AR)-Expressing Metastatic Breast Cancer (MBC)

BackgroundAR is a targetable pathway with AR modulation inhibiting estrogen- and androgen-mediated cell proliferation. Orteronel is an oral, selective, nonsteroidal inhibitor of 17, 20-lyase, a key enzyme in androgen biosynthesis. This study evaluated single-agent orteronel in AR+ metastatic breast cancer (MBC). MethodsMale/female patients with AR+ MBC were grouped in Cohort 1: AR+ TNBC with l-3 prior chemotherapy regimens or Cohort 2: AR+ HR+ (estrogen [ER+]/ progesterone receptor [PR+] positive) HER2+/- with 1 to 3 prior hormonal and at least 1 prior chemotherapy regimen. Patients with HER2+ MBC must have received at least 2 lines of HER2-targeted therapy. Orteronel was administered at 300 mg BID; response rate was the primary endpoint. ResultsSeventy patients were enrolled (Cohort 1, n = 26 and Cohort 2, n = 44). Median treatment duration was 7.1 weeks. Seven patients were on treatment for ≥6 months. One of the 21 evaluated patients in Cohort 1 (4.8%) had an objective response. In Cohort 2, none of the first 23 patients to be evaluated had a response and accrual was stopped. Median progression-free and overall survival were 1.8 and 8.3 months, respectively. Toxicities were predominantly Grade 1 or 2 nausea/vomiting (36%) and fatigue (31%). Grade 3 or 4 events in ≥5% of patients included increased amylase/lipase (10%) and hypertension (6%). ConclusionsOrteronel demonstrated limited clinical activity in heavily pre-treated AR+ MBC. Further development of orteronel in MBC is not recommended. Further efforts to validate the AR as a therapeutic target should focus on identifying new markers predictive of sensitivity to AR-targeted agents.

Abstract PS11-29: A phase 2 study evaluating orteronel, an inhibitor of androgen biosynthesis, in patients with androgen receptor (AR)-expressing metastatic triple-negative breast cancer (TNBC)

Abstract Background: Treatment options for TNBC are limited by the lack of estrogen and progesterone receptors as well as the absence of HER2 overexpression. AR is present in all breast cancer subtypes and up to 40% of TNBC have AR overexpression (AR+). Thus AR positivity in TNBC represents a potential targetable signaling pathway. Preclinical studies demonstrated that AR modulation inhibits cell proliferation, and clinical activity with anti-androgen monotherapy has been reported in breast cancer. Orteronel is a novel, oral, selective, nonsteroidal inhibitor of 17, 20-lyase, a key enzyme in androgen biosynthesis under evaluation as a potential therapeutic strategy in hormone-sensitive cancers. In this phase 2 study, we evaluated androgen blockade with single agent orteronel in AR+ metastatic breast cancer (MBC). Methods: Male or female pts with AR+ MBC (≥10% staining by central immunohistochemistry) were eligible. Pts were grouped into 2 cohorts for analysis: Cohort 1-TNBC (AR+/ER-/PR-/HER2-) and Cohort 2-ER+ (AR+/ER+/HER2 +/-). Results in Cohort 2 (ER+) have been previously reported; here we report results in the AR+ TNBC cohort. TNBC pts must have been previously treated with standard therapy (1-3 chemotherapy regimens for MBC). All pts received 300 mg orteronel PO BID over a 4 week cycle and underwent response assessment every 2 cycles. Treatment continued until disease progression or unacceptable toxicity. The hypothesized response rate for pts with previously treated metastatic AR+ TNBC was 11%. Results: From 7/2014 to 2/2019 a total of 26 AR+ TNBC pts were enrolled on cohort 1. The trial closed early due to slow accrual. Median age was 57 years (range, 33-92); 96% ECOG 0-1; all pts had ≥ 1 prior chemotherapy; 42% prior targeted therapy; 8% prior immunotherapy. All tumors were ER and PR negative per institutional standards. PI3K was mutated in 16% (3/19) tumors tested and 65% (13/20) were PTEN-negative. Median duration of treatment was 8 weeks (range 0.7-35.7) with 15% of pts on treatment ≥ 6 months (mo). All pts have discontinued treatment, 85% due to disease progression, and 15% due to AEs. Nausea and fatigue [8 pts each (31%)] were the most common AEs noted. G 3/4 AEs included hypertension, increased amylase and lipase [2 pts each (8%)] with 4 patients reporting SAEs (G2 pneumonitis, G2 chest pain and G2 peripheral edema, G4 prolonged QT and G4 hypokalemia). The ORR was 4% and DCR was 15%. Median PFS was 2.0 mo and median OS was 10.2 mo. Conclusions: Orteronel monotherapy was well tolerated but demonstrated limited clinical activity in this heavily pre-treated metastatic AR+ TNBC patient population. As novel AR targeting agents are being developed, future studies are needed to identify AR+ breast cancer patients most likely to benefit from AR inhibition. Citation Format: Denise A Yardley, Robyn R Young, Kerin B Adelson, Andrea L Silber, Michael D Kommor, Jose E Najera, Davey B Daniel, Nancy W Peacock, Mythili Shastry, John D Hainsworth, Howard A Burris, III. A phase 2 study evaluating orteronel, an inhibitor of androgen biosynthesis, in patients with androgen receptor (AR)-expressing metastatic triple-negative breast cancer (TNBC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-29.

