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

基本信息

批准号：
10364763
负责人：
Cullen Mitsuo Taniguchi
金额：
$ 37.1万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
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/10364763
关键词：
3-Dimensional Abdomen Address Anatomy Area Biology Blood Vessels Cancer Etiology Cessation of life Clinic Clinical Clinical Trials Colony-Forming Units Assay Complex Data Diagnosis Disease Enzymes Excision Exposure to Family Gastrointestinal tract structure Goals Grant Hemorrhage Human Hypoxia Hypoxia Inducible Factor Institution Intestines LGR5 gene Laboratories LacZ Genes Malignant neoplasm of lung Malignant neoplasm of pancreas Methodology Modeling Modification Molecular Mus Natural regeneration Normal tissue morphology Operative Surgical Procedures Oral Organoids Outcome Oxygen Pancreas Patients Perforation Pharmaceutical Preparations Pharmacology Phase III Clinical Trials Pre-Clinical Model Procollagen-Proline Dioxygenase Prognosis Proteins Publishing Radiation Radiation Dose Unit Radiation Injuries Radiation Protection Radiation Toxicity Radiation exposure Radiation induced damage Radiation therapy Reporter Research Role Signal Transduction Site Stomach System Techniques Technology Testing Therapeutic Tissues Toxic effect Translating Tumor-Derived Ulcer Unresectable Work cancer therapy chemotherapy clinically relevant conventional therapy experimental study gastrointestinal human tissue image guided improved improved outcome inhibitor innovation interdisciplinary approach novel strategies operation pancreatic cancer patients pancreatic neoplasm predicting response prevent promoter public health relevance radiation effect radiation response radioprotected sensor side effect single-cell RNA sequencing standard of care stem cell niche stem cell population stem cells surgery outcome therapy development transcription factor treatment response tumor

项目摘要

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.

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预后这种疾病目前是癌症相关死亡的第三大原因，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），一旦化疗完成，患者和拳头几乎没有治疗选择。放射治疗不能替代手术，因为对附近的胃和胃有病态的放射毒性。因此，治疗相关的胃肠道（GI）辐射发生在肿瘤得到控制之前。毒性可能是改善不可切除胰腺治疗反应的最大障碍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癌症的侵害。副作用，但我们之前发表过通过 EGLN 蛋白抑制信号传导可减少辐射灾难性辐射损伤模型中的损伤，现在我们建议了解这些影响我们实验室的长期目标是开发减少后遗症的疗法。临床相关且可能治愈的癌症治疗期间的辐射损伤。通过使用口服 EGLN 抑制剂 FG-4592 实现对 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。资助的目的是为了更深入地了解 EGLN 信号轴如何调节辐射响应肠道干细胞生态位和胰腺肿瘤中，以便将该技术安全地应用于患者。具体目标将检验以下假设：（目标 1）EGLN 抑制可降低辐射毒性对胰腺癌进行消融立体定向放射治疗，这将提高生存率（目标 2）EGLN；抑制作用主要通过刺激 +4 肠道干细胞发挥作用，这将通过谱系追踪进行测试报告小鼠实验；（目标 3）FG-4592 将选择性保护人体肠道组织免受辐射拟议的研究具有重要意义，因为 FG-4592 具有损害作用，但不影响人类胰腺癌。已完成非肿瘤适应症的 III 期临床试验，因此可以作为一种快速实施方案这种方法可用于替代放射治疗患者的手术。不可切除的胰腺癌，并作为未来 5 年临床试验的基础。创新，因为它采用多学科方法来解决具有复杂性的领域中的复杂临床问题我们使用患者来源的肿瘤类器官和肠道“迷你肠道”培养物。已在我们的机构生成，用于在对患者进行临床试验之前对这种复杂的生物学进行建模此外，使用单细胞 RNA seq 等尖端技术来探究干细胞动态肠道对辐射损伤和 EGLN 抑制的反应。