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.

Outcomes:

In 2011, the United States FDA first approved the use of everolimus (brand name Afinitor) to treat patients with progressive neuroendocrine tumors located in the pancreas (PanNETs) that cannot be removed by surgery or that have metastasized. Everolimus is a drug that 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 with 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. To improve upon this, we need a much better understanding of what aberrant mTORC1 signaling does to promote PanNET growth and the mechanism by which tumor cells are able “rewire” their signaling networks to ultimately resist the effects of turning it “OFF” through everolimus.

Over the course of this project, we have made several discoveries and new tools to answer this question.

First, we have confirmed our discovery that mTORC1 signaling in PanNETs turns on the cellular machinery to make unusually high amounts of protein building blocks (called amino acids) and have evidence that this is necessary for PanNET growth.

Second, we find that drugs that shut “OFF” this overproduction of amino acids halt PanNET cell growth and sensitize them to everolimus.

Third, by growing them in clinically relevant concentrations of everolimus, we made two different human PanNET cell lines that are resistant to effects of everolimus. We have profiled these resistant cells and have early evidence that they may utilize a new pathway way to turn the overproduction of amino acids back on. We are currently testing whether blocking this pathway will re-sensitize them to everolimus.

Our results suggest that a combination of a drugs that block both overproduction of amino acids and mTORC1 will be superior to either therapy alone. We propose to carefully test this idea in human PanNET cell lines and in mouse models that mimic advanced PanNETs. Our work has the potential to establish a new and more effective combination therapy for patients with advanced NETs.

Using these approaches, we have discovered two new potential drug targets in PanNETs—an amino acid transported called SLC1A5 and a poorly studied enzyme called RTCB. We are carrying out many follow-up studies to determine the potential benefits of targeting these players in PanNET models.

To better understand how widely expressed our new candidate targets are in human PanNETs, we recently constructed a tumor microarray (TMA) of ~40 samples of normal and PanNET tissue from patients. By placing a section of the TMA on a glass slide, we can now stain all 40 biopsies simultaneously for the protein of our choice. We expect that this will greatly speed up our efforts to find relevant targets for human PanNETs.

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