Development of a Second-Generation Antiandrogen for Treatment of Advanced Prostate Cancer

By C. Tran, Samedy Ouk, N. J. Clegg, Yu Chen, Philip A Watson, V. Arora, John Wongvipat, P. Smith-Jones, Dongwon Yoo, Andrew Kwon and 9 more. Science, 2009

2,232 citations recorded by the source corpus.

A Second Act for Antiandrogens Men with advanced prostate cancer are often treated with antiandrogens; drugs that inhibit the activity of male hormones, such as testosterone, that help drive tumor growth. Many of these drugs act by functionally disrupting the androgen receptor (AR), a transcriptional regulator of cell proliferation, but tumors eventually become resistant to the drugs by expressing higher levels of the AR. Tran et al. (p. 787, published online 9 April) have developed a “second-generation” antiandrogen, a thiohydantoin called MDV3100, which binds the AR with high affinity. MDV3100 retains its anticancer activity in cell culture and in mouse models even when AR levels are elevated. The drug appears to act both by inhibiting translocation of the AR into the nucleus and by reducing its transcriptional activity. MDV3100 is being tested in patients with advanced prostate cancer, the first group of which have shown a decline in blood levels of a marker of cancer growth, prostate-specific antigen. A drug that binds to the androgen receptor acts by disrupting its activity in the cell nucleus. 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.

Subfields: Endocrinology, Diabetes and Metabolism, Genetics, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/39b55262ee4123c67fc3a11553293a184d2fc96e

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Citations in the corpus

ARN-509: a novel anti-androgen for prostate cancer treatment (2012, positive): “To determine whether ARN-509 impairs AR nuclear localization and thus reduces the concentration of AR available to bind androgen response elements (ARE), LNCaP cells expressing AR-EYFP were treated with dimethyl sulfoxide (DMSO), R1881, bicalutamide, or ARN-509.”
The androgen receptor fuels prostate cancer by regulating central metabolism and biosynthesis (2011, methodology): “These findings are supported by clinical studies reporting the sensitivity of castrate-resistant prostate cancer to second-generation AR antagonists and hormone synthesis blockade (Attar et al, 2009; Attard et al, 2009; Tran et al, 2009).”
The genomic complexity of primary human prostate cancer (2011, neutral): “Non-silent coding mutations (high confidence) 16 (5) 20 (3) 24 (9) 32 (20) 13 (7) 43 (16) 14 (10)”
Glucocorticoid Receptor Confers Resistance to Anti-Androgens by Bypassing Androgen Receptor Blockade (2013, positive): “LNCaP/AR and VCaP cells were maintained as previously described (Tran et al., 2009).”
Constitutively active androgen receptor splice variants expressed in castration-resistant prostate cancer require full-length androgen receptor (2010, positive): “Because MDV3100 impairs the nuclear translocation efficiency of AR-FL (18), we considered the possibility of a similar effect on ARVs but saw no evidence that MDV3100 relocalized AR-V7 to the cytoplasm (Fig.”
Molecular genetics of prostate cancer: new prospects for old challenges. (2010, background): “In this regard, a second-generation AR antagonist, MDV3100, which completely lacks agonist activity and binds AR with greater affinity than bicalutamide, has provided new insights into castration resistance, and has given promising results in mouse models and in a human phase 1–2 trial (Tran et al. ”
EAU guidelines on prostate cancer. Part II: Treatment of advanced, relapsing, and castration-resistant prostate cancer. (2011, background): “Enzalutamide (formerly MDV3100) Enzalutamide (ENZ) is an orally administered drug that acts as an AR-signalling inhibitor and is a pure antagonist of the AR with 10 times greater affinity to the AR relative to bicalutamide [78].”
Enzalutamide in Men with Nonmetastatic, Castration‐Resistant Prostate Cancer (2018, neutral): “Hypertension 111 (12) 43 (5) 24 (5) 10 (2)”
Reciprocal feedback regulation of PI3K and androgen receptor signaling in PTEN-deficient prostate cancer. (2011, methodology): “In vitro experiments were conducted using the LNCaP and PC3 cell lines obtained from American Type Culture Collection and cell lines generated in our lab LAPC4 and LNCaP AR-ARE-Luciferase, which expresses exogenous AR and Luciferase expression under control of an androgen regulated promoter (Tran et”