Thursday, May 9, 2013
A new study from the Moldovan laboratory offers preclinical proof-of-concept for a novel candidate therapeutic target to treat this deadly disease. The study, published in April 15 in the journal “Cancer Research” shows that an element of the homologous recombination pathway of DNA repair, the PARP-binding protein C12orf48/PARI (PARPBP), is overexpressed specifically in pancreatic cancer cells where it is an appealing candidate for targeted therapy. PARI upregulation in pancreatic cancer cells or avian DT40 cells conferred DNA repair deficiency and genomic instability. Significantly, PARI silencing compromised cancer cell proliferation in vitro, leading to cell-cycle alterations associated with S-phase delay, perturbed DNA replication, and activation of the DNA damage response pathway in the absence of DNA damage stimuli. Conversely, PARI overexpression produced tolerance to DNA damage by promoting replication of damaged DNA. In a mouse xenograft model of pancreatic cancer, PARI silencing was sufficient to reduce pancreatic tumor growth in vivo. Taken together, these findings offered a preclinical proof-of-concept for PARI as candidate therapeutic target to treat PDAC.
O’Connor KW, Dejsuphong D, Park E, Nicolae CM, Kimmelman AC, D’Andrea AD, Moldovan GL. PARI Overexpression Promotes Genomic Instability and Pancreatic Tumorigenesis. Cancer Res. 73(8):2529-39. doi: 10.1158/0008-5472.CAN-12-3313.