TY - JOUR
T1 - Selective EGLN inhibition enables ablative radiotherapy and improves survival in unresectable pancreatic cancer
AU - Fujimoto, Tara N.
AU - Colbert, Lauren E.
AU - Huang, Yanqing
AU - Molkentine, Jessica M.
AU - Deorukhkar, Amit
AU - Baseler, Laura
AU - De La Cruz B., B.
AU - Yu, Meifang
AU - Lin, Daniel
AU - Gupta, Sonal
AU - Cabeceiras, Peter K.
AU - Kingsley, Charles V.
AU - Tailor, Ramesh C.
AU - Sawakuchi, Gabriel O.
AU - Koay, Eugene J.
AU - Piwnica-Worms, Helen
AU - Maitra, Anirban
AU - Taniguchi, Cullen M.
N1 - Funding Information:
C.M. Taniguchi reports receiving commercial research grant from Galera Therapeutics and is a consultant/advisory board member of Accuray. No potential conflicts of interest were disclosed by the other authors.
Funding Information:
We would like to acknowledge Ronald DePinho and Haoqiang Yang for their generous gift of KPC breeders for our colony. We thank Robert Bast and Joe Herman for their critical review of the data and manuscript. C.M. Taniguchi was supported by funding from the Cancer Prevention & Research Institute of Texas (CPRIT) grant RR140012, V Foundation (V2015-22), Sidney Kimmel Foundation, Sabin Family Foundation Fellowship, and the McNair Family Foundation. Additional funding sources that supported this work include National Cancer Institute of the NIH under award number R01CA207236 (to H. Piwnica-Worms). Support to M. de la Cruz Bonilla came from T32CA186892 and F31CA210631. This work was also supported by the NIH/NCI under award number P30CA016672 for use of the Small Animal Imaging Facility.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019
Y1 - 2019
N2 - When pancreatic cancer cannot be removed surgically, patients frequently experience morbidity and death from progression of their primary tumor. Radiation therapy (RT) cannot yet substitute for an operation because radiation causes fatal bleeding and ulceration of the nearby stomach and intestines before achieving tumor control. There are no FDA-approved medications that prevent or reduce radiationinduced gastrointestinal injury. Here, we overcome this fundamental problem of anatomy and biology with the use of the oral EGLN inhibitor FG-4592, which selectively protects the intestinal tract from radiation toxicity without protecting tumors. A total of 70 KPC mice with autochthonous pancreatic tumors received oral FG-4592 or vehicle control ± ablative RT to a cumulative 75 Gy administered in 15 daily fractions to a limited tumor field. Although ablative RT reduced complications from local tumor progression, fatal gastrointestinal bleeding was observed in 56%of mice that received high-dose RT with vehicle control. However, radiationinduced bleeding was completely ameliorated in mice that received high-dose RT with FG-4592 (0% bleeding, P < 0.0001 compared with vehicle). Furthermore, FG-4592 reduced epithelial apoptosis by half (P = 0.002) and increased intestinal microvessel density by 80%compared with vehicle controls. EGLN inhibition did not stimulate cancer growth, as treatment with FG-4592 alone, or overexpression of HIF2 within KPC tumors independently improved survival. Thus, we provide a proof of concept for the selective protection of the intestinal tract by the EGLN inhibition to enable ablative doses of cytotoxic therapy in unresectable pancreatic cancer by reducing untoward morbidity and death from radiation-induced gastrointestinal bleeding. Significance: Selective protection of the intestinal tract by EGLN inhibition enables potentially definitive doses of radiation therapy. This might allow radiation to be a surgical surrogate for unresectable pancreatic cancer.
AB - When pancreatic cancer cannot be removed surgically, patients frequently experience morbidity and death from progression of their primary tumor. Radiation therapy (RT) cannot yet substitute for an operation because radiation causes fatal bleeding and ulceration of the nearby stomach and intestines before achieving tumor control. There are no FDA-approved medications that prevent or reduce radiationinduced gastrointestinal injury. Here, we overcome this fundamental problem of anatomy and biology with the use of the oral EGLN inhibitor FG-4592, which selectively protects the intestinal tract from radiation toxicity without protecting tumors. A total of 70 KPC mice with autochthonous pancreatic tumors received oral FG-4592 or vehicle control ± ablative RT to a cumulative 75 Gy administered in 15 daily fractions to a limited tumor field. Although ablative RT reduced complications from local tumor progression, fatal gastrointestinal bleeding was observed in 56%of mice that received high-dose RT with vehicle control. However, radiationinduced bleeding was completely ameliorated in mice that received high-dose RT with FG-4592 (0% bleeding, P < 0.0001 compared with vehicle). Furthermore, FG-4592 reduced epithelial apoptosis by half (P = 0.002) and increased intestinal microvessel density by 80%compared with vehicle controls. EGLN inhibition did not stimulate cancer growth, as treatment with FG-4592 alone, or overexpression of HIF2 within KPC tumors independently improved survival. Thus, we provide a proof of concept for the selective protection of the intestinal tract by the EGLN inhibition to enable ablative doses of cytotoxic therapy in unresectable pancreatic cancer by reducing untoward morbidity and death from radiation-induced gastrointestinal bleeding. Significance: Selective protection of the intestinal tract by EGLN inhibition enables potentially definitive doses of radiation therapy. This might allow radiation to be a surgical surrogate for unresectable pancreatic cancer.
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U2 - 10.1158/0008-5472.CAN-18-1785
DO - 10.1158/0008-5472.CAN-18-1785
M3 - Article
C2 - 31043430
AN - SCOPUS:85065532231
SN - 0008-5472
VL - 79
SP - 2327
EP - 2338
JO - Cancer research
JF - Cancer research
IS - 9
ER -