Abstract PO-129: Using the castration resistant prostate cancer patient-derived xenograft (PDX) tumor model to identify mRNA/miRNA biomarkers which distinguish abiraterone treatment responders and non-responders

Abstract Prostate cancer (PCa) is the most frequent cancer occurring in men in the United States and is the second leading cause of cancer deaths in men. Median survival for patients with metastatic hormone refractory PCa (HRPC/CRPC) is around 18 months. Abiraterone (Abi) is a next-generation androgen receptor targeting agent which has significant effects on PCa patients' survival, and has been approved for treatment of metastatic and CRPC. However, it is clear that there is development of Abi resistance (Abi-R). Abi inhibits the steroidogenic enzyme CYP17A1, a critical enzyme in androgen biosynthesis in the adrenals, testis as well as tumor tissues. To screen and identify biomarkers (genes and microRNA (miRNA)) for Abi-R in a heterogenous tumor, we used patient derived PCa xenograft animal model (PCa-PDX mice). Recent advances in the development of PDX models and their increasing sophistication have led to their escalating use for anticancer drug research and development, and as predictive clinical models. Hence, for the correct identification of Abi-R markers, we proposed using PCa-PDX animal model (PDX mice). We hypothesized that changes in miRNA expression underlie Abi resistance (Abi-R) mechanisms. Each tumor bearing mouse was castrated resulting in tumor regression followed by regrowth/relapse phase. Mice were then treated with Abi. The tumors were collected either once they regressed (called CRABS), or reinoculated into castrated host if they showed continued growth. The new host was treated with Abi once tumors reached 50-300 mm3. Tumors were harvested when they reached a volume of ~600-800 mm3 (CRABR2). The RNA was extracted from tumors using the miRvana kits, and RNA/miRNA-seq performed. We compared the Abi sensitive vs the Abi resistant (CRABR2) groups, to identify 316 genes and 55 miRNA whose expression was significantly changed between these two groups. We used Venn diagrams to overlap the validated gene targets for the miRNA (5,557 genes) with our 316 gene dataset. 85 common genes were identified, of which 63 genes were validated targets of hsa-miR-335 (1.7 fold in CRABS vs CRABR2), and 8 genes were validated targets of hsa-miR-574 (0.4 fold in CRABS vs CRABR2). Hsa-miR-335 has been previously identified to function as a candidate tumor suppressor in PCa. Reduced expression of miR-335 was found in human PCa tissues comparing with paired adjacent benign prostate tissues (P < 0.05). Moreover, the increased expression of miR-335 suppressed cell proliferation, invasion and migration of PCa cell lines in vitro. It has been found to suppress bone metastasis in PCa via targeting endothelial nitric oxide synthase. MicroRNA-574-5p promotes metastasis of non-small cell lung cancer, triple negative breast cancer and colorectal cancer to name a few. However, their function in Abi resistance has not been explored. In conclusion, we have identified two promising miRNA for distinguishing Abi sensitive from resistant tumors whose targeting should have profound effects on sensitizing castration resistant tumors to Abi. Citation Format: Bin Ouyang, Dan Song, Jacek Biesiada, Yan Ren, Mario Medvedovic, Pheruza Tarapore. Using the castration resistant prostate cancer patient-derived xenograft (PDX) tumor model to identify mRNA/miRNA biomarkers which distinguish abiraterone treatment responders and non-responders [abstract]. In: Proceedings of the AACR Virtual Special Conference on Tumor Heterogeneity: From Single Cells to Clinical Impact; 2020 Sep 17-18. Philadelphia (PA): AACR; Cancer Res 2020;80(21 Suppl):Abstract nr PO-129.

