Translating Intestinal Radioprotection by EGLN Inhibition to Improve Clinical Outcomes in Unresectable Pancreatic Cancer

项目总结/摘要 胰腺癌几乎总是致命的，需要新的方法来改善胰腺癌的预后。 这种疾病现在是癌症相关死亡的第三大原因。胰腺癌不能治愈 不幸的是，近90%的患者存在不可切除的疾病（局部晚期）， + 转移性），一旦化疗完成，留给患者和临床医生的治疗选择非常少。 放射治疗不能代替手术，因为放射线对附近的胃有病态的毒性， 在肿瘤被控制之前发生的肠道。因此，治疗相关的胃肠道（GI）放射 毒性可能是改善不可切除胰腺癌治疗反应的最大障碍 癌目前还没有已知的药物可以选择性地保护胃和肠道免受这些疾病的侵害。 副作用，但我们以前发表的抑制信号通过EGLN蛋白减少辐射 灾难性辐射损伤模型中的损伤，现在我们建议在一个 临床相关系统。我们实验室的长期目标是开发减少后遗症的疗法， 在临床相关和潜在治愈性癌症治疗期间的辐射损伤。核心假设是 通过使用口服EGLN抑制剂FG-4592实现的EGLN酶的抑制将 选择性地保护肠道免受辐射毒性，而不保护肿瘤。的目的 格兰特是揭示一个更深入的了解如何EGLN信号轴调制辐射反应， 肠干细胞龛和胰腺肿瘤，以便安全地将这项技术转化为患者。 具体目的将检验以下假设：（目的1）EGLN抑制降低辐射毒性， 使立体定向放射治疗胰腺癌，这将提高生存率;（目的2）EGLN 抑制主要通过刺激+4肠干细胞起作用，这将通过谱系追踪进行测试。 报告小鼠实验;（目的3）FG-4592将选择性地保护人体肠道组织免受辐射 但不是人类胰腺癌。这项研究具有重要意义，因为FG-4592具有 已完成非肿瘤适应症的III期临床试验，因此可作为 辐射防护剂。这种方法可以用来潜在地取代手术与放射治疗的患者， 不可切除的胰腺癌，并作为未来5年临床试验的基础。本研究是 创新，因为它采取了多学科的方法来解决一个复杂的临床问题， 未满足的重大需求。我们使用患者来源的肿瘤类器官和肠道“小肠”培养物， 在我们的机构产生，在对患者进行临床试验之前， 此外，使用尖端技术，如单细胞RNA测序，以询问干细胞的动态， 肠对辐射损伤和EGLN抑制的反应。

PROJECT SUMMARY/ABSTRACT Pancreatic cancer is almost always fatal and new approaches are needed to improve the prognosis for a disease that is now the third leading cause of cancer-related death. Pancreatic cancer cannot be cured without surgery, and unfortunately, nearly 90% of patients present with unresectable disease (locally advanced + metastatic), leaving patients and clinicians with very few treatment options once chemotherapy is completed. Radiation therapy cannot substitute for surgery because of morbid radiotoxicity to the nearby stomach and intestines that occurs before the tumor is controlled. Thus, treatment-related gastrointestinal (GI) radiation toxicity may be the single greatest barrier to improving treatment responses for unresectable pancreatic cancer. There are no known medications that can selectively protect the stomach and intestines from these side effects, but we previously published that the inhibiting signaling through EGLN proteins reduces radiation damage in a model of catastrophic radiation injury and now we propose to understand these effects in a clinically relevant system. Our laboratory's long-term goal is to develop therapies that reduce sequelae from radiation injury during clinically relevant and potentially curative cancer treatments. The central hypothesis is that inhibition of the EGLN enzymes, achieved through the use of the oral EGLN inhibitor FG-4592, will selectively protect the intestinal tract from radiation toxicity without protecting tumors. The objective of this grant is to uncover a deeper understanding of how the EGLN signaling axis modulates the radiation esponse in the intestinal stem cell niche and in pancreatic tumors in order to safely translate this technology to patients. The specific aims will test the following hypotheses: (Aim 1) EGLN inhibition reduces radiation toxicity to enable ablative stereotactic radiation for pancreatic cancer, which will improve survival; (Aim 2) EGLN inhibition works chiefly by stimulating the +4 intestinal stem cells, which will be tested with a lineage tracing experiment in reporter mice; (Aim 3) FG-4592 will selectively protect human intestinal tissue from radiation damage but not human pancreatic cancer. The proposed research is significant because FG-4592 has completed Phase III clinical trials for a non-oncologic indication and could thus be rapidly implemented as a radioprotector. This approach could be used potentially replace surgery with radiation for patients with unresectable pancreatic cancer and serve as the basis for a clinical trial in the next 5 years. This research is innovative because it takes a multidisciplinary approach to solving a complex clinical problem in an area with a significant unmet need. We use patient derived tumor organoids and intestinal “mini-gut” cultures that have been generated at our institution to model this complex biology before a clinical trial with patients and moreover use cutting-edge techniques like single cell RNA seq to interrogate stem cell dynamics of the intestine in response to radiation injury and EGLN inhibition.