Radiosensitizer for GEP-NETs (GI SPORE Alliance)

NETs are second most prevalent neoplasm of GI origin and SEER database confirms a 6 fold increase in its incidence over past four decades. Treatment options are limited and most patients with metastatic disease will succumb to their illness from cancer progression. Peptide receptor radionuclide therapy (PRRT) with radiolabeled somatostatin analogues has led to significant advancements in NET therapeutics and is now FDA approved for gastroenteropancreatic NETs. Despite promising median PFS benefit, most patient treated with PRRT will eventually progress. Moreover, PRRT has a modest ORR (17%), while PRRT is good for disease stabilization, there is a dire need for therapies which can cytoreduce the tumors and have better ORR. This is especially true for patients with bulky metastatic liver involvement or symptomatic functional syndrome (carcinoid syndrome). Lastly, with a recent upsurge in PRRT utilization, we are now seeing a significant hike in PRRT resistant patients. Our research efforts are focused on identifying mechanisms of radiation resistance in NET patients that receive PRRT treatment and develop novel radiosensitizing strategies for NET patients with metastatic disease. We focus on two innovative concepts that have not been previously described: 1) radiation resistance and recurrence is associated high DNA-PK expression in CD90high/ALDHA1high stem cell population 2) DNA repair mechanisms inhibition with DNA-PK inhibitor M-3814 and RNR inhibitor, Triapine, in combination with radiation therapy will restore radiosensitivity in NET tumors. Our work will further define the critical role and function of DNA repair mechanisms and its role in CD90high/ALDHA1high cell population survival after radiation therapy. The outcomes of our studies have the potential to identify unique vulnerabilities that can define mechanistically the novel role and function of DNA-PK, and the possibility of providing novel strategies to improve radiation therapy outcomes in patients with metastatic NET. Currently two multi-center Phase I clinical trials utilizing DNA PKi and RNR as radiation sensitizers for PRRT in NETs have been sanctioned by NCI CTEP with Markey as the lead site (NCT04234568). Our pre-clinical work complements our ongoing clinical research and will help us not only understand the mechanism of radiation resistance in our patients but will help fine tune subsequent Phase II studies with these agents.