Abstract A22: Preclinical evaluation of Bmi1 inhibition in pancreatic ductal adenocarcinoma

Pancreatic Ductal Adenocarcinoma (PDA) is the fourth leading cause of cancer-related deaths in the United States with a five-year survival rate of 6% and a rising mortality rate. The majority of patients present with advanced disease that is unresponsive to chemotherapy, highlighting the need for novel therapeutic strategies. Bmi1, a member of the Polycomb Group (PcG) family of transcriptional repressors, is known to be upregulated in PDA beginning in early pre-malignancy. Elevated Bmi1 expression in pancreatic tumors has been shown to correlate with poor prognosis, increased metastasis, and chemotherapy resistance in patients. Additionally, a recent study found Bmi1 to be required for pancreatic neoplasia in a murine model of PDA. Together, these data support the hypothesis that Bmi1 promotes the growth and survival of pancreatic tumors, suggesting it may be a novel therapeutic target.Bmi1 is a critical member of the PcG PRC1 complex, where it interacts with E3 ligase Ring1B in a dose-dependent manner to promote mono-ubiquitination of H2AK119, a histone modification that results in repression of gene expression. Among the best-characterized functions of Bmi1 is its negative regulation of the cdkn2a locus, which encodes two tumor suppressor proteins and cell cycle regulators, p16Ink4a and p14Arf. This is notable, as p16Ink4a is inactivated in most pancreatic tumors, often through epigenetic mechanisms. More recently, Bmi1 was found to have an additional role in G2/M checkpoin...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Managing G2/M Control: Poster Presentations - Proffered Abstracts Source Type: research