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：
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
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/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

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阻滞 WT RAS CRC 结直肠癌（CRC）是美国与癌症相关死亡的第二大原因。财富蛋白质组信息已对CRC的分子发病机理有深入的了解，并且导致了改善该疾病的分类系统。但是，将CRC患者匹配到最佳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（mAbs;例如，panitumumab）已批准为晚期野生型患者（WT）患者 Ras CRC。但是，在晚期治疗中，只有12-17％的患者对EGFR mAb的持久反应单一疗法和在标准化疗中添加EGFR mAB的临床益处有限。清楚地，需要提高EGFR mAb和/或克服抗性效率的治疗策略，以及优先考虑患者进行这种治疗的新方法。增殖细胞链接信号的代谢要求养分积累的转导，导致增殖与代谢之间的直接联系。谷氨酰胺（GLN）是癌细胞使用的关键的消毒基底物，可提供能量，碳和氮满足快速和持续增长的需求。 GLN复制三核酸（TCA）周期的供应用于燃料生物合成的中间体，在耗尽细胞毒性活性氧中也起着至关重要的作用物种（ROS）。在许多癌症中，EGFR和GLN合作提供了“信号”和“燃料”的合作有丝分裂原活化蛋白激酶（MAPK）依赖性生长和增殖所必需的。科学该项目的前提是GLN提供了支持EGFR介导的扩散的“燃料”来源；阻塞 GLN代谢将巧妙地用于细胞生长和增殖所需的关键代谢“燃料”。总体假设是，GLN代谢的抑制作用将增强一组患者的EGFR MAB治疗与先前含EGFR MAB MAB的治疗方案失败的CRC。我们建议评估非侵入性宠物成像是GLN亲生的生物标志物，我们将从中发展出GLN PET衍生的基因特征。 GLN亲生的签名将允许使用此信息代替复杂的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和在先前的抗EGFR MAB治疗方面进展的WT RAS CRC患者的panitumumab。目标2。评估EGFR mAb-Naive和EGFR mab- fr症患者的定量GLN PET，以预测对治疗。 AIM 3。开发GLN亲生的PET成像衍生的基因特征，以预测对 GLN代谢的抑制剂。跨越实验室研究和临床试验，该项目的可交付成果包括一种新的理论组合，以提高反应并克服对抗EGFR mAb治疗的抵抗力 WT RAS CRC以及一种鉴定可能受益于GLN代谢抑制剂的患者的新方法。