Selective EGLN Inhibition Enables Ablative Radiotherapy and Improves Survival in Unresectable Pancreatic Cancer
Selective EGLN Inhibition Enables Ablative Radiotherapy and Improves Survival in Unresectable Pancreatic Cancer
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DOI：
10.1158/0008-5472.can-18-1785
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发表时间：
2019-05-01
期刊：
影响因子：
11.2
通讯作者：
Taniguchi, Cullen M.
中科院分区：
文献类型：
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作者：
Fujimoto, Tara N.;Colbert, Lauren E.;Taniguchi, Cullen M.
当胰腺癌不能手术切除时，患者经常因原发肿瘤的进展而发病和死亡。放射治疗（RT）还不能代替手术，因为在达到肿瘤控制之前，放射会导致附近的胃和肠的致命出血和溃疡。目前还没有fda批准的药物可以预防或减少辐射引起的胃肠道损伤。在这里，我们通过使用口服EGLN抑制剂FG-4592克服了解剖学和生物学的这个基本问题，它选择性地保护肠道免受辐射毒性而不保护肿瘤。共有70只患有原发性胰腺肿瘤的KPC小鼠接受口服FG-4592或对照对照+/-消融放疗，累计75 Gy，分15次每日给药到有限的肿瘤区域。尽管消融性放射治疗减少了局部肿瘤进展的并发症，但56%接受高剂量放射治疗的小鼠出现了致命性胃肠道出血。然而，在接受FG-4592高剂量放疗的小鼠中，辐射引起的出血完全改善（0%出血，与对照组相比P < 0.0001）。此外，与对照相比，FG-4592使上皮细胞凋亡减少一半（P = 0.002），肠道微血管密度增加80%。EGLN抑制不会刺激肿瘤生长，因为单独使用FG-4592治疗或在KPC肿瘤中单独过表达HIF2可改善生存。因此，我们为EGLN抑制对肠道的选择性保护提供了一个概念证明，通过减少辐射引起的胃肠道出血导致的不良发病率和死亡，使不可切除胰腺癌的细胞毒性治疗消融剂量成为可能。意义：EGLN抑制对肠道的选择性保护使放射治疗的潜在确定剂量成为可能。这可能使放疗成为无法切除的胰腺癌的外科替代疗法。
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 radiation-induced 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, radiation-induced 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.