Ann Arbor, MI, April 08: Researchers at the University of Michigan have identified a promising new target for treating gastroenteropancreatic neuroendocrine tumors (GEP-NETs), a rare type of tumor that arises in the pancreas or gastrointestinal tract. The discovery may pave the way for more effective therapies that overcome treatment resistance.
Neuroendocrine tumors are often slow-growing and difficult to treat, with current therapies targeting the mTOR pathway using drugs like everolimus. While mTOR inhibition slows tumor growth, it does not kill tumor cells, and patients often develop resistance.
In the new study, researchers screened cell pathways to identify alternative therapeutic targets and discovered that PIKfyve, a protein previously linked to prostate, pancreatic, and breast cancers, plays a key role in GEP-NET survival and growth.
“PIKfyve was present in higher levels in GEP-NETs compared to the normal surrounding tissues,” said Yuanyuan Qiao, Ph.D., Research Assistant Professor of Translational Pathology. “That suggested PIKfyve has a role in either promoting GEP-NET survival or growth.”
Using tumor models, the team confirmed that inhibiting PIKfyve reduced tumor volume and weight, demonstrating its critical role in tumor maintenance. PIKfyve influences autophagy, the cellular ‘cleanup’ process that helps tumor cells survive, and also affects lipid synthesis through a pathway distinct from mTOR.
Importantly, when both PIKfyve and mTOR were co-targeted in pancreatic neuroendocrine tumor models, mice exhibited fewer tumors and longer survival compared to targeting either pathway alone.
Currently, there are no FDA-approved PIKfyve inhibitors, but researchers are hopeful about ESK981, a PIKfyve inhibitor under phase 2 clinical trials at the Rogel Cancer Center, which could potentially be combined with mTOR inhibitors for enhanced therapeutic effect.
“By co-targeting these complementary mechanisms, we can transform a largely growth-suppressive therapy into one that more effectively drives tumor cell death, offering a promising new strategy to overcome treatment resistance,” said Arul Chinnaiyan, M.D., Ph.D., S. P. Hicks Endowed Professor of Pathology.
The next step for the research team is to evaluate this approach in patients with GEP-NETs, potentially opening a new frontier in the treatment of these challenging tumors.
