Review – Prostate CancerNovel Molecular Targets for the Therapy of Castration-Resistant Prostate Cancer☆
Introduction
Over the past year, multiple new systemic therapy agents have become available to treat men with metastatic castration-resistant prostate cancer (mCRPC) that provide modest but much needed benefits (Table 1). Docetaxel and cabazitaxel chemotherapy provide modest 2.5- to 3-mo extensions of median survival as first- and second-line chemotherapy, respectively [1], [2]. The realization of the importance of androgen-mediated signaling led to the eventual approval of abiraterone acetate, the CYP17 and potent androgen synthesis inhibitor, in the second-line post-docetaxel setting [3]. Despite these advances, the median survival in the first-line setting of mCRPC is approximately 20 mo and in the post-docetaxel setting is about 15 mo. Immunotherapy with the autologous antigen-presenting cell (APC)-based product expressing prostatic acid phosphatase-granulocyte macrophage-colony stimulating factor (PAP-GM-CSF), sipuleucel-T, extended median survival by approximately 4.5 mo in relatively asymptomatic and mostly chemotherapy-naive patients [4]. Finally, denosumab, a monoclonal antibody that targets receptor activator of nuclear factor κB ligand (RANKL), provided a modest incremental benefit, about 18%, over zoledronic acid in preventing skeletal-related events (SREs) in men with bone metastases [5].
Given the incremental benefits conferred by these recently approved agents, novel and tolerable agents are necessary to make further gains. Multiple ongoing trials are combining novel agents with first-line docetaxel-based chemotherapy (Table 2, Table 3). We review some of the most promising and emerging molecular targets in mCRPC and the efforts to develop agents against these targets.
Section snippets
Evidence acquisition
A review of the literature searching Medline and major cancer conferences for prospective trials and major preclinical and retrospective studies from the last 5 yr was performed in October 2011. The search strategy included the terms metastatic castration-resistant prostate cancer, targeted therapy, biologic agents, and immunotherapy.
Biology of castration-resistant prostate cancer
Prostate cancer appears to be androgen-pathway dependent through multiple lines of therapy to varying extents, as suggested by the activity of secondary hormonal manipulations and the activity of abiraterone acetate following docetaxel. Although immunotherapy, tubulin inhibition, and osteoclast inhibition by targeting the RANKL have also yielded broad benefits, all of the hallmarks of cancer may be invoked to drive growth (Fig. 1) [6]. These include sustaining proliferative signaling, evading
Conclusions
Although multiple new drugs have recently been approved for the treatment of mCRPC, improvement in overall survival remains modest at best, with all patients eventually experiencing disease progression and early mortality. In addition to immunotherapy and androgen pathway signaling, multiple other molecular targets promise to provide the next generation of advances. In recent years, the simultaneous development of novel and more potent classes of drugs targeting these pathways has emerged. A
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2017, European UrologyCitation Excerpt :These include further reductions of androgen production by targeting synthetic enzymes such as CYP17, the target of abiraterone acetate (Zytiga), and improved inhibition of the androgen receptor itself (enzalutamide/Xtandi, ARN-509/apalutamide) and downstream effects on transcription, proliferation, and survival of prostate cancer cells. These approaches have been reviewed elsewhere [8,9]. A critical question for these next-generation antiandrogen agents going forward is determining the patients that will most benefit from their use.
Ruffling the Immunotherapy Response Paradigm with a Novel Personalized Peptide Vaccine
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