Author ORCID Identifier
0000-0002-7829-0023
Date of Graduation
12-2017
Document Type
Dissertation (PhD)
Program Affiliation
Genes and Development
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Guillermina Lozano, PhD
Committee Member
Richard Behringer, PhD
Committee Member
Russell Broaddus, MD, PhD
Committee Member
Florian Muller, PhD
Committee Member
Nicholas Navin, PhD
Abstract
The p53 transcription factor is the most frequently altered in human cancers usually via missense mutations that undermine its transcriptional activity. Clinically, TP53 mutations have been shown to be remarkably predictive of refractoriness to treatment, resulting in poor outcome. Consequently, the development of p53 pathway activating agents is rapidly evolving and gaining more attention in cancer therapeutics research, with several small molecule compounds currently in preclinical and clinical trials. However, it remains largely unknown what types or proportions of p53-mutant tumors will respond to p53 restoration-based therapies.
Using a mouse model of Li Fraumeni syndrome, we genetically restored wild-type p53 in mice carrying a germline p53R172H(corresponding to the TP53R175H hotspot in humans) missense mutation and observed heterogeneous responses. We found that approximately 50% of tumors responded by regressing in volume whereas 50% of tumors failed to regress after p53 reinstatement. To gain insight into the molecular events underlying therapeutic response to p53 restoration, we sequenced the transcriptome of twelve p53-mutant thymic lymphomas that were sensitive (n=8) or resistant (n=4) to p53 restoration. Differential gene expression analyses suggested a critical role for the TNF pathway and RARγ, an effector in the TNF pathway, in promoting response as they were up-regulated in tumors sensitive to p53 restoration. Furthermore, we demonstrate that pharmacological activation of RARγ with the synthetic retinoid, CD437, sensitizes resistant tumors to p53 restoration while additively improving outcome and survival in tumors inherently sensitive to p53 restoration.
Keywords
mutant p53, p53 restoration, TNF, retinoic acid, therapeutic response, RARG