Novel Actions of Next-Generation Taxanes Benefit Advanced Stages of Prostate Cancer

Abstract

Purpose To improve the outcomes of patients with castrate resistant prostate cancer (CRPC), there is an urgent need for more effective therapies and approaches that individual specific treatments for patients with CRPC. The current studies compared the novel taxane, cabazitaxel with the previous generation docetaxel, and aimed to determine which tumors are most likely to respond. Experimental design Cabazitaxel (CBTX) and docetaxel (DCTX) were compared via in vitro modeling to determine molecular mechanism, biochemical and cell biological impact, and cell proliferation, which was further assessed ex vivo in human tumor explants. Isogenic pairs of RB knockdown and control cells were interrogated in vitro, and in xenograft tumors for cabazitaxel response. Results The data herein show that i. CBTX exerts stronger cytostatic and cytotoxic response compared to DCTX, especially in CRPC; ii. CBTX induces aberrant mitosis, leading to pyknotic and multinucleated cells; iii. taxanes do not act through the androgen receptor (AR); iv. Gene expression profiling reveals distinct molecular actions for CBTX v. tumors that have progressed to castration resistance via loss of RB show enhanced sensitivity to CBTX. Conclusions CBTX not only induces improved cytostatic and cytotoxic effects, but also impacts distinct molecular pathways, compared to DCTX, which could underlie its efficacy after DCTX treatment has failed in CRPC patients. Finally, RB is identified as the first potential biomarker that could define the therapeutic response to taxanes in metastatic CRPC. This would suggest that loss of RB function induces sensitization taxanes, which could benefit up to 50% of CRPC cases.

Resistance to docetaxel in prostate cancer is associated with androgen receptor activation and loss of KDM5D expression

“…Preclinical and clinical experience has documented minimal activity of taxane therapy alone in HSPC (24,25), and transcriptional response to this drug has recently been shown to be largely dependent on hormone status (26), suggesting that specific AR signaling modulates docetaxel insensitivity and that alteration of this signaling might sensitize prostate cancer cells to docetaxel. One well-known feature of AR signaling in prostate cancer involves ERG, which is overexpressed in at least 50% of prostate cancers as a result of gene fusions with genes such as TMPRSS2, SLC45A3, and NDRG1, which have AR promoter regions (27,28).…”

Differential impact of RB status on E2F1 reprogramming in human cancer

“…RB loss has been previously described to be prevalent in, enriched in, and causative for CRPC (34,(36)(37)(38). To expand analyses of the RB pathway to recent clinical findings, alterations in the androgen receptor (AR), RB, cyclin-CDK, and CDK inhibitor profiles were assessed using a cohort of CRPC tissue from the Stand Up to Cancer/Prostate Cancer Foundation (SU2C/PCF) prostate cancer collection ( Figure 1, A and B, and ref.…”

Effects of Thymoquinone on IL-6 Gene Expression and Some Cellular Signaling Pathways in Prostate Cancer PC3 Cells

“…Androgen ablation therapy is mainly used to treat hormone-sensitive PC. However, in most males usually after 2 to 3 years, metastatic PC leads to an androgen-independent state (7)(8)(9). It is shown that signaling pathways influence cell growth and its inhibition through cell cycle regulation (10).…”