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: 10700852
• 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
• 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/10700852
• 关键词: Address; Anabolism; Avidity; Biological Assay; Biological Markers; Biological Sciences; Cancer Cell Growth; Cancer Center; Cancer Etiology; Carbon; Cell Proliferation; Cessation of life; Cetuximab; Citric Acid Cycle; Classification; Clinical; Clinical Trials; Colorectal Cancer; Combined Modality Therapy; Complex; Data; Development; Disease; 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; Phase I Clinical Trials; Phase II Clinical Trials; Play; Positron-Emission Tomography; Prediction of Response to Therapy; Production; Proliferating; Reactive Oxygen Species; Refractory; Regimen; Resistance; Role; Signal Transduction; Solid Neoplasm; Source; System; Therapeutic; Tracer; Translations; 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; participant enrollment; patient derived xenograft model; pharmacologic; 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; 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.

项目总结/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 蛋白基因组学信息提供了对CRC分子发病机制的深入理解， 导致了疾病分类系统的改进。然而，将CRC患者与最佳 治疗方案仍然是一个主要的挑战。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） RAS CRC。然而，在晚期治疗中，只有12-17%的患者对EGFR mAb表现出持久的应答 单药治疗和在标准化疗中加入EGFR mAb的临床益处有限。很显然， 需要增强EGFR mAb的功效和/或克服耐药性的治疗策略，沿着 新的方法来优先考虑患者进行这种治疗。增殖细胞的代谢需要连接信号 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， 满足快速持续发展的需要。谷氨酰胺供应三羧酸（TCA）循环 用于燃料生物合成的中间体，并且在消耗细胞毒性活性氧方面也起着关键作用 物种（ROS）。在许多癌症中，EGFR和Gln合作提供“信号”和“燃料”，这是 丝裂原活化蛋白激酶（MAPK）依赖性生长和增殖所需。科学 该项目的假设是，谷氨酰胺提供了一种“燃料”来源，以支持EGFR介导的增殖;阻断 谷氨酰胺代谢将耗尽细胞生长和增殖所需的关键代谢“燃料”。整体 假设Gln代谢的抑制将增强EGFR mAb对选定患者组的治疗 既往含EGFR mAb方案失败的CRC患者。我们建议评估非侵入性PET 成像作为Gln亲合力的生物标志物，我们将从中开发Gln PET衍生的基因签名。的基因 Gln亲合力的特征将允许利用该信息代替复杂的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 帕尼单抗用于既往抗EGFR mAb治疗后疾病进展的WT RAS CRC患者。目标二。 评价EGFR mAb初治和EGFR mAb难治患者的定量Gln PET，以预测对 疗法目标3。开发PET成像衍生的Gln亲合力基因标签，以预测对 谷氨酰胺代谢抑制剂。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，用于改善抗EGFR mAb治疗的应答并克服其耐药性， WT RAS CRC，以及一种新的方法来确定患者可能受益于谷氨酰胺代谢抑制剂。