Abstract 979: EGLN inhibition reduces gastrointestinal radiation toxicity and improves survival in a murine model of locally advanced pancreatic cancer
Authors: Taniguchi Cullen M. , Fujimoto Tara N. , Colbert Lauren E. , Moilkentine Jessica M. , Deorukhkar Amit , Baseler Laura J. , Tailor Ramesh , Sawakuchi Gabriel O. 
Published: August 2018

Rationale: Pancreatic cancer is almost always fatal since chemotherapy is only modestly effective and surgery is often not possible. Radiation therapy (RT) can be a definitive treatment in localized pancreatic cancer, but gastrointestinal toxicity to the nearby duodenum limits its efficacy. There are no known medications that can prevent or treat this gastrointestinal radiotoxicity, but we find that FG-4592, a small molecule inhibitor of EGLN proteins, reduces radiation damage to the intestines by selectively enhancing HIF expression within normal intestines but not within tumors.

Methods: We developed a murine model of spontaneous pancreatic cancer (KrasLSL/+; Trp53FL/+; Ptf1aCre/+) that behaves similarly to locally advanced disease. KPC mice were screened for tumors by weekly ultrasounds and upon diagnosis were sequentially assigned to receive one of four possible treatments: Vehicle only (VEH), FG-4592 (FG), RT concurrent with vehicle (RT+VEH), or RT concurrent with FG-4592 (RT+FG). Mice were enrolled on a rolling basis and the total time from diagnosis to treatment end was approximately three weeks. Radiation treatments were planned to administer a total of 75Gy in 15 daily fractions.

Results: A total of 70 KPC mice were evaluated. The administration of high-dose radiation therapy of &gt;65Gy (high-dose) with or without radioprotection improved survival compared to all animals that received ≤65Gy (low-dose) of treatment or no RT (37 days [95% CI 33-41] vs. 15 days [10-21] vs. 15 days [10-20], respectively; p=0.005). KPC animals that received dose-escalated radiation lived significantly longer compared to unirradiated controls that received vehicle or FG-4592 alone. The median overall survival was compared amongst the treatment groups and was highest (p&lt;.001) for mice that received RT with FG-4592 for radioprotection (43 days, [95% CI 39-47]) versus RT with vehicle (36 days, [95% CI 10-62]), FG alone (29 days, [95% CI 21-37]), or vehicle alone (9 days, [95% CI 5-13]). High-dose RT reduced death from local progression as determined by reduced jaundice and obstruction on necropsy which was present in 64% (25/39) of mice who did not receive RT versus 0% (0/29) who received RT with or without radioprotection (p=0.02). The addition of FG-4592 to RT further improved survival compared to RT + vehicle controls by eliminating radiation-induced gastrointestinal toxicity. Approximately 56% (5/9) of animals that received high-dose RT without radioprotection died from fatal GI bleeding, whereas no bleeding was seen in animals who received high dose RT+ FG-4592 (P&lt;.0001). Thus, these experiments demonstrate a proof of concept that selective radioprotection of the intestinal tract by EGLN inhibition enables higher, and potentially curative, doses of cytotoxic therapy without any tumor protection.

Citation Format: Cullen M. Taniguchi, Tara N. Fujimoto, Lauren E. Colbert, Jessica M. Moilkentine, Amit Deorukhkar, Laura J. Baseler, Ramesh Tailor, Gabriel O. Sawakuchi. EGLN inhibition reduces gastrointestinal radiation toxicity and improves survival in a murine model of locally advanced pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 979.