Project 2: Targeting Glutamine Metabolism to Enhance EGFR Blockade in Wild-Type RAS CRC

项目 2：靶向谷氨酰胺代谢以增强野生型 RAS CRC 中的 EGFR 阻断

基本信息

批准号：
10443613
负责人：
JORDAN D BERLIN
金额：
$ 39.95万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
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：
2019-07-09 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10443613
关键词：
Address Anabolism Avidity Biological Assay Biological Markers Biological Sciences Cancer Cell Growth Cancer Center Cancer Etiology Carbon Cell Proliferation Cells Cessation of life Cetuximab Citric Acid Cycle Classification Clinical Clinical Trials Colorectal Cancer Combined Modality Therapy Complex Data Development Disease Enrollment Enzymes Epidermal Growth Factor Receptor Exhibits Future Glucose Glutamates Glutaminase Glutamine Goals Growth In Vitro Investigation Laboratory Study Link Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Mediating Metabolic Metabolism Mitochondria Mitogen-Activated Protein Kinases Molecular Monoclonal Antibodies Monoclonal Antibody Therapy Nitrogen Nutrient Pathogenesis Pathway interactions Patients Pharmacodynamics Pharmacology Phase I Clinical Trials Phase II Clinical Trials Play Positron-Emission Tomography Production Proliferating Reactive Oxygen Species Refractory Regimen Resistance Role Signal Transduction Solid Neoplasm Source System Therapeutic Tracer Translations base cancer cell cell growth chemotherapy colon cancer patients combinatorial cytotoxic efficacy evaluation genetic signature improved in vivo inhibitor member metastatic colorectal mouse model neutralizing monoclonal antibodies novel novel therapeutic intervention novel therapeutics panitumumab patient derived xenograft model precision medicine preclinical study predict responsiveness predicting response predictive marker proteogenomics receptor-mediated signaling refractory cancer response statistics targeted treatment transcriptome sequencing translational approach translational goal treatment response tumor tumor metabolism

项目摘要

PROJECT SUMMARY/ABSTRACT: P2. Targeting Glutamine Metabolism to Enhance EGFR Blockade in WT RAS CRC Colorectal cancer (CRC) is the second leading cause of cancer-related death in the US. A wealth of proteogenomic information has provided a deep understanding of the molecular pathogenesis of CRC and has led to improved classification systems of the disease. However, matching a CRC patient to the optimum therapeutic regimen remains a major challenge. Epidermal growth factor receptor (EGFR) neutralizing monoclonal antibodies (mAbs; e.g., panitumumab) are approved for patients with advanced wild-type (WT) RAS CRC. However, in late-line therapy, only 12–17% of patients exhibit durable responses to EGFR mAb monotherapy and addition of EGFR mAbs to standard chemotherapy has limited clinical benefit. Clearly, therapeutic strategies that enhance efficacy of EGFR mAb and/or overcome resistance are needed, along with novel ways to prioritize patients for such therapy. The metabolic requirements of proliferating cells link signal transduction with nutrient accumulation, resulting in a direct link between proliferation and metabolism. Glutamine (Gln) is a key anaplerotic substrate used by cancer cells, providing energy, carbon, and nitrogen to meet the demands of rapid and sustained growth. Gln replenishes the supply of tricarboxylic acid (TCA) cycle intermediates used to fuel biosynthesis, and also plays a critical role in depleting cytotoxic reactive oxygen species (ROS). In many cancers, EGFR and Gln cooperate to provide both `signals' and `fuel', which are required for mitogen activated protein kinase (MAPK)-dependent growth and proliferation. The Scientific Premise of this project is that Gln provides a `fuel' source to support EGFR-mediated proliferation; blocking Gln metabolism will deplete a critical metabolic `fuel' required for cell growth and proliferation. The Overall Hypothesis is that inhibition of Gln metabolism will enhance EGFR mAb therapy for a select group of patients with CRC who have failed prior EGFR mAb-containing regimens. We propose to evaluate non-invasive PET imaging as a biomarker of Gln avidity, from which we will develop a Gln PET-derived gene signature. A gene signature of Gln avidity will allow this information to be utilized in lieu of complex PET imaging. Our project has three Specific Aims. Aim 1. Conduct a phase II clinical trial evaluating the efficacy of combined CB-839 and panitumumab in patients with WT RAS CRC who progressed on prior anti-EGFR mAb therapy. Aim 2. Evaluate quantitative Gln PET in EGFR mAb-naive and EGFR mAb-refractory patients to predict response to therapy. Aim 3. Develop a PET imaging-derived gene signature of Gln avidity to predict responsiveness to inhibitors of Gln metabolism. Spanning laboratory studies and clinical trials, deliverables of this project include a new therapeutic combination to improve response and overcome resistance to anti-EGFR mAb therapy in WT RAS CRC, as well as a new way to identify patients likely to benefit from inhibitors of Gln metabolism.

项目摘要/摘要：P2. 靶向谷氨酰胺代谢以增强 EGFR 阻断 WT RAS CRC 结直肠癌 (CRC) 是美国癌症相关死亡的第二大原因。蛋白质组学信息提供了对结直肠癌分子发病机制的深入了解，并已然而，改进了疾病的分类系统，将 CRC 患者与最佳匹配。表皮生长因子受体（EGFR）中和治疗方案仍然是一个主要挑战。单克隆抗体（mAb；例如帕尼单抗）被批准用于晚期野生型 (WT) 患者然而，在晚期治疗中，只有 12-17% 的患者对 EGFR mAb 表现出持久的反应。显然，单一疗法以及在标准化疗中添加 EGFR mAb 的临床益处有限。需要增强 EGFR mAb 功效和/或克服耐药性的治疗策略，以及优先考虑患者进行此类治疗的新方法增殖细胞的代谢需求将信号联系起来。转导与营养积累，导致增殖和代谢之间的直接联系。谷氨酰胺 (Gln) 是癌细胞使用的关键回补底物，为癌细胞提供能量、碳和氮。满足快速持续增长的需求，补充三羧酸（TCA）循环的供应。用于为生物合成提供燃料的中间体，并且在消耗细胞毒性活性氧方面也发挥着关键作用在许多癌症中，EGFR 和 Gln 共同提供“信号”和“燃料”。丝裂原激活蛋白激酶 (MAPK) 依赖性生长和增殖所需的。该项目的前提是 Gln 提供“燃料”来源来支持 EGFR 介导的增殖阻断；谷氨酰胺代谢会耗尽细胞生长和增殖所需的关键代谢“燃料”。假设抑制 Gln 代谢将增强特定患者组的 EGFR mAb 治疗对于之前含有 EGFR mAb 的治疗方案失败的 CRC 患者，我们建议评估非侵入性 PET。成像作为 Gln 亲和力的生物标志物，我们将从中开发 Gln PET 衍生的基因特征 A 基因。 Gln 亲和力的签名将允许利用该信息来代替复杂的 PET 成像。三个具体目标 1. 进行 II 期临床试验，评估 CB-839 和 CB-839 联合用药的疗效。帕尼单抗用于治疗先前接受抗 EGFR 单克隆抗体治疗但病情进展的 WT RAS CRC 患者。评估 EGFR mAb 初治患者和 EGFR mAb 难治性患者的定量 Gln PET，以预测对治疗的反应目标 3. 开发 PET 成像衍生的 Gln 亲和力基因特征，以预测对 Gln 的反应。该项目的成果包括 Gln 代谢抑制剂。一种新的治疗组合，可改善抗 EGFR mAb 疗法的反应并克服耐药性 WT RAS CRC，以及一种识别可能受益于 Gln 代谢抑制剂的患者的新方法。