Targeting Metastatic Hormone Sensitive Prostate Cancer: Chemohormonal Therapy and New Combinatorial Approaches.

Androgen deprivation therapy alone has been the standard of care for metastatic hormone sensitive prostate cancer for the last 75 years. This review focuses on recent trials and mechanisms which highlight the new paradigm of combining androgen deprivation therapy with other agents, changing the treatment of patients with prostate cancer who have advanced disease. We searched the peer reviewed literature on the PubMed® and Web of Science® databases through January 2018 using the key words, "metastatic hormone sensitive prostate cancer," "metastatic castration sensitive prostate cancer," "docetaxel," "abiraterone" and "senescence in cancer." ClinicalTrials.gov was queried for ongoing studies. Relevant data recently presented at major urology and medical oncology meetings were also evaluated. Recently published, phase III trials using androgen deprivation therapy combinations for metastatic hormone sensitive prostate cancer can be broadly grouped into chemohormonal studies (docetaxel) or trials of androgen signaling inhibitors. The CHAARTED (Chemohormonal Therapy versus Androgen Ablation Randomized Trial for Extensive Disease in Prostate Cancer) and STAMPEDE (Systemic Therapy in Advancing or Metastatic Prostate Cancer: Evaluation of Drug Efficacy) studies showed a survival advantage when combining androgen deprivation therapy with chemotherapy, as well as increased time to progression to castration resistant status. The abiraterone arm of the STAMPEDE and LATITUDE trials, which analyzed combining androgen deprivation therapy with abiraterone, revealed improved overall and progression-free survival. Androgen deprivation therapy generates a number of phenotypes in resistant cancer cells, including quiescence, autophagy and cellular senescence. Senescent cells represent a metabolic target for synergistic lethality with drugs such as metformin. Ongoing trials are under way to examine the effect of combining newer antiandrogens and novel drugs with androgen deprivation therapy in patients with metastatic hormone sensitive prostate cancer. Combination therapy has evolved as the standard of care for metastatic hormone sensitive prostate cancer. The ideal combination is tailored to patients after individualized counseling taking into account general health and comorbid illness status.

TSPYL Family Regulates CYP17A1 and CYP3A4 Expression: Potential Mechanism Contributing to Abiraterone Response in Metastatic Castration-Resistant Prostate Cancer.

The testis‐specific Y‐encoded‐like protein (TSPYL) gene family includes TSPYL1 to TSPYL6. We previously reported that TSPYL5 regulates cytochrome P450 (CYP) 19A1 expression. Here we show that TSPYLs, especially TSPYL 1, 2, and 4, can regulate the expression of many CYP genes, including CYP17A1, a key enzyme in androgen biosynthesis, and CYP3A4, an enzyme that catalyzes the metabolism of abiraterone, a CYP17 inhibitor. Furthermore, a common TSPYL1 single nucleotide polymorphism (SNP), rs3828743 (G/A) (Pro62Ser), abolishes TSPYL1's ability to suppress CYP3A4 expression, resulting in reduced abiraterone concentrations and increased cell proliferation. Data from a prospective clinical trial of 87 metastatic castration‐resistant prostate cancer patients treated with abiraterone acetate/prednisone showed that the variant SNP genotype (A) was significantly associated with worse response and progression‐free survival. In summary, TSPYL genes are novel CYP gene transcription regulators, and genetic alteration within these genes significantly influences response to drug therapy through transcriptional regulation of CYP450 genes.

