Abstract
Abstract Introduction: When pancreatic cancer cannot be removed by surgery, radiation can be used to approximate a resection. Unfortunately, conventional radiation therapy cannot achieve ablative doses in the pancreas due to potential radiotoxicity to the nearby intestinal tissues. Thus, treatment-related gastrointestinal (GI) toxicity may be the most significant barrier to improving treatment responses for unresectable pancreatic cancer. There are no medications that can selectively protect the intestine from radiation damage, but we previously demonstrated that the genetic or pharmacologic inhibition of the EGLN prolyl hydroxylases protects murine intestines from radiation injury. To translate these findings to patients, we sought to test the EGLN inhibitor, FG-4592, and its mechanism of selective radioprotection in patient-derived intestinal organoids (also known as enteroids or mini-guts). Methods: The patient-derived enteroids (PDEs) were grown from duodenal tissue of non-oncologic patients, embedded in Matrigel, and cultured in media impregnated with essential growth factors. These PDEs have the capacity to recapitulate the full array of intestinal cells that are present in the crypt-villus axis. We first treated PDEs with FG-4592 then irradiation at 24 hours followed by RT-qPCR at 72 hrs post-exposure to gauge the effects of radiation on markers associated with intestinal stem cells (ISCs) and differentiated epithelial cells. Single cell RNA seq techniques were used to identify shifts in cellular populations FG-4592 and/or radiation treatment of human enteroids. Results: Irradiation produced a signature of enhanced Crypt Base Columnar (CBC) cells and +4 quiescent stem cells markers (Bmi1, Tert, Dclk1) suggesting these specialized cells awaken upon crypt damage and start to proliferate to restore the ISC pool. The +4 cell markers are further enhanced in FG-4592 treated irradiated group, suggesting EGLN inhibition leads to activation of these specialized cell population along with restoration of other intestinal cells like secretory progenitors and Paneth cells. Further, gene set enrichment analysis after FG-4592 treatment showed the activation of key pathways involved in proliferation, maintaining homeostasis, metabolism, and DNA repair that could lead to intestinal proliferation and recovery from radiation damage. Conclusion: Taken together, these preliminary data suggest that HIF stabilization by FG-4592 upregulates the normally quiescent +4 stem cells, a radioresistant stem population historically thought to become active upon radiation injury, along with activation of several other pathways required for normal proliferation and recovery from radiation injury. Our study justifies further exploration in clinical trials as a radioprotective or radio mitigative agent. Citation Format: Neeraj Kumari, Maya Ferrell, Carolina G. Garcia, Cullen M. Taniguchi. Exploring the hypoxia pathway for gastrointestinal radioprotection in human minigut model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1107.
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