Project title: Radiosensitizing NETs: a two-pronged approach using ERa and Pin1 inhibition
Xavier M. Keutgen, MD University of Chicago
- Status: Active
- Year(s): 2022
- Grant Type: Investigator
- Research Type: Basic
- Primary Tumor Site: Multiple
- Area of Inquiry: DNA Repair
Description
Dr. Keutgen’s research project focuses on understanding the unique components of DNA repair in neuroendocrine tumor (NET) cells. More specifically, Dr. Keutgen and his colleagues will investigate how estrogen receptor alpha (ERa) and the enzyme Peptidyl-prolyl cis-trans isomerase (Pin1) interact to modulate DNA repair response to radiation therapies like peptide receptor radionuclide therapy (PRRT).
What critical NET problem/question will researchers try to answer?
Understanding how NET cells repair their DNA defects is crucial to identify new therapeutic targets and improve the response rates to radiation therapies like PRRT. Inhibiting tumor cells’ ability to repair the DNA defects caused by radiation may induce greater cell death and thus enhanced and prolonged tumor shrinkage. In addition, finding therapies that have no or little side effects will greatly increase the chances they will be used in the clinics in combination with PRRT.
Why is this important?
Response rates for patients who have metastatic NET and receive radiation therapies like PRRT are sub-optimal at best. Most patients’ cancer may recur within a few years of treatment. Therefore, understanding how to enhance PRRT efficacy (by inhibiting DNA repair of NET cells) could greatly benefit most patients who receive this therapy.
What will the researchers do?
Dr. Keutgen and his colleagues will study how ERa and Pin1 affect DNA repair in NET cells and whether inhibition with Fulvestrant (a estrogen receptor inhibitor used for the treatment of breast cancer) and/or ATRA (a vitamin A metabolite) increases the effects of radiation therapy in NET cells. These results will then be validated in a newly developed metastatic mouse model.
How might this improve treatment of NETs?
Both Fulvestrant and ATRA are well-tolerated drugs with few side effects. If Dr. Keutgen and his team confirm that these drugs radiosensitize NET cells, the drugs could be combined with PRRT and other radiation therapies to enhance tumor shrinkage and prolong patient survival.
What is the next step?
Dr. Keutgen will first aim to understand how ERa and Pin1 interact to repair DNA in different NET cell lines (pancreas, lung and small bowel NET cells) and use inhibitors to study their effects alone and in combination with radiation, including PRRT.
Additional Details
- City: Chicago
- State: Illinois
- Country: United States
- Grant Duration: 2 years
DISCLAIMER
NETRF funds laboratory research to understand the development of neuroendocrine tumors and translational research to explore new concepts in treatment. Research grant descriptions and research updates from NETRF are not intended to serve as medical advice. It can take years for research discoveries to be fully validated and approved for patient care. Always consult your health care providers about your treatment options.