TRIMODAL GENE THERAPY FOR PROSTATE CANCER

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DESCRIPTION (adapted from application) Prostate cancer is the most commonly diagnosed malignancy in men. Although conventional therapies (surgery, radiation, androgen ablation) produce high cure rates of early stage disease, many tumors recur and an effective therapeutic regimen is still lacking for advanced stages of the disease. Our research program has developed a novel, multifaceted, gene therapy approach for the treatment of prostate cancer. Our approach utilizes a modified, replication competent adenovirus (FGR) to selectively and efficiently deliver a pair of therapeutic suicide genes to prostate tumors. Preclinical studies in animals have demonstrated that the FGR virus itself generates a potent antitumor effect by replicating in and preferentially destroying human prostate cancer cells that lack a functional p53 tumor suppressor protein. The therapeutic effect of the FGR virus can be enhanced by invoking two suicide gene systems (CD/5FC and HSV1 TK/GCV), which render malignant cells sensitive to specific pharmacological agents (prodrugs), and more importantly, sensitizes them to radiation. A strength of our approach is that it simultaneously makes use of three modalities viral, double suicide gene, and radiation therapies to selectively destroy prostate cancer cells with minimal toxicity towards normal tissues. Our research efforts are currently at the cusp of preclinical/phase I clinical studies. A phase I clinical protocol involving the FGR virus concomitant with double prodrug therapy has been approved by our IRB. A pre-IND meeting with the FDA has been held, and we expect to begin phase I trials in 1999. As a means to further enhance the efficacy of our approach, this application will: 1) evaluate the merit of adding androgen ablation as a fourth therapeutic arm, 2) evaluate the effectiveness of FGR viral therapy against disseminated disease, and 3) evaluate the specificity of each therapeutic arm with respect to tumor p53 status and determine whether treatment failure correlates with p53 status.