PLAG1 deficiency impairs spermatogenesis and sperm motility in mice

Deficiency in pleomorphic adenoma gene 1 (PLAG1) leads to reduced fertility in male mice, but the mechanism by which PLAG1 contributes to reproduction is unknown. To investigate the involvement of PLAG1 in testicular function, we determined (i) the spatial distribution of PLAG1 in the testis using X-gal staining; (ii) transcriptomic consequences of PLAG1 deficiency in knock-out and heterozygous mice compared to wild-type mice using RNA-seq; and (iii) morphological and functional consequences of PLAG1 deficiency by determining testicular histology, daily sperm production and sperm motility in knock-out and wild-type mice. PLAG1 was sparsely expressed in germ cells and in Sertoli cells. Genes known to be involved in spermatogenesis were downregulated in the testes of knock-out mice, as well as Hsd17b3, which encodes a key enzyme in androgen biosynthesis. In the absence of Plag1, a number of genes involved in immune processes and epididymis-specific genes were upregulated in the testes. Finally, loss of PLAG1 resulted in significantly lowered daily sperm production, in reduced sperm motility, and in several animals, in sloughing of the germinal epithelium. Our results demonstrate that the subfertility seen in male PLAG1-deficient mice is, at least in part, the result of significantly reduced sperm output and sperm motility.

Abstract P5-14-04: A phase 2 study evaluating orteronel, an inhibitor of androgen biosynthesis, in patients with androgen receptor (AR)-expressing metastatic breast cancer: Interim analysis

Abstract Background: The frequency of AR expression varies in the different breast cancer subtypes with 88%, 59%, and 32% expression reported in ER+, HER2+, and triple negative tumors, respectively. AR expression is associated with resistance to endocrine therapy in ER+ breast cancer. Androgen levels frequently increase following treatment with aromatase inhibitors suggesting a role for androgen synthesis inhibitors in ER+ breast cancer. AR signaling and expression are seen in triple negative breast cancer (TNBC), and a distinct AR TNBC subtype can be identified by gene expression profiling. AR expression in TNBC offers a potential therapeutic target. Preclinical and clinical studies demonstrated anti-androgen agent activity in breast cancer cell lines; preliminary clinical data suggests activity in TNBC. Orteronel is a novel, oral, selective, nonsteroidal inhibitor of 17, 20-lyase, a key enzyme in androgen biosynthesis that is being evaluated as endocrine therapy in various hormone-sensitive cancers. In this phase 2 study we are evaluating single agent orteronel in AR+ MBC. Methods: Pts with AR expressing MBC (≥10% staining by central immunohistochemistry) were eligible. Pts were grouped into 2 cohorts for analysis: Cohort 1-TNBC and Cohort 2-ER+ (HER2 could be +/- in this cohort). Pts must have been previously treated with standard therapy for MBC (1-3 chemotherapy regimens for TNBC, 1-3 hormonal therapies + 1 chemotherapy for ER+ patients, ≥2 HER2-targeted regimens for HER2+ patients). A 6 pt lead-in for safety and tolerability of orteronel in AR+ female MBC pts was followed by open enrollment to either cohort. All pts received 300 mg orteronel PO BID over a 4 week cycle and underwent response assessment every 2 cycles. Treatment was continued until disease progression or unacceptable toxicity. The hypothesized response rate for Cohort 1 was 10% and 13% for Cohort 2. We present the results of a protocol-specified interim analysis of the ER+ MBC pts (Cohort 2). Results: From 3/2014 to 4/2015, a total of 29 pts were enrolled on cohort 2. Median age was 65 years (range, 39-79); 90% ECOG ≤1; 90% HER2-/10% HER2+; median of 7 prior therapies (range 3-11). 93% had prior chemotherapy. Pts received a median of 2 cycles of orteronel treatment (range 1-4) and 3 pts (10%) are still on treatment. Of the 26 pts (90%) pts that have discontinued, 19 (66%) discontinued due to disease progression, 4 (14%) due to pt decision, 2 (7%) due to adverse event (AE), and 1 (3%) due to non-compliance. The most common treatment-related G 3/4 AEs were increased lipase [3 pts (10%)] and hypertension [2 pts (7%)]. There were no treatment-related SAEs or deaths on study. Three pts (10%) had stable disease as their best response. Further response evaluation is underway. Conclusions: Orteronel monotherapy was well tolerated but appears to have limited single-agent activity in this heavily pre-treated ER+ MBC pt population. The full results from this interim analysis will be presented. Citation Format: Yardley DA, Peacock N, Young RR, Silber A, Chung G, Webb CD, Jones SF, Shastry M, Midha R, DeBusk LM, Hainsworth JD, Burris HA. A phase 2 study evaluating orteronel, an inhibitor of androgen biosynthesis, in patients with androgen receptor (AR)-expressing metastatic breast cancer: Interim analysis. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-14-04.

