Cancer Prevention-Interception Targeted Agent Discovery Program at Fox Chase Cancer Center

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PROJECT SUMMARY - OVERALL Hereditable cancer-predisposing mutations are estimated to be an underlying cause of more than 100,000 adult cancers in the US each year. For many hereditary cancer syndromes, the life-time risk of developing cancer approaches 100%. Despite revolutionary advances in “omics” technologies, our understanding of the molecular alterations required to support the establishment of precancerous lesions and promote early tumor development remains very limited, thus hindering the development of efficacious interventions. A multidisciplinary team of accomplished investigators at Fox Chase Cancer Center (FCCC), with combined expertise in cancer prevention, heritable cancer risk, cancer biology, molecular modeling, and drug discovery has been assembled to address this unmet in an unprecedented way. The goal of the FCCC CAP-IT Center is to effectively coordinate the development of efficacious molecularly-targeted agents for precision cancer prevention and early interception in populations at high risk for cancer. All studies are facilitated by the unique resources of the FCCC Risk Assessment Program, which includes over 12,000 families at high risk for cancer and 2000 confirmed germline mutation carriers. A comprehensive pipeline for the development of agents for cancer prevention and interception is proposed that consists of three well-developed research domains: target validation (Aim 1), agent identification and screening (Aim 2), and pilot in vivo efficacy studies (Aim 3). Each domain will be led by a FCCC investigator, who is a national leader in the respective field. Two highly innovative projects are proposed that illustrate the robustness of the CAP-IT framework. Project 1 (entering at Target Validation) focuses on the development of a newly-identified agent that refolds mutant p53. Its ability to target the TP53 mutations associated with Li- Fraumeni Syndrome and inhibit precancerous lesions in a setting of mutant p53 will be evaluated. Project 2 (entering at Agent Identification and Screening) uniquely targets the initiated pancreatic stroma as a strategy for early interception in the formation of pancreatic cancer. A neutralizing antibody against the stromal protein Netrin G1, that can revert fibroblasts to a tumor-suppressive phenotype, has been discovered. Antibodies with improved potency will be identified and tested in vivo for their ability to intercept the progression of pancreatic intraepithelial neoplasia. All CAP-IT research and training will be strongly supported by the Leadership Team and coordinating activities of the Administrative Core, led by Dr. Clapper. Expertise in biostatistics, bioinformatics, and data management will be provided to CAP-IT investigators by an Informatics Core, led by Dr. Ross. Collaborations among the NCI, FCCC and other CAP-IT Centers, as well as the sharing of data and resources through the Data and Resource Coordination Center, will foster productivity and integration across the CAP-IT Network (Aim 4). The long legacy of FCCC in clinical risk assessment and preclinical preventive agent development, when combined with extensive expertise in drug design and cancer biology, makes this Center uniquely poised to be instrumental in the discovery of molecularly-targeted agents to prevent or intercept early oncogenesis.