Attacking aggressive p53 mutants in gynecologic cancer

项目总结/文摘

Project Summary/Abstract I am currently a mentored assistant research scientist in the Department of Obstetrics and Gynecology at the University of Iowa. My long-term goal is to establish an independent research program to improve outcomes for women with ovarian and endometrial cancer through the safe delivery of effective and personalized treatment regimens. I intend to pursue an independent tenure-track faculty position at a competitive research institution, building upon my postdoctoral training in novel RNA-based therapeutics and current work in personalized medicine for gynecologic cancers. The objective for my independent K22 research program is to mechanistically distinguish between common missense p53 mutants and develop synthetic RNA-based therapeutics to overcome the deleterious functions. Approximately 40-50% of all observed p53 mutations are single nucleotide variants that result in missense mutations that change a single amino acid. Missense mutations not only abrogate canonical DNA binding and interaction with co-factors, but also confer new activities, including transcription of non-canonical targets and new in protein:protein interactions. Studies will focus on endometrial and ovarian cancer given the widespread occurrence of p53 mutations in these cancer types and the extremely poor 5-year survival of patients with p53 mutant cancers. I hypothesize that missense mutations in p53 that result in protein hyperstabilization activate different transcriptomic signatures that can be perturbed using novel RNA aptamers evolved to be specific for each mutant p53. This work leverages a highly innovative strategy to isolate native p53 from patient-derived organoid (PDO) cultures, which allows for study of p53 mutations in their endogenous environment. First, I will determine the mechanism(s) of survival and chemoresistance for recurrent p53 mutants by calculating the DNA binding specificity native p53 mutants and link this to genomic localization, gene regulation and chemosensitivity. This work includes a novel approach to isolate p53 mutant proteins from PDO models to capture the native protein conformation, posttranslational modifications and splice isoforms. Next, I will restore chemosensitivity in models with p53 mutants by perturbing the deleterious activity of individual p53 mutants with mutant-specific RNA aptamers. These studies will provide the first comprehensive assessment of the functional consequences of a large panel of p53 mutants using native protein and establish the feasibility of developing aptamer-based tools that inactivate p53 mutants. This project merges my graduate work in cell signaling, postdoctoral training in RNA aptamer-based therapeutics and more recent work in translational studies of gynecologic cancers. With funding from this K22 award and my multi-disciplinary collaborators, I will be well-equipped to establish an independent research program to improve outcomes for women with gynecologic cancer.