Abiraterone in the management of castration-resistant prostate cancer prior to chemotherapy.

The treatment armamentarium for metastatic castration-resistant prostate cancer (mCRPC) has increased significantly over the past several years. Approved drugs associated with improved survival include androgen pathway-targeted agents (abiraterone acetate and enzalutamide), chemotherapeutics (docetaxel and cabazitaxel), an autologous vaccine (sipuleucel-T) and a radiopharmaceutical (radium-223). Abiraterone acetate, a prodrug of abiraterone, inhibits the CYP17A enzyme, a critical enzyme in androgen biosynthesis. Abiraterone has regulatory approval in mCRPC in both chemotherapy-naïve patients and in the post-docetaxel setting based on results from two randomized phase III studies. In the COU-AA-302 trial, abiraterone demonstrated significant improvement in the coprimary endpoints of radiographic progression-free survival and overall survival, as well as in a number of secondary endpoints including time until initiation of chemotherapy, time until opiate use for cancer-related pain, prostate-specific antigen progression-free survival and decline in performance status. Abiraterone is well-tolerated, although adverse events associated with this agent include abnormalities in liver function testing and mineralocorticoid-associated adverse events. This review evaluates the use of abiraterone in mCRPC prior to the use of chemotherapy.

Activity of abiraterone acetate in metastatic patients with castration-resistant prostate cancer (mCRPC) previously treated with ketoconazole: A prospective phase II study from the prostate cancer clinical trials consortium.

53 Background: Abiraterone acetate (AA), like ketoconazole (keto), inhibits CYP17, the rate-limiting enzyme in androgen biosynthesis. Since patients (pts) with prior keto treatment were excluded from the pivotal phase III AA trials, the utility of AA after keto is not well understood. This prospective study evaluated the efficacy of AA in pts who had received prior keto. Methods: Pts with progressive castration-resistant prostate cancer (mCRPC), prior keto therapy 28 days or more, and normal baseline organ function (including ACTH stimulation) tests were treated with AA 1,000 mg PO daily and prednisone 5 mg PO BID. Pts with prior chemotherapy were excluded. Serum androgen levels, including dehydroepiandrosterone (DHEA), were measured by liquid chromatography/mass spectroscopy (LC/MS) at baseline and during treatment for exploratory analyses. Radiographic progression-free survival (rPFS) was defined as freedom from: death, radiographic progression, or unequivocal clinical progression. Results: Forty two pts were enrolled. Median age was 71. Median prostate-specific antigen (PSA) was 47.5ng/dL. Median duration of prior keto was 38 weeks (range 5 to 207). Treatment with AA resulted in 30% or greater decline in PSA at 12 weeks in 20 pts (48%, 95% CI, 32-63%), and 50% or greater decline in PSA at 12 weeks in 16 pts (38%, 95% CI 24-54%). Median time to PSA progression (TTPP) was 16 weeks (range 4 to 64). Median rPFS was 24 weeks (range 1 to 88). Baseline serum DHEA levels were measured in 40 pts. Nine pts had DHEA less than the limit of quantitation (LOQ, 0.250ng/mL), and 31 pts had DHEA greater than or equal to LOQ. One pt with DHEA less than LOQ (1 out of 9, 11%, 95% CI 0.6-49%) had PSA decline 30% or more at 12 weeks, compared to 17 pts (17 out of 31, 55%, 95% CI 36-72%) with DHEA greater than or equal to LOQ (p=0.028). Median time to pain progression (TTPP) was 8 weeks (range 4 to 32) for pts with DHEA less than LOQ, compared to 18 weeks (range 4 to 64) for pts with DHEA greater than or equal to LOQ (p=0.012). Median rPFS was 12 weeks (range 4 to 24) for pts with DHEA less than LOQ, compared to 36 weeks (range 1 to 88) for pts with DHEA greater tha or equal to LOQ (p = 0.0006). Six pts remain on AA. Conclusions: A significant proportion of pts with prior keto exposure demonstrate clinical response to AA. DHEA levels via LC/MS merits further study as a predictive biomarker in pts treated with androgen synthesis inhibitors. Clinical trial information: NCT01199146.

