Date of Award
Fall 2023
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Experimental Pathology
First Advisor
Bindra, Ranjit
Abstract
Genomic instability is one of the hallmarks of cancer, which underlies cancer development and progression. This DNA repair vulnerability presents cancer researchers with a therapeutic opportunity. Targeted therapies designed to overwhelm DNA repair pathways in cancer have proven largely effective as anti-cancer treatments. However, there are currently three major issues with their widespread use in cancer. Firstly, for cancers such as glioblastomas (GBMs), there have been no targeted therapies approved for decades. Secondly, for most targeted therapies there is an incomplete understanding of their precise mechanism of action, which limits their clinical utility. Thirdly, cancers develop resistance to most targeted therapies, preventing durable drug responses in patients. For my thesis, I aimed to overcome these drawbacks associated with targeted therapies. In Chapter 2 of my thesis, I present my research outlining the development and characterization of a novel DNA repair inhibitor for use in GBMs. This inhibitor can be explored in combination with radiation therapy, the current standard of care treatment for GBMs, to allow greater tumor cell killing while sparing the surrounding normal tissue. In Chapter 3 of my thesis, I present my research towards understanding the mechanism of action of poly (ADP-ribose) glycohydrolase inhibitors (PARGi), which are currently in clinical development for the treatment of DNA repair-deficient cancers. These results will inform clinical trials with PARGi moving forward. In Chapter 4 of my thesis, I outline our current understanding of resistance mechanisms to poly (ADP-ribose) polymerase inhibitors (PARPi), which have been approved for use in breast, ovarian, prostate, and pancreatic cancer. I present mechanistic insight into a specific mechanism of PARPi resistance, and propose recommendations for better stratifying patients in PARPi clinical trials. In all, these three chapters are focused on improving targeted therapies for use in DNA repair-deficient cancers with the aim of positively affecting cancer patient response and survival.
Recommended Citation
Paradkar, Sateja, "Exploiting DNA Repair Deficiencies in Cancer to Develop and Characterize Novel Therapeutics" (2023). Yale Graduate School of Arts and Sciences Dissertations. 1128.
https://elischolar.library.yale.edu/gsas_dissertations/1128
