Xavier M. Keutgen, MD, FACS
Assistant Professor, Department of Surgery, University of Chicago
The role of MEN1 loss of function and Estrogen Receptor α inhibition in radiosensitizing Pancreatic Neuroendocrine Tumors
Why do only a subset of Pancreatic Neuroendocrine Tumors respond to radiation and can we use estrogen receptor blockers to improve radiation response in these tumors?
Pancreatic Neuroendocrine tumors (PanNETs) are a deadly form of pancreatic cancer; these cancers are uncommon, but their incidence is steadily increasing. Unlike most neuroendocrine tumors, previous research has shown that roughly 50% of PanNETs respond well to radiation. Dr. Keutgen has recently discovered that a commonly found DNA mutation in the MEN1 gene in PanNet tumor cells is responsible for at least part of the increased response rates to radiation. MEN1 is related to DNA repair, which is how some tumor cells survive the damage that radiation therapy inflicts on cancer cells. Dr. Keutgen hopes to better understand how the MEN1 gene affects DNA repair and thus how MEN1 mutations make PanNETs more radiosensitive. MEN1 mutations also might prove to be a useful identifier of those tumors that are likely to respond to radiotherapy. Directly connecting MEN1 mutations to radiosensitivity could allow clinicians to better identify other neuroendocrine tumors that might be treated with radiation.
Dr. Keutgen hypothesizes that a specific protein, called ESR1 (or Estrogen Receptor α) is necessary for MEN1 to repair DNA after radiation damage and that when there are mutations in the MEN1 gene, there is not enough ESR1 to allow cancer cells to repair their DNA and resist radiotherapy. He suspects that by inhibiting this protein, he can recreate the inability to repair the DNA damage that radiotherapy uses to kill cancer cells and thus make PanNets more vulnerable to radiotherapy. Additionally, he has a drug in mind to block ESR1 that is already safely in use against other cancers. Dr. Keutgen will use his CRF Young Investigator Award to determine how ESR1 works to help MEN1 repair cancer cell DNA and whether blocking ESR1 might be a target for therapies to make radiation more effective in PanNets and potentially other neuroendocrine tumors.