Synthetic Lethality as a Targeted Approach to Advanced Prostate Cancer
Abstract
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 Ras/Raf/MEK/ERK 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 are testing 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.
Document Details
- Document Type
- Technical Report
- Publication Date
- Mar 01, 2012
- Accession Number
- ADA590822
Entities
People
- Douglas V. Faller
Organizations
- Boston University