Abstract 2049: A novel, potent, Cyp17 inhibitor with favorable pharmacokinetics and oral bioavailability for potential treatment of human castration resistant prostate cancer (CRPC).

Abstract Cytochrome P450 17α-hydroxylase/C17,20-lyase (CYP17) is a key enzyme in androgen bio-synthesis in adrenals and testes. It has been validated clinically as an effective target for CRPC through successful clinical trials with abiraterone acetate. Abiraterone acetate is a selective, potent inhibitor of Cyp17, and was recently approved as a treatment for CRPC. We have designed a novel Cyp17 inhibitor, BMN680, with improved pharmacokinetic (PK) profile and oral bioavailability while maintaining potent Cyp17 inhibition. BMN680 inhibits Cyp17 lyase activity with IC50 of 0.8 nM and reduces testosterone production in human adrenal cancer cell line H295R cells with IC50 of 3.87 nM. in vitro metabolic stability studies indicate that BMN680 has a half-life of 5-hr in human liver microsome and 8-hr half-life in human hepatocytes. Animal PK profiling in rats and monkeys demonstrated BMN680 has in vivo half-life of >4 hr and oral bioavailability of >30%. Single oral dosing of BMN680 at 10 mg/kg in normal, intact, Cynomolgus monkeys resulted in suppression of plasma testosterone level for up to 24 hour. Pharmacodynamic (PD) effect of single and multi-day oral dosing of BMN680 in monkey will be presented. In human liver microsome Cyp panel screen, BMN680 exhibited IC50 greater than 1.5 uM for all Cyp enzymes tested including 1A2, 2C9, 2C19, 2D6, 3A4, indicating low potential of drug-drug interaction. In conclusion, BMN680 is a potent Cyp17 inhibitor with low interaction with Cyp450 isoforms, and desirable PK and oral bioavailability. BMN680 can effectively suppress testosterone production in vivo, and will be further evaluated in preclinical development. Citation Format: Ying Feng, Bing Wang, Daniel Chu, Leonard Post, Yuqiao Shen. A novel, potent, Cyp17 inhibitor with favorable pharmacokinetics and oral bioavailability for potential treatment of human castration resistant prostate cancer (CRPC). [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2049. doi:10.1158/1538-7445.AM2013-2049

Clinical Trial Update and Novel Therapeutic Approaches for Metastatic Prostate Cancer

Recurrent prostate cancer (PCa) remains a major clinical challenge. Invasive and metastatic PCa lesions often exhibit a partial and time-limited response to therapy before the cancer progresses and the patient succumbs to the disease. Despite recent advances in early diagnosis and treatment, approximately one-third of treated patients will relapse and become resistant to currently available treatments. In this review we evaluate current treatment practices and recent advances in therapy for localized prostate malignancy and advanced, metastatic prostate cancer. Some of the promising new drugs for PCa treatment include MDV3100, an androgen receptor (AR) antagonist that prevents androgens from binding to the AR and nuclear translocation and co-activator recruitment of the ligand-receptor complex; abiraterone, an orally administered drug that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis, CYP17; and several newer cytotoxic drugs (epothilones, satraplatin). Key new insights are that cancer stem cells play a role in PCa and that PCa cells are dependent on the AR for proliferation, even in the hormone refractory state of the disease. We also discuss potential molecular targets for new drug candidates for the treatment of metastatic PCa.

Abiraterone Acetate, A Novel Adrenal Inhibitor in Metastatic Castration-Resistant Prostate Cancer

The androgen receptor remains the key player in patients with castration-resistant prostate cancer (CRPC). Available agents capable of blocking early adrenal androgen production have limited activity and can lead to significant toxicities. Abiraterone acetate, a pregnenolone analog, is a small molecule that irreversibly inhibits CYP17, a rate-limiting enzyme in androgen biosynthesis. Several clinical trials have demonstrated the safety and efficacy of this compound in men with metastatic CRPC. Recently, a randomized phase 3 trial evaluating abiraterone acetate in docetaxel-refractory CRPC patients demonstrated a survival improvement over placebo-treated patients (14.8 vs 10.9months; HR 0.646; P < 0.0001). A similar trial in the pre-chemotherapy setting has completed accrual and is undergoing analysis. Here we review the rationale and clinical development of abiraterone acetate in men with CRPC.

