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.

项目概要/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 现在，胰腺癌是癌症相关死亡的第三大原因，如果不进行手术就无法治愈。 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）， 辐射 治疗不能替代手术，因为对附近的胃和肠道有病态的放射毒性， 发生在肿瘤得到控制之前，因此，与治疗相关的胃肠道（GI）放射毒性可能是原因。 改善不可切除的胰腺癌治疗反应的最大障碍不存在。 已知的药物可以选择性地保护胃和肠道免受这些副作用的影响，但我们 先前发表的文章称，通过 EGLN 蛋白抑制信号传导可减少模型中的辐射损伤 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。 该实验室的长期目标是开发减少临床治疗过程中放射损伤后遗症的疗法。 相关且具有潜在治愈性的癌症治疗方法的中心假设是抑制 EGLN。 通过使用口服 EGLN 抑制剂 FG-4592 实现的酶将选择性地保护肠道 免受辐射毒性而不保护肿瘤 这笔赠款的目的是加深了解。 EGLN 信号轴如何调节肠道干细胞生态位中的辐射反应以及 为了将这项技术安全地转化给胰腺肿瘤患者，具体目标将进行以下测试。 假设：（目标 1）EGLN 降低抑制性放射毒性，从而实现消融立体定向放射治疗 胰腺癌，这将提高生存率；（目标 2）EGLN 抑制主要通过刺激 +4 发挥作用； （目标 3）FG-4592 将 选择性地保护人类肠道组织免受辐射损伤，但不能保护人类胰腺癌。 拟议的研究意义重大，因为 FG-4592 已完成非肿瘤药物的 III 期临床试验 指示，因此可以作为辐射防护剂快速实施，这种方法有潜在的用途。 对于无法切除的胰腺癌患者，用放射替代手术，并作为治疗的基础 这项研究是创新的，因为它采用了多学科方法。 我们使用患者来源的肿瘤来解决需求未得到满足的领域的复杂临床问题。 我们的机构生成了类器官和肠道“迷你肠道”培养物来模拟这种复合物 在对患者进行临床试验之前进行生物学研究，此外还使用单细胞 RNA seq 等尖端技术 研究肠道干细胞响应辐射损伤和 EGLN 抑制的动态。