FCCC CAP-IT Center has two projects and two administrative supplement awards.
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. (For additional information, please visit NIH RePORTER)
Project 2 (entering at Agent Identification & 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. (For additional information, please visit NIH RePORTER)
In this supplement, we will carry out proof-of-principle studies and determine whether DNA Polymerase Theta (Polθ) is an effective target for BRCA1 cancer prevention with the aim to evaluate Brca1 cancer initiation and Polq gene mutations. These preliminary studies will determine whether Polθ is an effective target for the interception and lay the groundwork for future studies using small molecule Polθ inhibitors. (For additional information, please visit NIH RePORTER)
Germline or somatic mutations reducing the expression or function of the von Hippel-Lindau (VHL) tumor suppressor are the most common genetic features of clear cell renal cell carcinoma (ccRCC), with many of these mutations being missense. Evidence in the scientific literature suggests that pathogenic missense mutations impact VHL function by 1) Increasing the ratio of partially unfolded or misfolded (dysfunctional) protein to functional protein; or 2) disrupting specific contacts between VHL and essential protein partners. Using computational modeling approaches, a specific, novel binding pocket on the VHL protein surface has been identified, and small molecule compounds have been generated that are predicted to bind this site and stabilize the ratio of folded to unfolded VHL, boosting protein function. The goal of this supplement is to specifically determine whether these compounds are effective in reversing the dysfunction induced by germline mutations in VHL that occur in discrete protein domains. (For additional information, please visit NIH RePORTER)