Germline P72R Polymorphism as a Determinant of Rescuable p53 Mutants
Abstract
The TP53 gene encodes p53, a potent tumor suppressor that inhibits tumor growth through various means. It is considered the guardian of the genome because it plays a crucial role in controlling the fidelity of DNA replication, thereby ensuring the integrity of the genome after each cell division. Not surprisingly, mutations in TP53 result in the loss of genome integrity and tumor-suppressive properties. Consequently, TP53 mutations promote abnormal cell growth and cancer through additional alterations in the genome. In high-grade serous ovarian cancer (HGSC), TP53 is almost universally mutated, which often results in high levels of mutant p53 expression. Because TP53 mutation is an early event in the development of HGSC, mutant p53 expression is present in all tumor cells during the progression of HGSC. This widespread and elevated expression of p53 mutants represents a new opportunity for therapy development if p53 mutants can be rescued to restore their normal tumor suppressor function. Some TP53 mutations alter the normal form and function of p53, such that these mutants can be functionally rescued by a drug to restore the normal tumor-suppressive function. One such drug, APR-246, is currently undergoing a Phase III clinical trial together with azacitidine (NCT03745716). It should be noted that not all mutations in TP53 are expected to be responsive to rescue/restoration by APR-246; therefore, testing APR-246 in an unselected patient population will likely result in clinical trial failure. Unfortunately, we do not have a complete knowledge of which p53 mutants are rescuable by APR-246. This knowledge is critical for appropriately testing the clinical benefit of APR-246. Therefore, we propose to perform a genetic screen that will allow us to identify and confirm which p53 mutants are responsive to APR-246 so that the appropriate patient population can be selected and tested for the clinical benefits. We will accomplish this goal by creating a library of p53 mutants and testing their response to APR-246. APR-246 responsive mutants will be further confirmed in additional studies, and gene signature, protein markers, and metabolite biomarkers that are associated with APR- 246 responsive p53 mutants will be identified. The clinical relevance of these markers will be tested using patient samples and data sets from collaborators and international genome consortia. Our studies will advance clinically actionable knowledge by identifying which p53 mutants are responsive to APR-246. Our team is uniquely qualified to conduct these studies because we have complementary expertise in cancer genomics, p53 genetics, gynecologic histopathology, and experimental therapeutics. Drs. Chien, Karnezis, and Fiehn have participated in large-scale omics studies and established expertise in genomics, metabolomics, p53 genetics, and pathology. Dr. Chien is a cancer researcher who has recently shown that germline variations in the codon 72 of TP53 (P72R polymorphism) modify TP53 mutation effects. Dr. Karnezis is a gynecologic pathologist who has previously contributed to preclinical studies showing that p53 reactivation can promote a therapeutic effect in high-grade tumors. Dr. Fiehn is the Director of the NIH-funded West Coast Metabolomics Center and has contributed to analytical methods, data analysis, and bioinformatics tool development in metabolomics and is uniquely qualified to perform the proposed metabolomics discovery studies. These complementary interdisciplinary research expertise and mutual research interests are joined together in this proposal to advance a current gap in clinically important knowledge for the p53-targeting drug APR-246. These three teams are housed within the University of California, Davis (UCD) research program and have collaborated in previous studies. The UCD is a home to an NCI-designed Comprehensive Cancer Center, and it supports leading research in Cancer Therapeutics, Molecular Oncolog
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210318
Entities
People
- Jeremy Chien
Organizations
- United States Army
- University of California, Davis