|Gregory David, Ph.D.|
|NYU School of Medicine|
Scrutinizing Cancer Cell Inflammation to Develop Therapies in Pancreatic Cancer
Pancreatic ductal adenocarcinoma (PDAC) is almost invariably a fatal disease. KRAS is the defining genetic lesion in PDAC, but the lack of KRAS-targeted therapies highlights the need for alternate treatment strategies.
PDAC exhibit pronounced inflammation from their earliest stages to advanced disease, and experimental studies point to an essential role for inflammation in PDAC initiation, progression, and maintenance. Dr. David’s team recently identified the transcriptional corepressor Sin3B protein as a critical mediator KRAS-driven PDAC, which acts as a master regulator of pro-inflammatory cytokine gene expression.
Based on these observations, Dr. David proposes to elucidate how specific chromatin modifiers, including Sin3B, connect the oncogenic signal to the induction of an inflammatory program, thus revealing novel opportunities for therapeutic intervention in PDAC and other inflammatory cancers.
Thanks to a better understanding of the molecular events that drive cancer initiation and progression, approaches to cancer therapy have begun to change dramatically in recent years. Classic chemotherapies aim at killing all proliferating cells, hoping that this will affect tumor cells to a higher extent than normal cells. By contrast, novel therapies are meant to specifically target tumor cells by identifying their inherent properties, and disrupting the biological pathways that are necessary for these cells to proliferate.
Cellular Senescence in a New Light
In the last year, Dr. David’s team made the surprising discovery that a process that was widely thought to prevent cancer progression, known as cellular senescence, was instead contributing to pancreatic cancer progression. Using unbiased approaches, they identified a key regulator of this process, whose expression promotes the generation of an inflamed milieu in the pancreas. This setting in turn further promotes cancer progression.
Dr. David’s project maintains that by targeting the processes that lead to this inflammation, and that his team has begun to identify, he could be able to intervene therapeutically to prevent pancreatic cancer progression.