Importins and exportins as therapeutic targets in cancer

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Importins and exportins as therapeutic targets in cancer. to overcome drug resistance. F876L mutation, which confers resistance to enzalutamide, was observed in circulating tumor CD-161 DNA from anti-androgen therapy-resistant patients.11 Recent evidence suggests that the combination of anti-androgen therapies could have additive effects on androgen signaling. STAMPEDE is a randomized controlled multi-group and multi-stage study on the CD-161 effects of the combination of multiple anti-AR therapies. A recently published STAMPEDE report demonstrated an obvious survival benefit of the combination of abiraterone and ADT. In a total of 1917 patients not previously treated with hormone therapy, the 3-year survival was 83% in the combination group compared with 76% in the ADT alone group (hazard ratio [HR]: 0.63, 95% confidence interval [CI]: 0.52C0.76, 0.001).8 This encouraging finding warrants further studies of additional anti-androgen drugs in combination. However, not all anti-androgen combination studies have shown a positive outcome. Preliminary data from the PLATO trial (“type”:”clinical-trial”,”attrs”:”text”:”NCT01995513″,”term_id”:”NCT01995513″NCT01995513) on the combination of abiraterone and enzalutamide did not show a benefit on progression-free survival of CRPC.13 Long-term observations are needed for a more objective evaluation. In addition to conventional AR-targeted therapy, lipid nanoparticle-delivered antisense therapy represents a promising therapeutic direction. Antisense therapy is activated through binding to a specific RNA sequence and inhibiting the function of RNA. Lee and compared with the single agent.17 In this report, the authors also described an altered AR cistrome and enhanced AR dependence following inhibition of EZH2 in CRPC, suggesting a potentially increased efficiency of anti-androgen therapy in the presence of EZH2 inhibitor.17 The promising results from these preclinical studies provide a rationale to further investigate the clinical effects of the combination of antisense and targeted therapies. Targeting AR and AR variants The deregulation of AR splicing variants is another important mechanism of anti-androgen therapy resistance. AR variants lacking the C-terminal ligand binding domain exhibit nuclear localization and are constitutively active in the absence of androgens.18,19,20 AR-V7 is one of the most well-studied AR variants in preclinical and clinical studies. AR-V7 expression in circulating tumor cells is strongly associated with resistance to enzalutamide and abiraterone therapies in prostate cancer patients.10 The clinical findings are supported by evidence showing that knockdown of AR-V7 expression in an androgen-independent prostate cancer cell line restores the response to anti-androgen therapy.21 Given that currently available anti-androgen drugs mainly target the C-terminal ligand binding domain of AR and are expected to CD-161 be ineffective for inhibiting AR variants, how to block the activity of AR variants has become an attractive topic in recent years. One possible strategy is to develop inhibitors targeting conserved regions of both AR and AR variants. The N-terminal activation function-1 (AF-1) domain of AR is essential for both full-length AR and AR variants. Thus, the N-terminal domain of AR is a promising drug target to overcome AR variant-induced CD-161 anti-androgen drug resistance. EPI belongs to a set of small molecules that target the N-terminal domain of AR. EPI-001 was found to bind to AR and block the protein-protein interaction of AR and coactivators, in turn inhibiting the transcriptional activity of both AR and AR variants.22,23 However, the excessive high pill burden caused early termination of phase I/II trials of EPI-506 in CRPC with progression after enzalutamide or abiraterone (“type”:”clinical-trial”,”attrs”:”text”:”NCT02606123″,”term_id”:”NCT02606123″NCT02606123). Notably, the excessive adverse effects may be solved by the addition of a secondary anti-androgen therapy. Theoretically, the dose of each drug can be lowered in combination to achieve a similar efficacy. The AR N-terminal targeting antagonist sintokamide A (SINT-1) is CD-161 shown to block the protein-protein interactions with AR functional partners and inhibit the activity of both AR and AR variants.24 Although SINT-1 and EPI compound both targets the N-terminal part of AR, these drugs may exert anti-androgen functions via different mechanisms. EPI was observed to inhibit AR expression at both mRNA and protein levels, and it was able to block interleukin 6 (IL-6)-induced transactivation of AR. In contrast, SINT-1 did not affect AR expression and was able to significantly inhibit forskolin-induced AR transactivation.24 Importantly, this report demonstrated an additive inhibitory effect on PSA luciferase activity in cells treated with the combination of EPI and SINT-1 compared with either drug alone. The DNA-binding domain (DBD) is another conserved region in both AR and AR variants. Researchers have Rabbit polyclonal to IL13 identified a surfaced exposed pocket on DBD, which can serve as a potential target site. DBD targeting compounds VPC-14228/14449 have been shown to diminish the interaction of AR with androgen response element; therefore, VPC-14228/14449 can.