New target identified to overcome resistance in neuroendocrine tumors

Neuroendocrine cells are unique in their ability to act both as nerve cells and hormone-making cells.

They're scattered throughout the body, including the stomach, intestines, pancreas and lungs.

Tumors that arise from these cells are called neuroendocrine tumors and are often rare and slow growing.

Around 70% of all neuroendocrine tumors arise in the pancreas or gastrointestinal tract and are known as gastroenteropancreatic neuroendocrine tumors, or GEP-NETs.

Targeting these tumors is often challenging because cells become resistant to treatment.

In a recent study, University of Michigan researchers have identified a new target that can suppress tumor growth.

Their findings may lead to new treatment methods for GEP-NETs.

The typical treatment for GEP-NETs involves targeting mTOR, which controls protein and lipid synthesis.

Inhibiting mTOR, through the medication everolimus, slows down tumor growth but does not kill the cells.

Therefore, patients respond to treatment only for a short period of time before developing resistance.

In the present study, the team screened for cell pathways that can target GEP-NETs.

They found that PIKfyve, a therapeutic target in prostate, pancreatic and breast cancer, is also important in GEP-NETs.

"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 researchers confirmed that inhibiting PIKfyve reduced tumor volume and weight compared to the control.

They found that PIKfyve controls the cell's 'cleanup' process, called autophagy, where cellular components are recycled to help cells survive.

As a result, PIKfyve also influenced lipid synthesis, but through a different pathway when compared to mTOR.

The researchers found that when both PIKfyve and mTOR were targeted in pancreatic neuroendocrine tumor models, the mice had fewer tumors and survived longer compared to the controls or targeting only one of the pathways.

Although PIKfyve has been identified as a target in other tumors, there are no FDA-approved PIKfyve inhibitors.

The researchers are hoping that ESK981, a PIKfyve inhibitor that is currently being as a phase 2 drug in the Rogel Cancer Center, can eventually be used in combination with mTOR inhibitors.

"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, of course, will be to evaluate this approach in patients with gastroenteropancreatic neuroendocrine tumors."