Targeting Therapeutically Relevant Vulnerabilities Induced by Pancreatic Ductal Adenocarcinoma Genetics and Microenvironment

Jefferson Digital Commons 2019-01-01T08:00:00Z

Modern medicine has provided miraculous advances in effectively treating cancers that were previously a death sentence. In point of fact, lung cancer, breast cancer, melanoma, leukemia, and prostate cancer, among others, have seen significant improved in patient outcomes. One of the cancers that has not benefited from these advancements is pancreatic ductal adenocarcinoma (PDAC). Less than 10% of PDAC patients survive for five years after diagnosis, partly due to a lack of early detection strategies, while in diseases such as breast cancer early detection has vastly enhanced patient outcomes. PDAC has been underfunded and understudied; for instance, among the 73 cancer cell lines that encompass the NCI60 library of cell lines, no lines are derived from PDAC. Moreover, standard chemotherapeutics, targeted therapeutics, and even novel immune checkpoint therapies, have failed to improve outcomes in the vast majority of PDAC patients. Moving forward, we posit that the field is in desperate need of novel therapeutics that account for PDAC’s genetic makeup and its unique tumor microenvironment. The most common genetic defect in PDAC cells is the loss of p16 (which is caused by either a mutation or promoter hypermethylation in 98% of PDAC cases). This near ubiquitous PDAC mutation is targetable. Normally p16 acts to inhibit the cell cycle by inhibiting CDK4/6, and cells with a loss of p16 become dependent on the aberrant and constitutive activation of this pathway. CDK4/6 inhibitors which inhibit this pathway have been found to have increased efficacy in patients with p16 pathway alterations. We have demonstrated the activity of the potent CDK4/6 inhibitor abemaciclib both in vitro (where we demonstrated abemaciclib caused both senescence and apoptosis) and in vivo. Daily treatment in vivo not only caused a decrease in tumor growth (3.2 fold reduction), but also caused a reduction in Ki67 staining, phosphorylated retinoblastoma protein staining, and an increase in TUNNEL s

Cellular biology|Biochemistry|Biology; text

ENG

TVJ oai:jdc.jefferson.edu:dissertations-1475
1363134185

THOMAS JEFFERSON UNIV
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