Evaluating The Therapeutic Efficacy of Restoring Wild-Type P53 Activity In P53-Mutant Tumors

<p>The p53 transcription factor is the most frequently altered in human cancers usually via missense mutations that undermine its transcriptional activity. Clinically, <em>TP53</em> 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 <em>p53</em>-mutant tumors will respond to p53 restoration-based therapies.</p> <p>Using a mouse model of Li Fraumeni syndrome, we genetically restored wild-type <em>p53</em> in mice carrying a germline <em>p53^R172H</em>(corresponding to the <em>TP53^R175H</em> 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.</p>

Name thesis:degree_name

Doctor of Philosophy (PhD)

Level thesis:degree_level

Dissertation (PhD)

Year dc:date.available

2017

Authors dc:creator

• Larsson, Connie A
• <p>0000-0002-7829-0023</p>

Contributors dc:contributor

• Guillermina Lozano, PhD
• Richard Behringer, PhD
• Russell Broaddus, MD, PhD

• mutant p53
• p53 restoration
• TNF
• retinoic acid
• therapeutic response
• RARG
• Genetics and Genomics
• Oncology
• Therapeutics

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/815

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1859