DNA PK Inhibitors is a trimeric nuclear serine kinase composed of a large catalytic subunit

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 . Docetaxel and cabazitaxel chemotherapy provide modest . to mo extensions of median survival as first and second line chemotherapy, respectively The realization of the importance of DNA-PK Inhibitors androgen mediated signaling led to the eventual approval of abiraterone acetate, the CYP and potent androgen synthesis inhibitor, in the second line post docetaxel setting . Despite these advances, the median survival in the first line setting of mCRPC is approximately mo and in the post docetaxel setting is about 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 approx imately . mo in relatively asymptomatic and mostly chemotherapy naive patients .
Finally, denosumab, a monoclonal antibody that targets receptor activator Dasatinib of nuclear factor kB ligand RANKL , provided a modest incremental benefit, about %, over zoledronic acid in preventing skeletal related events SREs in men with bone metastases . 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 VX-770 chemotherapy Tables and . We review some of the most promising and emerging molecular targets in mCRPC and the efforts to develop agents against these targets 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 yr was performed in October .
The Vorinostat search strategy included the terms metastatic castration resistant prostate cancer, targeted therapy, biologic agents, and immunotherapy Evidence synthesis Biology of castration resistant prostate cancer Prostate cancer appears to be androgen pathway depen dent through multiple lines of therapy to varying extents, as suggested by the activity of secondary hormonal manipula tions and the activity of abiraterone acetate Telaprevir 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. These include sustaining proliferative signaling, evading growth suppres sors, resisting cell death, enabling replicative immortality, inducing angiogenesis, and activating invasion and metas tasis. Increasingly recognized supportive pathways are cellular metabolism alterations, evasion of immunologic destruction, genomic instability, and inflammation by innate immune cells. A unique fusion between the prostate specific androgen regulated TMPRSS gene and the ETS genes ERG, ETV, or ETV has been described in about % of tumors.
Although the therapeutic implications of this translocation are unclear, a tumorigenic role in early androgen regulated prostate cancers appears likely . A systems biology approach may identify the most relevant signaling pathways as opposed to discrete molecules and enable focused study of the pathophysiology of prostate cancer. For example, one study identified four pathways that appeared central including c Myc, p, androgen receptor AR , and prostate specific antigen PSA . The Catalogue of Somatic Mutations in Cancer database maintained by the Wellcome Trust Sanger Institute has identified common gene alterations with the caveat that these were mostly localized disease , which may help focus on the appropriate targets for therapy.

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