Project title: Discovering new inhibitors of pancreatic NET glucose consumption

Description 

Clark and his team will work to identify compounds that selectively target elevated sugar consumption, a key metabolic vulnerability in pancreatic neuroendocrine tumors.

What question will you try to answer through your research?

Pancreatic NETs consume sugar at a much higher rate than surrounding healthy cells, and studies suggest that blocking this sugar consumption may reduce or stop tumor growth. However, healthy cells also need sugar and currently there is no way to block pancreatic NETS from consuming sugar without harming healthy cells. My study aims to identify compounds that selectively block sugar consumption in pancreatic NETs.

Why is this important?

It is important to find new ways to target aggressive pancreatic NETs while leaving healthy tissue unharmed. My team and I will explore possible compounds to selectively target sugar consumption in tumor cells. The same process that these compounds will block can be visualized non-invasively in patients with a type of PET scan. If these compounds reach clinical studies, we will know quickly whether the compounds are effective in blocking sugar consumption in aggressive tumor cells.

What will you do as part of this research project?

We will screen thousands of compounds to find those that decrease sugar consumption in pancreatic NET cells and then study whether these compounds also affect healthy cells. Once these compounds are identified, we will study how they affect the ability of pancreatic NET cells to grow and survive.

How might your research improve the treatment of NETs?

New treatments are needed for aggressive pancreatic NETs that are more effective and less toxic. Our study aims to identify one such treatment. Since this treatment strategy could be linked to a non-invasive imaging technique, the approach would also improve the way in which patients with pancreatic NETs are treated. Using the imaging technique, we may quickly tell whether a treatment is working, increasing the effectiveness of the treatment while limiting unnecessary side effects.

What is your next step?

If compounds blocking sugar consumption are found, we will test the compounds in more advanced preclinical models of pancreatic NETs before moving them into early clinical trials. An advantage of this approach is that many of the compounds we will test have been used to treat other diseases, so they are already known to have limited toxicities and can be readily repurposed to test in patients with pancreatic NETs.

Outcomes:

A defining feature of the most aggressive pancreatic neuroendocrine tumors is that they consume sugar faster than healthy cells in the body, and studies suggest that this represents an important vulnerability for these tumor cells. However healthy cells still need sugar, and figuring out how to target sugar consumption in the pancreatic neuroendocrine tumor cells without affecting the healthy cells has remained a challenge. We recently developed a way to test thousands of compounds all at once to find ones that might block sugar consumption selectively in the tumor cells and not the healthy cells. We tested thousands of drugs that are already FDA approved for the treatment of other diseases, and identified a handful that at least in pancreatic neuroendocrine tumor cell lines blocks their sugar consumption. We’re now trying to understand these compounds in more detail and test them in more advanced tumor models.

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