Synthetic Lethality as a Targeted Approach to Advanced Prostate Cancer
Final rept. 1 Mar 2011-29 Feb 2014
TRUSTEES OF BOSTON UNIV MA
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Prostate carcinogenesis is closely linked to aberrant activation of Ras or Ras signaling pathways e.g., Raf-MEK, or PI3K pathways. The incidence of activating PI3K mutations in early and advanced prostate cancer, or loss of PTEN is very high. Increased expression of the RasRafMEKERK pathway has been associated with advanced prostate cancer, hormonal independence and a poor prognosis. We have demonstrated that, when aberrantly activated, Ras is lethal to the cell unless a survival pathway also initiated by Ras is active. This survival pathway requires PKC . Unlike the classical PKC isozymes, PKC is not required for cell survival, and its inhibition or down-regulation in normal cells and tissues has no significant adverse effects. Inhibition of PKC in human and murine cells containing an activated Ras protein, however, initiates rapid and profound apoptosis. In this work, we have validated the hypothesis that inhibition or down-regulation of PKC in human and murine models of prostate cancer with aberrant activation of Ras signaling will cause targeted cytotoxicity in these tumors. We have developed PKC specific small molecule inhibitors and demonstrated their anti-tumor activity against prostate cancer in vitro and in vivo.
- Medicine and Medical Research