Berberine reduces insulin resistance induced by dexamethasone in theca cells in vitro

Theca cells with dexamethasone-induced insulin resistance showed defective glucose uptake and excessive testosterone production, both of which were effectively antagonized by berberine. Therefore, insulin-resistant theca cells may contribute to the pathogenesis of hyperandrogenism in polycystic ovary syndrome.

Abiraterone Acetate: A Promising Drug for the Treatment of Castration-Resistant Prostate Cancer

Abiraterone acetate (CB7630), a pregnenolone analog, is an orally administered small molecule that irreversibly inhibits a rate-limiting enzyme in androgen biosynthesis, CYP17, and blocks the synthesis of androgens in the testes, adrenal glands and prostate without causing adrenal insufficiency. In clinical studies, abiraterone acetate is well tolerated and shows promising clinical activity in castration-resistant prostate cancer. The recommended Phase II dose of abiraterone acetate is 1000 mg orally daily in combination with prednisone 5 mg twice daily. Side effects are minimal and mostly associated with secondary mineralocorticoid excess, owing to a compensatory increase in upstream steroids, such as deoxycorticosterone and corticosterone. These include hypertension, hypokalemia and edema and are easily manageable with a selective mineralocorticoid antagonist, such as eplerenone, or low-dose corticosteroids. Currently, abiraterone acetate is being tested in a Phase III trial for men with progressive castration-resistant prostate cancer who are chemotherapy naive. A Phase III trial for patients following prior chemotherapy has been completed and is awaiting analysis.

Abiraterone acetate for castration resistant prostate cancer

Importance of the field: Androgen deprivation therapy has been the standard of care in advanced prostate cancer for > 50 years. Although castration is initially effective, most patients eventually develop progressive disease despite low levels of testosterone (termed castration resistant prostate cancer, CRPC). Intratumor and extra-gonadal androgens (specifically adrenal androgens) represent a means for continued androgen receptor-mediated growth in CRPC and have thus become therapeutic targets. One novel therapeutic is abiraterone acetate (AA): an inhibitor of CYP17, an enzyme that catalyzes two key serial reactions in androgen and estrogen biosynthesis. Data from Phase I and II trials suggest that clinically important antitumor activity is seen in up to 70% of castrate patients with advanced prostate cancer resistant to currently available endocrine therapies. The toxicity profile has also been found to be acceptable. Two large Phase III clinical trials are currently open to accrual and will hopefully validate the impressive Phase II data.Areas covered in the review: The chemistry, pharmacodynamics, pharmacokinetics, clinical efficacy and safety/tolerability of AA.What the reader will gain: Readers will understand the function of non-gonadal androgens, the importance of continued androgen deprivation in advanced prostate cancer and the role/clinical efficacy of AA.Take home message: The recent realization that non-gonadal sources of androgens (adrenal and intracrine de novo synthesis) may be a major mediator of disease progression forms the biological rationale behind the development of abiraterone acetate and related drugs. Abiraterone acetate is an orally administered, specific inhibitor of CYP17A1, a rate-limiting enzyme in androgen biosynthesis. Preliminary data from Phase I and II trials suggest that prostate specific antigen declines occur in a large proportion of patients and that the toxicity profile is acceptable. Two large Phase III clinical trials are currently open to accrual and, if proven to be efficacious, will result in widespread use of a drug specifically developed to suppress adrenal androgens.

A multicenter phase II study of abiraterone acetate (AA) in docetaxel pretreated castration-resistant prostate cancer (CRPC) patients (pts)

