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Targeting the "BRCAness" Phenotype in Pancreas Cancer

Milind Javle

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University of Texas MD Anderson Cancer Center
The 5-year survival of pancreatic ductal adenocarcinoma (PDAC) is <5%. About 5% of PDAC cases are associated with BRCA mutations. BRCA mutations lead to homologous recombination repair deficiency (HRD), making these cancers susceptible to PARP-inhibition. Additional 10% have family history of BRCA-associated cancers in the absence of BRCA mutation. These cases have phenotypic similarity to BRCA mutated cases [family history, prognosis and cisplatin sensitivity] and are referred to as having ‘BRCAness’. ATM loss occurs in 25% of familial PDAC. Peng et al, used gene expression profiling to identify 230 genes contributing to the HRD signature, which may predict sensitivity to PARP-1 inhibitors. Our collaborators have developed the Data-mining synthetic-lethality-identification pipeline (DAISY) to identify synthetic lethal partners of target genes, including PARP-1. This platform uses gene expression data to predict synthetic lethal and dosage lethal effects. They have also developed an ex-vivo PDAC model to study the effect of targeted inhibition.

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