Date of Award
Spring 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Experimental Pathology
First Advisor
Bindra, Ranjit
Abstract
There is growing evidence that mutations in the PPM1D gene are implicated in the development and malignancy of tumors, specifically for cancers like high-grade gliomas. These mutations enhance the activity of canonical PPM1D functions, causing the dysregulation of the DNA damage response and cell cycle progression. Recently, PPM1D mutations were reported to cause a synthetically lethal interaction to inhibitors targeting the enzyme, NAMPT, which is critical for NAD+ biogenesis. These mutations lead to global DNA hypermethylation, resulting in the epigenetic silencing of the enzyme NAPRT. Importantly, NAPRT loss was linked to NAMPT inhibitor (NAMPTi) sensitization, making it a biomarker for therapeutic intervention. However, NAMPT inhibitors are known to have extensive toxicity and are ineffective for tumors protected by the blood brain barrier, but developments in drug delivery technology can overcome these issues. This work reports a novel drug delivery modality for the NAMPTi GMX1778 that effectively treated in vivo intracranial xenografts of high-grade gliomas lacking NAPRT expression. Two unique copolymeric formulations were optimized that displayed no discernable toxicity with retained sensitivity, making it practical for clinical use. Moreover, this work investigates the regulation of the NAPRT locus to find universal patterns that indicate when epigenetic loss will occur, pan-cancer. Several key cellular pathways stipulated in its regulation were identified, and those related to epigenetic regulation were experimentally profiled. Together, this work establishes an optimized drug delivery strategy for NAMPTis that overcomes its clinical issues while uncovering the biology of NAPRT to determine additional indications for effective NAMPTi targeting beyond glioma.
Recommended Citation
Murray, Matthew A., "Defining the Function and Therapeutic Potential of Mutant PPM1D in High-Grade Glioma" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1498.
https://elischolar.library.yale.edu/gsas_dissertations/1498
