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

Available for download on Tuesday, May 01, 2018

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