Ras-Targeted Therapeutic for Cancer
The concept of targeting cancer therapeutics towards specific mutations or abnormalities in tumor cells which are not found in normal tissues offers potential advantages of high selectivity for the tumor and correspondingly low secondary toxicities. Ninety per cent of all human malignancies display different activating mutations in the p21Ras genes or over-activity of p21Ras-signaling pathways.
Phoenicia scientists previously discovered that over-activity of p21Ras signaling sensitizes tumor cells to apoptosis induced by suppression of PKC-delta activity, which is not toxic to cells with normal levels of p21Ras activity. This property, designated “Ras-mediated apoptosis,” is being exploited as a targeted cancer therapeutic. We have characterized Ras-mediated apoptosis molecularly, demonstrated its selectivity in vitro and in vivo, identified the specific target PKC isozyme (PKC-δ), identified lead compounds for inducing cell death in tumors containing activated Ras or Ras pathways, and obtained intellectual property protection on Ras-mediated apoptosis as a therapeutic approach.
In this Program, Phoenicia has developed highly-potent PKC-δ inhibitors, and is evaluating multiple analogues in in vitro and in vivo studies to identify the optimal inducer of Ras-mediated apoptosis for pharmaceutical application. The optimal compound can be developed for IND application within one year.
• Supported by the National Cancer Institute