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

• 批准号: 10218110
• 负责人: JORDAN D BERLIN
• 金额: $ 41.01万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 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/10218110
• 关键词: Address; Anabolism; Avidity; Biological; 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/antagonist; 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; tumor; tumor metabolism

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。丰富的 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 从而改进了疾病的分类系统。然而，将 CRC 患者与最佳匹配 治疗方案仍然是一个重大挑战。表皮生长因子受体 (EGFR) 中和 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 RAS CRC。然而，在晚期治疗中，只有 12-17% 的患者对 EGFR mAb 表现出持久反应 单一疗法以及在标准化疗中添加 EGFR mAb 的临床益处有限。清楚地， 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链接信号 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。 Gln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 物种（ROS）。在许多癌症中，EGFR 和 Gln 合作提供“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。科学的 该项目的前提是 Gln 提供“燃料”来源来支持 EGFR 介导的增殖；阻塞 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”。整体 假设抑制 Gln 代谢将增强特定患者组的 EGFR mAb 治疗 先前含有 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。一个基因 Gln 亲和力的特征将允许利用该信息来代替复杂的 PET 成像。我们的项目有 三个具体目标。目标 1. 进行 II 期临床试验，评估 CB-839 和 帕尼单抗用于治疗先前接受抗 EGFR mAb 治疗但病情进展的 WT RAS CRC 患者。目标2。 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 治疗。目标 3. 开发 PET 成像衍生的 Gln 亲和力基因特征，以预测对 Gln 代谢抑制剂。该项目涵盖实验室研究和临床试验，可交付成果包括 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。