Dr. O’Bryan will discuss using Monobody technology to identify critical allosteric regions important for wild type and mutant RAS activity. His research is revealing new complexities of RAS signaling in addition to identifying new regions of RAS that can be targeted by small molecule inhibitors.

Inhibiting the ERK MAPK pathway or autophagy alone has been ineffective in treating KRAS driven pancreatic cancer. Dr. Bryant’s research revealed that inhibiting ERK creates an unappreciated metabolic vulnerability – increased dependence on autophagic flux, which can be exploited with combination therapy of MEK or ERK inhibitors and chloroquine, an inhibitor of lysosomal acidification. This potential new approach to treating pancreatic cancer and is currently being evaluated in clinical trials. The Bryant Lab’s current work is aimed at determining additional sensitizers to anti-autophagy therapies, as well as new inhibitors of the autophagy pathway.

Dr. Leopold will discuss a drug development strategy to target two oncogenic drivers, EGFR and PI3K, implicated in resistance of KRAS mutant tumors to molecular targeted therapies. Her research has identified a small molecule approach to selectively impair signaling of both of these critical kinases in a single molecule to render KRAS mutant cancers sensitive to MEK inhibition. MTX-211, a rationally designed first-in-class highly selective dual inhibitor of PI3K and EGFR kinases, has been shown to attack KRAS oncogenic signaling.

Dr. Ruscetti will discuss his previous and ongoing research characterizing a new approach to treating K-RAS dependent pancreatic cancer: targeting MEK and CDK4/6 simultaneously. Inhibiting both pathways not only suppresses pancreatic cancer cell proliferation but also induces changes in the tumor microenvironment through a process called cellular senescence that lead to new susceptibilities to existing chemo- and immunotherapy regimens. He will touch on his recent work investigating the intrinsic and extrinsic regulation of senescence and ways to harness its ability to remodel tumor microenvironments to overcome immune suppression and potentiate immunotherapy in pancreas cancer and other RAS-driven malignancies.