Lindeberger Comprehensive Cancer Center
University of North Carolina at Chapel Hill
Kirsten L. Bryant, PhD (PI), is Res. Assistant Professor in the Department of Pharmacology. Her work focuses on the relatively unexplored mechanisms by which the KRAS oncogene drives the altered metabolic processes that fuel pancreatic cancer growth. She performed her postdoctoral studies in the laboratory of Dr. Channing Der at the University of North Carolina at Chapel Hill (UNC-Chapel Hill).
“Identification of novel signaling nodes for autophagy inhibition”
Mutational activation of the KRAS oncogene is found in ~95% of pancreatic ductal adenocarcinoma (PDAC) and KRAS is an essential driver of this disease. The crucial role of KRAS is mediated, in part, by its deregulation of metabolic processes that support the increased energy needs of cancer cells. One such metabolic process is autophagy, which is a means of “self-eating” to fuel cancer growth.
Our findings led to the initiation of our Phase I clinical trial evaluating the MEK inhibitor binimetinib (MEKi), and our Phase II trial evaluating the ERK inhibitor LY3214996 (ERKi), combined with HCQ (NCT04132505 and NCT04386057). These clinical trials will provide a more rigorous assessment of the efficacy of MEKi/ERKi plus HCQ for pancreatic cancers. HCQ is the only clinical autophagy inhibitor yet is limited in both potency and selectivity. Thus, we aim to develop improved anti-autophagy therapeutics. Our preliminary data suggests that a lipid kinase in the endocytic pathway may be a potential target for autophagy inhibition. Our first aim is focused on validating this target. In our second aim, we propose an autophagy specific CRISPR/Cas9 genetic loss-of-function screen, to identify autophagy genes that are most essential for PDAC cell viability.
Read the December 2020 Research Update here.