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: 10593058
• 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
• 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/10593058
• 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; 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; Radiosensitization; Reporter; Research; Role; Signal Transduction; Site; Stomach; System; Techniques; Technology; Testing; Therapeutic; Tissues; Toxic effect; Translating; Ulcer; Unresectable; Work; cancer therapy; chemotherapy; clinically relevant; conventional therapy; experimental study; gastrointestinal; human tissue; image guided; improved; improved outcome; inducible Cre; inhibitor; innovation; interdisciplinary approach; novel strategies; operation; pancreatic cancer patients; pancreatic neoplasm; pharmacologic; 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; 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; 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; Radiosensitization; Reporter; Research; Role; Signal Transduction; Site; Stomach; System; Techniques; Technology; Testing; Therapeutic; Tissues; Toxic effect; Translating; Ulcer; Unresectable; Work; cancer therapy; chemotherapy; clinically relevant; conventional therapy; experimental study; gastrointestinal; human tissue; image guided; improved; improved outcome; inducible Cre; inhibitor; innovation; interdisciplinary approach; novel strategies; operation; pancreatic cancer patients; pancreatic neoplasm; pharmacologic; 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

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 现在是与癌症相关死亡的第三大原因的疾病。胰腺癌无法治愈 没有手术，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），一旦化学疗法完成，就会使患者和临床医生几乎没有治疗选择。 放射疗法由于在附近的胃中病态的放射性毒性而无法代替手术 控制肿瘤之前发生的肠。那是与治疗相关的胃肠道（GI）辐射 毒性可能是改善无法切除胰腺的治疗反应的最大障碍 癌症。没有已知的药物可以选择性地保护胃和肠子 副作用，但我们先前发表过，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害，现在我们建议在A中了解这些影响 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 临床相关和潜在治愈性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EGLN酶的抑制作用将 有选择地保护肠道免受辐射毒性的影响，而无需保护肿瘤。这个目的 格兰特将更深入地了解EGLN信号轴如何调节辐射辅助 为了将该技术安全地转化为患者，肠道干细胞生态位和胰腺肿瘤中。 具体目的将检验以下假设：（目标1）EGLN抑制作用可将辐射毒性降低至 为胰腺癌启用消融的立体定向辐射，这将改善生存； （AIM 2）EGLN 抑制作用主要是通过刺激+4肠干细胞来起作用的，该干细胞将通过谱系跟踪进行测试 记者小鼠的实验； （AIM 3）FG-4592将有选择地保护人肠组织免受辐射 损害但不是人类胰腺癌。拟议的研究很重要，因为FG-4592具有 完成了非综合学指示的III期临床试验，因此可以迅速实施 辐射保护剂。可以使用这种方法可能会用辐射替代手术 不可切除的胰腺癌，并作为未来5年临床试验的基础。这项研究是 创新性，因为它采用多学科的方法来解决一个具有 大量未满足的需求。我们使用患者衍生的肿瘤类器官和具有 在我们的机构中​​生成，以对这种复杂的生物学进行建模，并在与患者进行临床试验之前，并 此外 肠道响应辐射损伤和EGLN抑制作用。