Project title: mTORC1 Signaling Drives Amino Acid Biosynthesis to Promote PanNET Growth

Description

Approved for patients with advanced pancreatic neuroendocrine tumors (PanNETs), the mTORC1 inhibitor everolimus generally results in tumor control benefits that are short-lived. Through his research program Dr. Oakes aims to understand how mTORC1 signaling promotes PanNET growth, uncover mechanisms that allow the tumors to circumvent mTORC1 inhibition, and use this knowledge to design novel strategies to improve the effectiveness and durability of mTORC1 inhibition in this disease. 

What critical NET problem/question will researchers try to answer?

In 2011, the Food and Drug Administration approved the use of everolimus (brand name Afinitor) to treat patients who have progressive neuroendocrine tumors in the pancreas (PanNETs) that cannot be removed by surgery or that have metastasized. Everolimus blocks an important growth signaling protein in the tumor cells called mTORC1, which is inappropriately turned “on” in PanNET cells and tells them to grow. While many patients who have PanNETs initially respond to everolimus, its benefits are often short-lived, as the tumors eventually become resistant to the drug for reasons that remain poorly understood. 

Why is this important?

A better understanding of what mTORC1 signaling does to promote PanNET growth and how the tumor cells are able to “rewire” their signaling networks is needed to ultimately resist the effects of turning it “off” through everolimus.

What will the researchers do?

The Oakes laboratory recently discovered that mTORC1 signaling in PanNETs turns on the cellular machinery to make unusually high amounts of protein building blocks (called amino acids) necessary for PanNET growth. They also found that drugs that shut “off” this overproduction of amino acids halt PanNET cell growth and sensitize them to everolimus. Their results suggest that a combination of drugs that block both the overproduction of amino acids and mTORC1 will be superior to either therapy alone. They propose to carefully test this idea in human PanNET cell lines and in mouse models that mimic advanced PanNETs. 

How might this improve treatment of NETs?

This work has the potential to establish a new and more effective combination therapy for patients who have advanced neuroendocrine tumors. 

What is the next step?

If successful in preclinical studies, these results could quickly translate into a clinical trial of this combination in patients who have PanNETs.

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