Agostini LC, Jain A, Shupp A, Nevler A, McCarthy GA, Bussard KM, Yeo CJY & Brody JR. Combined targeting of PARG and Wee1 causes decreased cell survival and DNA damage in an S-phase dependent manner. Molecular Cancer Research 19(2):207-21, 2021.
In this study, we evaluated a novel synergistic combination treatment in pancreatic ductal adenocarcinoma (PDAC) and colorectal carcinoma cells by inhibiting a DNA Damage Response-related protein, poly (ADP-ribose) glycohydrolase (PARG), and a checkpoint kinase protein, Wee1. Through both in vitro and in vivo analyses we found that combined inhibition of these two proteins in two different cancer models exhibit synergy and increased DNA damage in an S-Phase specific manner.
Haber AO, Jain A, Mani C, Nevler A, Agostini LC, Golan T, Palle K, Yeo CJ, Gmeiner WH & Brody JR. AraC-FdUMP (CF10) is a next generation fluoropyrimidine with potent antitumor activity in PDAC and synergy with PARG inhibition. Molecular Cancer Research 19(4):565-572, 2021.
Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer-related death in the United States, with a 5-year survival rate of 10%. 5-FU (5-fluorouracil) is an integral component of standard of care FOLFIRINOX therapy for PDAC, which is inefficiently metabolized to FdUMP, and limits the therapeutic effects of this standard of care. We found that CF10, a next generation fluoropyrimidine is a potent agent that has therapeutic advantages relative to 5-FU in PDAC and synergizes with inhibition of a DNA damage response protein PARG, thus unravelling a novel combination therapy for PDAC.
Jain A, Agostini LC, McCarthy GA et al: Poly (ADP) ribose glycohydrolase can be effectively targeted in pancreatic cancer. Cancer Res 79(17):4491-4502. 2019.
In this study, we identified that poly (ADP) ribose glycohydrolase (PARG) as a strong candidate therapeutic target in PDAC using both genetic silencing of PARG and established small-molecule PARG inhibitors (PARGi), PDDX-01/04. Homologous repair-deficient cells compared with homologous repair-proficient cells were more sensitive to PARGi in vitro. In vivo, silencing of PARG significantly decreased tumor growth. PARG inhibition also synergized with DNA-damaging agents (i.e., oxaliplatin and 5-fluorouracil), but not with PARPi therapy. We also show that combination of PARGi and oxaliplatin treatment led to persistence of detrimental PARylation, increased expression of cleaved caspase-3, and increased γH2AX foci (a marker of apoptosis). SIGNIFICANCE: PARG is a potential target in pancreatic cancer as a single-agent anticancer therapy or in combination with current standard of care.
Jain A, Brown S, Thomsett HL, Londin E, & Brody JR (2019): Evaluation of Post-Transcriptional Gene Regulation in Pancreatic Cancer Cells: Studying RNA Binding Proteins and their mRNA Targets. In Methods Molecular Biology: Pancreatic Cancer (Su GH, ed.), Chapter 22, Volume 1882. Humana Press, New York, NY