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

通过 EGLN 抑制转化肠道放射防护以改善不可切除胰腺癌的临床结果

• 批准号: 10308266
• 负责人: Cullen Mitsuo Taniguchi
• 金额: $ 6.91万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10308266
• 关键词: Area; Biology; Cancer Etiology; Cessation of life; Clinical; Clinical Trials; Complex; Disease; Enzymes; Goals; Grant; Human; Institution; Intestines; Laboratories; Malignant neoplasm of pancreas; Modeling; Mus; Operative Surgical Procedures; Oral; Organoids; Outcome; Patients; Pharmaceutical Preparations; Phase III Clinical Trials; Prognosis; Proteins; Publishing; Radiation; Radiation Injuries; Radiation Protection; Radiation Toxicity; Radiation induced damage; Radiation therapy; Reporter; Research; Signal Transduction; Stomach; System; Techniques; Technology; Testing; Tissues; Translating; Tumor-Derived; Unresectable; Work; cancer therapy; chemotherapy; clinically relevant; experimental study; gastrointestinal; improved; inhibitor/antagonist; innovation; interdisciplinary approach; novel strategies; pancreatic neoplasm; radiation response; side effect; single-cell RNA sequencing; stem cell niche; stem cells; therapy development; treatment response; tumor

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.

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疾病的预后 这是与癌症相关死亡的第三大主要原因。胰腺癌不需要手术就无法治愈， 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）， 化学疗法完成后，使患者和临床医生几乎没有治疗选择。辐射 由于病态的放射性毒性在附近的摊位和肠道上，治疗不能代替手术 在控制肿瘤之前发生。那，与治疗相关的胃肠道（GI）辐射毒性可能是 改善无法切除的胰腺癌治疗反应的最大障碍。没有 可以选择性保护胃和肠子免受这些副作用的已知药物，但是我们 先前发表的说明，通过EGLN蛋白抑制信号传导可减少 灾难性的辐射损伤，现在我们建议在临床相关的系统中了解这些影响。我们的 实验室的长期目标是开发疗法，以减少临床期间辐射损伤后遗症 相关且潜在的治愈性癌症治疗。中心假设是抑制EGLN 通过使用口服EGLN抑制剂FG-4592实现的酶将有选择地保护肠道 从辐射毒性中，而无需保护肿瘤。这笔赠款的目的是揭示更深入的理解 eGLN信号轴如何调节肠道干细胞生态位的辐射反应和 胰腺肿瘤是为了将该技术安全地转化为患者。具体目标将测试以下 假设：（ AIM 1）EGLN抑制作用降低了辐射毒性，以实现消融的立体定向辐射 胰腺癌将改善生存； （AIM 2）EGLN抑制主要是通过刺激+4来起作用 肠道干细胞将通过记者小鼠的谱系追踪实验进行测试； （AIM 3）FG-4592将 有选择地保护人肠组织免受辐射损伤，而不是人类胰腺癌。这 拟议的研究很重要，因为FG-4592已完成了非综合学的III期临床试验 指示，因此可以迅速作为辐射保护剂实施。可以使用这种方法 用不可切除的胰腺癌患者的辐射替换手术，并作为A的基础 未来5年的临床试验。这项研究具有创新性，因为它采用了多学科的方法 在没有明显未满足的区域解决复杂的临床问题。我们使用患者衍生的肿瘤 器官和肠道“迷你态”培养物已在我们的机构中​​产生，以模拟这一复杂 生物学在与患者进行临床试验之前，此外使用尖端技术（如单细胞RNA SEQ） 响应辐射损伤和EGLN抑制作用的肠道干细胞动力学。