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A Syngeneic Pancreatic Cancer Mouse Model to Study the Effects of Irreversible Electroporation
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Poly (ADP) Ribose Glycohydrolase Can Be Effectively Targeted in Pancreatic Cancer
Aditi Jain1,2, Lebaron C Agostini1,2, Grace A McCarthy1,2
1The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.
Cancer Research
|July 6, 2019
Summary
Poly (ADP) ribose glycohydrolase (PARG) is a promising target for pancreatic cancer. PARG inhibitors show efficacy alone and synergize with DNA-damaging agents in preclinical models.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Metastatic pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, necessitating novel therapeutic targets.
- Poly (ADP) ribose glycohydrolase (PARG) is identified as a potential target due to its link with the mRNA stability factor HuR (ELAVL1).
Purpose of the Study:
- To evaluate poly (ADP) ribose glycohydrolase (PARG) as a therapeutic target in pancreatic ductal adenocarcinoma (PDAC) models.
- To assess the efficacy of PARG inhibitors (PARGi) alone and in combination with standard chemotherapies.
Main Methods:
- Genetic silencing of PARG and treatment with small-molecule PARG inhibitors (PDDX-01/04) in PDAC models.
- In vitro sensitivity assays comparing homologous repair-deficient and proficient cells.
- In vivo tumor growth studies and combination therapy assessments with DNA-damaging agents and PARP inhibitors.
Main Results:
- Homologous repair-deficient cells exhibited increased sensitivity to PARGi in vitro.
- PARG silencing significantly reduced tumor growth in vivo.
- PARGi demonstrated synergy with oxaliplatin and 5-fluorouracil, but not with PARP inhibitors.
Conclusions:
- Poly (ADP) ribose glycohydrolase (PARG) is validated as a relevant therapeutic target in pancreatic ductal adenocarcinoma (PDAC).
- PARG inhibitors show potential as a single-agent therapy or in combination with DNA-damaging agents for pancreatic cancer treatment.
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