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

项目摘要/摘要 胰腺癌几乎总是致命的，需要新的方法来改善预后。 这种疾病现在是癌症相关死亡的第三大原因。胰腺癌无法治愈 在没有手术的情况下，不幸的是，近90%的患者患有无法切除的疾病(局部晚期 +转移性)，一旦化疗完成，患者和临床医生几乎没有治疗选择。 放射治疗不能替代手术，因为放射治疗对附近的胃和 在肿瘤被控制之前发生的肠道。因此，与治疗相关的胃肠道(GI)放射 毒性可能是提高不能切除的胰腺的治疗效果的最大障碍 癌症。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伤害。 副作用，但我们之前发表了通过EGLN蛋白抑制信号减少辐射 在灾难性辐射损伤模型中的损害，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 在临床相关和可能治愈的癌症治疗过程中的辐射损伤。中心假设是 通过使用口服EGLN抑制剂FG-4592实现的对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。这样做的目的是 GRANT是为了揭示EGLN信号轴是如何调制辐射响应的更深层次的理解 为了将这项技术安全地移植到患者身上，肠道干细胞的利基和胰腺肿瘤中的干细胞。 具体的目标将检验以下假设：(目标1)EGLN抑制降低辐射毒性 允许对胰腺癌进行消融性立体定向放射治疗，这将提高存活率；(目标2)EGLN 抑制主要通过刺激+4肠道干细胞起作用，这将通过谱系追踪进行测试。 在报告鼠身上的实验；(目标3)FG-4592将选择性地保护人体肠道组织免受辐射 损害但不是人类胰腺癌。拟议的研究具有重要意义，因为FG-4592具有 已完成非肿瘤学适应症的第三阶段临床试验，因此可以作为一种 辐射防护器。这种方法有可能用放射治疗来取代手术。 无法切除的胰腺癌，并作为未来5年临床试验的基础。这项研究是 创新，因为它需要多学科的方法来解决一个具有 重大的未得到满足的需求。我们使用患者来源的肿瘤器官和肠道“迷你肠道”培养物 在对患者进行临床试验之前，在我们的机构中产生了这种复杂的生物学模型 此外，使用尖端技术，如单细胞RNA序列，询问干细胞动力学 肠道对辐射损伤的反应和EGLN的抑制。

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.