Project title: Deciphering and Potentiating Intrinsic Radiosensitivity of Pancreatic Neuroendocrine Tumors

Dr. Xavier M. Keutgen will explore increased radiosensitivity (the level of tumor cell death following exposure to radiation therapy) of a certain subset of pancreatic neuroendocrine tumors to improve current therapies for these tumors.

What problem/questions will researchers try to answer?

Neuroendocrine tumors (NETs) respond differently to radiation therapy. For example, certain therapies like peptide receptor nucleotide therapy (PRRT) work well on some tumors but not on others. It is estimated that half of all pancreatic NETs treated with PRRT experience tumor shrinkage compared to less than 30% of other neuroendocrine tumor types. Dr. Keutgen will study why a subset of pancreatic NETs are more radiosensitive and exploit this tumor weakness to improve PRRT response.

Why is this important?

Understanding why certain NETs are more radiosensitive than others will allow us to predict which patients would benefit most from certain radiation therapies, to improve PRRT response rates and/or its effectiveness in combination with other NET drug treatments.

What will researchers do?

Dr. Keutgen will aim to decipher whether a certain mutation (change in the tumor’s genetic code) found in pancreatic NETs is responsible for an increase in radiosensitivity of pancreatic NETs. He will study how these tumors repair DNA damage after radiation exposure and combine PRRT with DNA repair inhibitors to assess whether tumors with a particular mutation respond better to radiation therapy.

How might this improve treatment of NETs?

PRRT response rates could be improved not just for pancreatic NETs but also for other neuroendocrine tumor types by understanding what makes certain neuroendocrine tumors more sensitive to radiation therapy.

What is the next step?

Dr. Keutgen will explore how a certain mutation affects DNA repair in pancreatic NETs by studying how proteins interact with each other in this repair mechanism. He will then combine PRRT with DNA repair inhibitors in a mouse model of pancreatic NETs and assess whether this combination therapy is superior to PRRT alone.

Outcomes:

With the support of the NANETS BTSI grant, we discovered that a commonly found DNA mutation in the MEN1 gene is responsible for at least part of the increased response rates after radiation of PanNETs. We observed that MEN1 mutations affect the DNA repair machinery of tumor cells, which is integral to tumor cells if they want to survive damage that radiation usually causes.

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