Novel Approaches to p53-Based Therapy: ONYX-015

Cancer is caused by gain of function of proteins involved in proliferation and survival, and loss of function of proteins that regulate these processes (Hanahan and Weinberg, 2000). Strategies for treating cancer generally involve development of small molecules that block hyperactive enzymes, or take advantage of abnormal expression of protein targets on the surface of cancer cells. Developing therapies based on loss of function of tumor suppressors presents novel challenges. Loss of the protein phosphates PTEN and loss of the G1/S checkpoint protein pRB occurs frequently in cancer, and offers a number of potential drug targets. Loss of PTEN leads to hyperactivation of downstream enzymes such as AKT and mTOR (McCormick, 2004) whereas loss of pRB leads to hyper-activation of the transcription factor E2F, and increased expression of numerous potential targets, some of which have already been exploited for cancer therapy (dihydrofolate reductase and thymidylate synthase, for example, are the targets of methotrexate and 5-fluorouracil, respectively). Loss of p53, on the other hand, does not appear to offer any direct targets for intervention: in contrast to PTEN and pRB, p53 is a positive regulatory protein, whose targets are obviously lost rather than hyper-activated in cancer cells.