Super-Penetrant Androgen Receptor: Overcoming Enzalutamide Sensitivity in Castration-Resistant Prostate Cancer
01 Jul 2016-
TL;DR: The hypothesis is that CRPCs could endow super-penetrance to AR, via camouflaging it with post-translational marks, making CRPC cells resistant to Enzalutamide treatment.
Abstract: : Prostate cancer cells rely critically on the androgen receptor (AR) for initiation, growth and progression to castration resistant prostate cancer (CRPC) -providing a compelling molecular basis for it as a therapeutic target. Enzalutamide or MDV3100, an AR antagonist, is now routinely used for the treatment of CRPC patients. Enzalutamide impedes both the nuclear translocation and chromatin recruitment of AR. However, recent studies reveal that while Enzalutamide provides palliative benefits, even the most responding patients relapsed within 2 years. AR, being a versatile transcriptional co-activator, interacts with critical proteins to adapt rapidly to androgen deprivation. In recent years, distinct AR modifications, have garnered considerable attention, primarily due to their direct correlation with pathogenic AR activation in CRPCs. Notably, some of these mechanisms confer both androgen-independence and anti-androgen resistance to PC cells -an underlying basis for their clinical association with hormone refractory and metastatic prostate cancers. The hypothesis is that CRPCs could endow super-penetrance to AR, via camouflaging it with post-translational marks. Modified AR can translocate to the nucleus in the presence of Enzalutamide due to its tight association with the modifying enzymes. Subsequently, super-penetrant phosphoAR, is recruited to the chromatin in an androgen independent manner to regulate distinct transcription program, making CRPC cells resistant to Enzalutamide treatment. Importantly, this proposal will use an innovative chemical proteomics- mass spectrometry based method to uncover novel targets and inhibitors to overcome Enzalutamide resistance of CRPCs. The objectives are; First, examine whether modifications in AR promote differential association with Enzalutamide. Second, determine whether Enzalutamide-bound phosphoAR translocates to the nucleus and is recruited to the AR- target gene promoters.
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TL;DR: The diarylthiohydantoins RD162 and MDV3100 are characterized, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression that appear to be promising candidates for treatment of advanced prostate cancer.
Abstract: Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called castration-resistant prostate cancer, driven by elevated expression of the androgen receptor. Here we characterize the diarylthiohydantoins RD162 and MDV3100, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression. Both compounds bind to the androgen receptor with greater relative affinity than the clinically used antiandrogen bicalutamide, reduce the efficiency of its nuclear translocation, and impair both DNA binding to androgen response elements and recruitment of coactivators. RD162 and MDV3100 are orally available and induce tumor regression in mouse models of castration-resistant human prostate cancer. Of the first 30 patients treated with MDV3100 in a Phase I/II clinical trial, 13 of 30 (43%) showed sustained declines (by >50%) in serum concentrations of prostate-specific antigen, a biomarker of prostate cancer. These compounds thus appear to be promising candidates for treatment of advanced prostate cancer.
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