Poly (ADP) Ribose Glycohydrolase Can Be Effectively Targeted in Pancreatic Cancer.

Autor:	Jain A; The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Agostini LC; The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., McCarthy GA; The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Chand SN; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Ramirez A; The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Nevler A; The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Cozzitorto J; The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Schultz CW; The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Lowder CY; The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Smith KM; Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom., Waddell ID; Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom., Raitses-Gurevich M; Oncology Institute, Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel., Stossel C; Oncology Institute, Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel.; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Gorman YG; Oncology Institute, Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel., Atias D; Oncology Institute, Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel., Yeo CJ; The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania.; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania., Winter JM; Surgical Oncology, University Hospitals Cleveland Medical Center, Cleveland, Ohio., Olive KP; Department of Medicine and Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, New York., Golan T; Oncology Institute, Chaim Sheba Medical Center, Tel Aviv University, Tel Aviv, Israel.; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel., Pishvaian MJ; Department of Gastrointestinal Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, Texas., Ogilvie D; Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom., James DI; Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom., Jordan AM; Drug Discovery Unit, Cancer Research UK Manchester Institute, The University of Manchester, Manchester, United Kingdom., Brody JR; The Jefferson Pancreas, Biliary and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania. jonathan.brody@jefferson.edu.; Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, Pennsylvania.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2019 Sep 01; Vol. 79 (17), pp. 4491-4502. Date of Electronic Publication: 2019 Jul 04.
DOI:	10.1158/0008-5472.CAN-18-3645
Abstrakt:	Patients with metastatic pancreatic ductal adenocarcinoma (PDAC) have an average survival of less than 1 year, underscoring the importance of evaluating novel targets with matched targeted agents. We recently identified that poly (ADP) ribose glycohydrolase (PARG) is a strong candidate target due to its dependence on the pro-oncogenic mRNA stability factor HuR ( ELAVL1 ). Here, we evaluated PARG as a target in PDAC models 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. PARGi synergized with DNA-damaging agents (i.e., oxaliplatin and 5-fluorouracil), but not with PARPi therapy. Mechanistically, combined PARGi and oxaliplatin treatment led to persistence of detrimental PARylation, increased expression of cleaved caspase-3, and increased γH2AX foci. In summary, these data validate PARG as a relevant target in PDAC and establish current therapies that synergize with PARGi. SIGNIFICANCE: PARG is a potential target in pancreatic cancer as a single-agent anticancer therapy or in combination with current standard of care. (©2019 American Association for Cancer Research.)
Databáze:	MEDLINE
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