Targeting SHP2 - Stand Up To Cancer

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Pancreatic Cancer Collective Research Team:
Targeting SHP2 in Pancreatic Cancer New Therapies Challenge

Grant Terms
Round 1: November 2018–December 2019
Round 2: January 2020–December 2022

The team is studying whether inhibiting cellular processes in pancreatic tumors can stop the out-of-control growth that is characteristic of cancer. Pancreatic cancers with mutations in the KRAS gene are weakened when a protein called SHP2 is blocked in the RAS pathway—a cellular pathway that may be essential to the growth of pancreatic cancer cells. Another means to block this pathway involves a protein called MEK. In Round 1 pre-clinical work, the team has shown that inhibiting both of these components, they can better control growth of pancreatic cancertumors. In Round 2, the team will test the combination in a phase 1/1b clinical trial to better understand how this double inhibition works and to inform continued clinical trials.

ABOUT THIS TEAM’S RESEARCH

More than 90% of pancreatic tumors carry a mutation in the KRAS oncogene. The RAS pathway may be essential to promote the growth of pancreatic cancerous cells. This pathway helps transmit proliferation-promoting signals from the cell’s surface receptors toward the nucleus, where these signals affect the regulation of other key genes that instruct the cell to divide. Mutant RAS genes become more active in signaling, and therefore keep pushing the cell toward uncontrolled proliferation. So far, no targeted therapies are clinically available against the active protein encoded by the mutant RAS gene.

The team has discovered that tumors carrying an activating KRAS mutation are sensitive to the inhibition of SHP2, a protein that helps the transmission of the growth-promoting signal from the cell surface receptors. Moreover, the team has found that SHP2 inhibitors cooperate with inhibitors of MEK, a key RAS downstream effector, to achieve better control of tumor growth. Given these findings, the researchers are studying a combination of SHP2 inhibitors and MEK inhibitors for the treatment of KRAS-mutant pancreatic cancer patients.

This team is part of the Pancreatic Cancer Collective, an initiative of the Lustgarten Foundation for Pancreatic Cancer Research and Stand Up To Cancer.

SEE SCIENTIFIC ABSTRACT

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