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: 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
• 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

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。靶向谷氨酰胺代谢增强血管内皮细胞生长因子受体阻断 WT RAS CRC 结直肠癌(CRC)是美国癌症相关死亡的第二大原因。一大笔钱 蛋白质基因组学信息为结直肠癌的分子发病机制提供了深入的了解 从而改进了疾病的分类系统。然而，将结直肠癌患者与最佳 治疗方案仍然是一个重大挑战。表皮生长因子受体的中和作用 单抗(mAbs；例如Panitumumab)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单抗表现出持久的反应 单一治疗和在标准化疗的基础上加用EGFR单抗的临床益处有限。显然， 需要提高EGFR单抗的疗效和/或克服耐药性的治疗策略，以及 确定患者接受此类治疗的优先顺序的新方法。增殖细胞的代谢要求与信号联系 转导和营养积累，导致增殖和新陈代谢之间的直接联系。 谷氨酰胺(Gln)是癌细胞使用的一种关键的抗癌底物，为癌细胞提供能量、碳和氮 适应快速持续增长的要求。谷氨酰胺补充三羧酸(TCA)循环 中间体是生物合成的燃料，也是消耗细胞毒性活性氧的关键。 种(ROS)。在许多癌症中，EGFR和Gln共同提供“信号”和“燃料”，它们是 丝裂原活化蛋白激酶(MAPK)依赖的生长和增殖所必需的。《科学》 这个项目的前提是谷氨酰胺提供了一个支持EGFR介导的增殖的“燃料”来源； 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”。整体而言 假说是，抑制谷氨酰胺代谢将加强EGFR单抗治疗对特定患者的作用 与先前EGFR单抗方案失败的结直肠癌患者进行比较。我们建议评估无创PET 成像作为谷氨酰胺亲和力的生物标志物，我们将从中开发出谷氨酰胺PET衍生的基因签名。A基因 谷氨酰胺亲和力的签名将使这一信息用于替代复杂的PET成像。我们的项目已经 三个具体目标。目的1.进行II期临床试验，评估CB-839和 在既往抗EGFR单抗治疗进展的WT RAS结直肠癌患者中应用Panitumumab。目标2. 评估EGFR单抗初治和EGFR单抗耐药患者的定量谷氨酰胺PET对疗效的预测 心理治疗。目的3.建立谷氨酰胺亲和力的PET成像衍生基因特征，以预测对 谷氨酰胺代谢的抑制剂。该项目涵盖实验室研究和临床试验，可交付成果包括 一种新的联合治疗方案，以提高抗EGFR单抗治疗的疗效并克服其耐药性 WT RAS CRC，以及一种识别可能受益于谷氨酰胺代谢抑制剂的患者的新方法。