Selective Androgen Receptor Modulators-Transformative Drugs or Heralds of the Next Drug Epidemic?

This Viewpoint examines whether selective androgen receptor modulators have the potential to be transformative drugs or whether they herald the next drug epidemic.

Abiraterone acetate versus nonsteroidal antiandrogen with androgen deprivation therapy for high-risk metastatic hormone-sensitive prostate cancer.

BACKGROUND: Although prostate cancer is a very common form of malignancy in men, the clinical significance of androgen deprivation therapy (ADT) with abiraterone acetate versus the nonsteroidal antiandrogen bicalutamide has not yet been verified in patients with high-risk metastatic hormone-sensitive prostate cancer (mHSPC). The present study was designed to initiate this verification in real-world Japanese clinical practice. METHODS: We retrospectively analyzed the records of 312 patients with high-risk mHSPC based on LATITUDE criteria and had received ADT with bicalutamide (n = 212) or abiraterone acetate (n = 100) between September 2015 and December 2020. Bicalutamide was given at 80 mg daily and abiraterone was given at 1000 mg daily as four 250-mg tablets plus prednisolone (5-10 mg daily). Overall survival (OS), cancer-specific survival (CSS), and time to castration-resistant prostate cancer (CRPC) were compared. The prognostic factor for time to CRPC was analyzed by Cox proportional hazard model. RESULTS: Patients in the bicalutamide group were older, and more of them had poor performance status (≧2), than in the abiraterone group. Impaired liver function was noted in 2% of the bicalutamide group and 16% of the abiraterone group (p < 0.001). Median follow-up was 22.5 months for bicalutamide and 17 months for abiraterone (p < 0.001). Two-year OS and CSS for bicalutamide versus abiraterone was 77.8% versus 79.5% (p = 0.793) and 81.1% versus 82.5% (p = 0.698), respectively. Median time to CRPC was significantly longer in the abiraterone group than in the bicalutamide group (NA vs. 13 months, p < 0.001). In multivariate analysis, Gleason score ≧9, high alkaline phosphatase, high lactate dehydrogenase, liver metastasis, and bicalutamide were independent prognostic risk factors for time to CRPC. Abiraterone prolonged the time to CRPC in patients with each of these prognostic factors. CONCLUSIONS: Despite limitations regarding the time-dependent bias, ADT with abiraterone acetate significantly prolonged the time to CRPC compared to bicalutamide in patients with high-risk mHSPC. However, further study with longer follow-up is needed.

Tratamiento del cáncer de próstata resistente a la castración y riesgo de interacciones farmacológicas en pacientes polimedicados / Treatment for castration-resistant prostate cancer and drug interaction risk in polymedicated patients

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Sponging off nature for new drug leads.

Marine sponges have consistently been the richest source of new marine natural products with unprecedented chemical scaffolds and potent biological activities that have been reported in the chemical literature since the early 1970s. During the last 40years, chemists in the Andersen laboratory at UBC, in collaboration with biologists, have discovered many novel bioactive sponge natural products. Four experimental drug candidates for treatment of inflammation and cancer, that were inspired by members of this sponge natural product collection, have progressed to phase I/II/III clinical trials. This review recounts the scientific stories behind the discovery and development of these four drug candidates; IPL576,092, HTI-286 (Taltobulin), EPI-506 (Ralaniten acetate), and AQX-1125.

Spironolactone and glucose metabolism, a systematic review and meta-analysis of randomized controlled trials.

Diabetes predicts cardiovascular disease (CVD); some drugs are effective for CVD prevention but increase the risk of diabetes. In a systematic review and meta-analysis of placebo-controlled trials, we assessed if spironolactone, a mineralocorticoid receptor antagonist, affected glycemic control. We searched PubMed using ("spironolactone" or "aldactone") and trial and ("glucose" or "diabetes" or "insulin" or "insulin resistance") until January 4, 2016. In total, 18 eligible trials were identified; 10 on fasting glucose, 8 on hemoglobin A1c (HbA1c), 7 on homeostatic model assessment (HOMA)-insulin resistance (IR), and 8 on insulin. Spironolactone increased HbA1c (0.16%, 95% confidence interval 0.02 to 0.30) but had no clear effect on fasting glucose, HOMA-IR, and insulin. A mechanistic randomized controlled trial in people with and without diabetes might provide insight concerning these pleiotropic effects on diabetes and CVD relevant to prevention of both diseases.

Development and validation of a prognostic index for fracture risk in older men undergoing prostate cancer treatment.

