Description
- Abstract:
- Ovarian cancer remains a significant clinical gap due to late-stage diagnosis and frequent development of resistance to standard therapies, including platinum-based chemotherapy and PARP inhibitors. Homologous recombination deficiency (HRD) is commonly observed in ovarian cancers which creates vulnerabilities in the DNA damage and repair pathway. Most small molecule inhibitors such as PARPi therapies have been a well-known treatment for ovarian cancers; however, resistance to these current targeted therapies remain a major clinical challenge. Poly (ADP-ribose) glycohydrolase (PARG) inhibition has emerged as a potential strategy to disrupt DNA repair by increasing poly(ADP-ribose) (PAR) accumulation and impairing cellular survival mechanisms. In this study, we evaluated the effects of multiple different PARGi on PAR accumulation across a panel of ovarian cancer cell lines. Furthermore, we investigated combination treatments such as supplementation of the NAD+ precursor NRH that modulated PAR synthesis to enhance cellular effects of PARG inhibition. In addition, combining PARGi with other DNA damage response (DDR) inhibitors such as PARPi and genotoxic agents were assessed to identify and quantify PAR accumulation and foci formation using confocal microscopy and high-content imaging platforms. Overall, these studies aim to characterize the impact of PARG inhibition on ovarian cancer cell survival in cancer cell survival and DNA repair signaling. Identifying combination strategies like NRH supplementation may also have an impact on overcoming therapeutic resistance. This study would help to understand differences and significances of inhibition across differenct ovarian cancer models. These findings may inform the development of a novel treatment approach for ovarian cancers, particular those resistant to current DNA repair-targeted therapies.
- Notes:
- Thesis (Sc. M.)--Brown University, 2026
Citation
Magro, Emelia,
"Characterization of PARG Inhibitors and Their Effects on DNA Damage, Repair, and Survival in +/- HRD Cancers"
(2026).
Biotechnology, Biology and Medicine Theses and Dissertations.
Brown Digital Repository. Brown University Library.
https://repository.library.brown.edu/studio/item/bdr:e7z3j6k6/
Relations
Collections:
-
Biology and Medicine Theses and Dissertations
Theses and Dissertations for the Biology and Medicine department....