5047 Background: Despite castration, androgens remain critical to prostate cancer. Abiraterone acetate (AA) specifically and irreversibly inhibits CYP17, a key enzyme in androgen biosynthesis. Methods: 47 CRPC pts who had failed androgen deprivation therapy and had prior docetaxel chemotherapy received AA orally (1000mg QD) in 28 day cycles. Low dose glucocorticoids were allowed. Results: Patient demographics in table . Total maximal PSA declines with AA at any point on study of ≥30%, ≥50%, and ≥ 90% were observed in 32 (69%), 24 (51%) and 7 (15%) pts respectively. A similar trend in PSA response was seen at wk 12. 35 pts were evaluable by RECIST; 6 (17%) pts had a partial response and 23 (66%) pts had stable disease. 23% of pts showed ECOG improvement (PS 1 to 0 in 10 pts, PS 2 to 1 in 1 pt); 53% of pts maintained PS. Median duration on treatment was 167 days (95% CI 130–201). 17 pts received &gt;6 cycles of AA; 8 pts received ≥ 12 cycles. Toxicities related to mineralocorticoid excess were mainly grade 1–2 (hypokalemia 51%; HTN 17%; edema 13%) and were treated with eplerenone or corticosteroids. Conclusions: AA has anti-tumor activity in these heavily pretreated pts, as evidenced by sustained PSA declines, improvement in PS and RECIST responses. A phase III trial assessing the efficacy and safety of AA and prednisone in CRPC pts who have failed docetaxel chemotherapy is underway. [Table: see text] [Table: see text]

Preliminary study of RNA interference inhibiting androgen biosynthesis by depressing 17α-hydroxylase/17,20-lyase activity

OBJECTIVE: Polycystic Ovarian Syndrome (PCOS) is the most common disease presenting hyperandrogenism, and accounts for 70∼80%. Study showed PCOS hyperandrogenism is often caused by 17α-hydroxylase/17,20-lyase hyperfunction. Therefore the key enzyme in androgen biosynthesis became potential therapeutic target for anti-hyperandrogenism therapy. The objective of this study is to verify the knockdown effect of constructed CYP17 lentivirus shRNA on cultured rat ovarian theca interstitial cells, and establish a method for in vivo study of inhibiting androgen biosynthesis by RNA interference in the future.

C16‐ and C17‐Substituted Derivatives of Pregnenolone and Progesterone as Inhibitors of 17α‐Hydroxylase‐C17,20‐lyase: Synthesis and Biological Evaluation.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Effects of novel 17α-hydroxylase/C17, 20-lyase (P450 17, CYP 17) inhibitors on androgen biosynthesis in vitro and in vivo

Aiming at the development of new drugs for the treatment of prostate cancer, the effects of steroidal compounds and one non-steroidal substance on androgen biosynthesis were evaluated in vitro and in vivo. Sa 40 [17-(5-pyrimidyl)androsta-5,16-diene-3β-ol], its 3-acetyl derivate Sa 41 and BW 19 [3,4-dihydro-2-(4-imidazolylmethyl)-6-methoxy-1-methyl-naphthalene] are compounds from our group, which have been developed as inhibitors of CYP 17 (17α-hydroxylase-C17, 20-lyase, the key enzyme in androgen biosynthesis). They have been compared with CB 7598 [abiraterone: 17-(3-pyridyl)androsta-5,16-diene-3β-ol], its 3-acetyl compound CB 7630 and ketoconazole, compounds which already have been used clinically. The most potent compound toward human CYP 17 (testicular microsomes) was Sa 40 (IC 50 value of 24 nM), followed by Sa 41, CB 7598, BW 19, CB 7630 and ketoconazole. Sa 40 shows a type II difference spectrum and a non-competitive type of inhibition ( K i value of 16 nM). No recovery of enzyme activity was observed after preincubation of CYP 17 with Sa 40 and subsequent charcoal treatment. In Escherichia coli cells coexpressing human CYP 17 and NADPH-P450 reductase, Sa 40 was more active than CB 7598 and BW 19, whereas the acetyl compounds were not active. The latter three compounds were equally active towards rat CYP 17. Male Sprague–Dawley (SD) rats were administered daily for 14 days BW 19 and the acetyl derivatives Sa 41 and CB 7630 as prodrugs (0.1 mmol/kg intraperitoneally). The test compounds strongly reduced plasma testosterone concentration, as well as prostate and seminal vesicles weights. They showed moderate inhibitory effects on the weights of levator ani, bulbocavernosus and testes, whereas they led to an increase in adrenal and pituitary weights. The only exception was BW 19 which did not change pituitary weights. Based on its superiority on the human enzyme, it was concluded that Sa 40 in its 3β-acetate form ( Sa 41) could be a promising candidate for clinical evaluation.