OBJECTIVES: Men treated with androgen deprivation therapy (ADT) or radiation therapy (RT) for prostate cancer have an increased risk for fractures. Given uncertainty as to whether specific clinical factors can identify men at increased risk, we sought to develop a prognostic index for risk of fracture in this population. MATERIALS AND METHODS: We used the Surveillance, Epidemiology, and End Results-Medicare database to identify men who received ADT or RT after being diagnosed with localized prostate cancer in 2007-2009. Cox proportional hazards models tested the association of potential risk factors with fracture. In a derivation group, hazard ratios were used to assign points for factors independently related to fracture. The prognostic index was then applied to a validation group. RESULTS: The sample of 5824 men had a median age of 73.0 years; 82.9% were white and 8.6% had a fracture within 2 years of treatment for prostate cancer. The Cox model identified 8 variables (age, race, hormone treatment, Elixhauser score, anxiety, Parkinson's, fall-inducing medications and disability status) independently associated with fracture. In the derivation cohort, 4.3% of the sample experienced a fracture in the low-risk group, 8.9% in the intermediate group, and 19.2% in the high-risk group (C statistic, 0.749). The index was applied to the validation cohort (C statistic, 0.782). CONCLUSION: The prognostic index can help to identify patients at increased risk for fracture. This underscores the importance of identifying risk factors for fracture, given the substantial variation in fracture risk in men treated with ADT or RT.

Assessment of the potential of polyphenols as a CYP17 inhibitor free of adverse corticosteroid elevation.

Inhibition of 17α-hydroxylase/17,20-lyase (CYP17), which dictates the proceeding of androgen biosynthesis, is recommended as an effective treatment for androgen-dependent diseases. However, androgen depletion by selective CYP17 inhibition is accompanied with corticosteroid elevation, which increases risk of cardiovascular diseases. In this study, we evaluated the likelihood of polyphenols as a CYP17 inhibitor without cardiovascular complications. All examined polyphenols significantly inhibited CYP17 in human adrenocortical H295R cells, but their effects on androgen and cortisol biosynthesis were diverse. Resveratrol was the most potent CYP17 inhibitor with an approximate IC50 of 4 µM, and the inhibition might weigh on the 17α-hydroxylase activity more than the 17,20-lyase activity. Resveratrol also inhibited 21α-hydroxylase (CYP21) essential for corticosteroid biosynthesis but to a lesser extent, thus preventing the occurrence of cortisol elevation following CYP17 blockade. Although transcriptional down-regulation was important for α-naphthoflavone-mediated CYP17 inhibition, resveratrol inhibited CYP17 and CYP21 mainly at the level of enzyme activity rather than enzyme abundance and cytochrome P450 electron transfer. Daidzein also inhibited CYP17 and CYP21 although less potent than resveratrol. Daidzein was the only polyphenol showing inhibition of 3ß-hydroxysteroid dehydrogenase type II (3ßHSD2). The exceptional 3ßHSD2 inhibition led to dehydroepiandrosterone accumulation alongside daidzein-caused androgen biosynthetic impairment. In contrast, androgen and cortisol secretion was increased or remained normal under α-naphthoflavone and ß-naphthoflavone treatments, suggesting that CYP17 inhibition was counteracted by increased substrate generation. α-naphthoflavone and ß-naphthoflavone also enhanced the formation of cortisol from 17-hydroxyprogesterone and testosterone from androstenedione. Our findings suggest a potential application of resveratrol in androgen deprivation therapy.

FoxA1 corrupts the antiandrogenic effect of bicalutamide but only weakly attenuates the effect of MDV3100 (Enzalutamide™).

Prostate cancer growth depends on androgens. Synthetic antiandrogens are used in the cancer treatment. However, antiandrogens, such as bicalutamide (BIC), have a mixed agonist/antagonist activity. Here we compare the antiandrogenic capacity of BIC to a new antiandrogen, MDV3100 (MDV) or Enzalutamide™. By reconstitution of a hormone-regulated enhancer in Xenopus oocytes we show that both antagonists trigger the androgen receptor (AR) translocation to the nucleus, albeit with a reduced efficiency for MDV. Once in the nucleus, both AR-antagonist complexes can bind sequence specifically to DNA in vivo. The forkhead box transcription factor A (FoxA1) is a negative prognostic indicator for prostate cancer disease. FoxA1 expression presets the enhancer chromatin and makes the DNA more accessible for AR binding. In this context the BIC-AR antiandrogenic effect is seriously compromised as demonstrated by a significant chromatin remodeling and induction of a robust MMTV transcription whereas the MDV-AR complex displays a more persistent antagonistic character.