Enthusiasm for the development of molecularly targeted agents has been spurred by the clinical successes of trastuzumab and imatinib mesylate, and the more recent approvals of gefitinib, cetuximab, and bevacizumab. One of the lessons learned from the development of these agents is the importance of target selection. Appropriate targets are the aberrant pathways or molecules upon which the cancer cell is critically dependent. The challenge here is whether targeting a single pathway or molecule will impact tumor burden given the redundancies in signaling pathways and the molecular heterogeneity inherent in the tumor cell population. In light of this problem, an approach that might prove effective is the targeting of convergence points of multiple signaling pathways, such as Akt. Modulation of such targets may provide more complete inhibition than those farther upstream, such as cell surface receptors. Of course, the potential benefits of such an approach will have to be balanced by careful evaluation of potential toxicities, as such points of signaling confluence are utilized in multiple cellular functions, including those in normal cell populations. Nevertheless, given the importance of signaling through PI3K/Akt in prostate cancer, targeting components of this pathway, either alone or in combination with cytotoxic agents or other targeted therapeutics, holds substantial promise.
Molecularly targeted agents that alter pathways critical to cancer cell survival and progression will undoubtedly compose, either alone or in combination, the foundation for future chemotherapeutic strategies for HRPC. The rate at which these strategies can mature and be translated to the clinical setting will rely in part on the identification and validation of appropriate targets, the consideration of more global signaling profiles or signatures in tumor cells that will facilitate the identification of critical pathways that can be targeted in combination, utilization of modern drug discovery/medicinal chemistry resources, access of clinician-scientists to new investigational agents developed by these resources, development of innovative means to identify patients who harbor a relevant target, and to assess drug responses in these patients, and on substantive and informative interactions among basic scientists and clinicians.
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