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疾病的预后 现在是癌症相关死亡的第三大原因。胰腺癌不手术是治不好的， 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。辐射 治疗不能代替手术，因为对附近的胃和肠有病态的放射毒性， 在肿瘤得到控制之前。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。没有 已知的药物，可以选择性地保护胃和肠道免受这些副作用，但我们 先前发表的研究表明，通过EGLN蛋白抑制信号传导减少了辐射损伤模型中的辐射损伤。 灾难性的辐射损伤，现在我们建议在临床相关系统中了解这些影响。我们 实验室的长期目标是开发治疗方法，减少放射性损伤的后遗症， 相关和潜在的治愈性癌症治疗。核心假设是抑制EGLN 通过使用口服EGLN抑制剂FG-4592获得的酶将选择性地保护肠道 而不保护肿瘤。这笔赠款的目的是揭示一个更深层次的理解 EGLN信号轴如何调节肠干细胞龛中的辐射反应， 胰腺肿瘤，以便将这项技术安全地应用于患者。具体目标将检验以下方面 假设：（目的1）EGLN抑制降低放射毒性，使消融立体定向放射治疗 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，将在报告小鼠中进行谱系追踪实验;（目的3）FG-4592将 选择性地保护人类肠道组织免受辐射损伤，但对人类胰腺癌没有保护作用。的 拟议的研究是重要的，因为FG-4592已经完成了非肿瘤学的III期临床试验。 指示，并因此可以作为辐射防护剂快速实施。这种方法可能会被用来 对于不能切除的胰腺癌患者，用放射治疗代替手术，并作为治疗的基础。 在未来5年内进行临床试验。这项研究是创新的，因为它采取了多学科的方法， 在一个有着显著未满足需求的领域解决复杂的临床问题。我们使用患者来源的肿瘤 在我们的机构中产生的类器官和肠道“迷你肠道”培养物来模拟这种复合体 在对患者进行临床试验之前进行生物学研究，并使用单细胞RNA测序等尖端技术， 询问肠对辐射损伤和EGLN抑制的响应的干细胞动力学。

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 response 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.