The Houston Center for Acquired Resistance Research (H-CARR)

休斯顿获得性耐药研究中心 (H-CARR)

• 批准号: 10518173
• 负责人: Jeffrey Nicholas Myers
• 金额: $ 123.73万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10518173
• 关键词: Accounting; Acute; Adrenergic Agents; Algorithms; Amino Acids; Biological; Biological Markers; Biomass; Cancer Etiology; Carbon; Cessation of life; Cetuximab; Chronic; Cisplatin; Citric Acid Cycle; Clinical; Clinical Trials; Data; Dependence; Development; Distant Metastasis; Extinction (Psychology); FADH2; GPX2 gene; Generations; Genomics; Genotoxic Stress; Glutathione; Glycolysis; Goals; Gold; Head and Neck Squamous Cell Carcinoma; Human; Human Papillomavirus; Image; Immune checkpoint inhibitor; Individual; Infrastructure; Invaded; Link; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of esophagus; Malignant neoplasm of lung; Medicine; Metabolic; Metabolic stress; Modality; Modeling; Molecular; Mutation; Neoadjuvant Therapy; Neoplasm Circulating Cells; Neoplasm Metastasis; Neurons; Paracrine Communication; Pathway interactions; Patients; Pharmaceutical Preparations; Phenotype; Pre-Clinical Model; Production; Pyruvate; Regimen; Research; Research Personnel; Resistance; Resistance development; Role; Signal Transduction; Solid Neoplasm; Stress; TP53 gene; Technical Expertise; Testing; Time; Tumor Biology; Tumor Immunity; University of Texas M D Anderson Cancer Center; Upper aerodigestive tract cancer; afferent nerve; base; cancer cell; cancer imaging; cancer survival; chemotherapeutic agent; chemotherapy; clinical application; clinical practice; college; design; early detection biomarkers; experimental study; imaging study; immunogenic; improved; individual patient; insight; metabolic imaging; metabolomics; multidisciplinary; neoplastic cell; non-invasive imaging; novel; precision oncology; prevent; prospective; response; standard of care; targeted agent; transcriptomics; translational potential; tumor; tumor metabolism; tumor-immune system interactions

Overall SUMMARY Head and neck squamous cell carcinoma (HNSCC) remains a leading cause of cancer deaths worldwide with ~500,000 cases/year. Cisplatin is the gold standard systemic agent for HNSCC. Cisplatin resistance, both intrinsic and acquired, has been described in preclinical models and is frequently encountered in clinical practice; when it occurs it is deadly. The overarching goal of H-CARR is to develop a robust biological understanding of the key drivers of cisplatin resistance in HNSCC and develop the means of detecting it early in development and overcoming it once it arises. We previously showed that: 1) cellular processing of cisplatin generated metabolic stress is a critical driver of sensitivity and/or resistance and 2) coordinated genomic (TP53 mutation) and transcriptomic (Nrf-2 activation) reprogramming is essential to organizing the metabolic response to cisplatin generated stress. H-CARR brings together our biological and metabolic models of cisplatin resistance and our translational capabilities to image tumor metabolism non-invasively and detect biological shifts using circulating tumor cells (CTCs), to provide a comprehensive window into acquisition of cisplatin resistance as outlined in the Projects listed below, supported by a robust administrative and analytical infrastructure organized into 3 Cores. Project 1 will use state of the art metabolomic studies to identify the critical metabolic dependencies of cisplatin resistant HNSCC, identify opportunities for effective metabolic inhibition and improve our understanding of the cross-talk between the acquisition of cisplatin resistance and modulation of the tumor immune microenvironment. Project 2 will explore the genomic and transcriptomic reprogramming required to sustain the metabolic shifts which accompany development of resistance and interrogate how Nrf-2 dependent and independent signaling drives resistance and enhanced distant metastasis through intrinsic cellular mechanisms and paracrine signaling between tumor cells and adrenergic neurons. Project 3 will test whether the metabolic reprogramming outlined in Project 1 is detectable via non-invasive imaging (hyperpolarized magnetic resonance imaging) and whether the biological shifts outlined in Project 2 due to clonal extinction and expansion can be detected using CTC analysis in patients undergoing cisplatin-based treatment. H-CARR has the potential to realize the full clinical utility of cisplatin by identifying acquisition of resistance early during treatment and developing the means to overcome this and associated phenotypes such as enhanced distant metastasis. Successful completion of the proposed experiments will generate the new clinical standard for precision oncology approaches to clinical utilization of cisplatin in HNSCC and related upper- aerodigestive tract cancers of the lung and esophagus and therefore have a major impact on cancer survival worldwide.

总体总结 头颈鳞状细胞癌 (HNSCC) 仍然是全球癌症死亡的主要原因 每年约 500,000 例。顺铂是治疗 HNSCC 的金标准全身药物。顺铂耐药，两者 内在的和获得性的，已在临床前模型中得到描述，并且在临床实践中经常遇到； 当它发生时，它是致命的。 H-CARR 的总体目标是建立强有力的生物学理解 HNSCC 顺铂耐药的关键驱动因素，并开发早期检测方法 并在它出现时克服它。我们之前表明：1）顺铂的细胞加工产生 代谢应激是敏感性和/或耐药性的关键驱动因素，2) 协调基因组（TP53 突变） 转录组（Nrf-2 激活）重编程对于组织顺铂的代谢反应至关重要 产生的压力。 H-CARR 汇集了我们的顺铂耐药性的生物和代谢模型以及我们的 非侵入性地成像肿瘤代谢并利用循环检测生物变化的转化能力 肿瘤细胞（CTC），为获得顺铂耐药性提供一个全面的窗口，如 下面列出的项目由分为 3 个核心的强大管理和分析基础设施支持。 项目 1 将利用最先进的代谢组学研究来确定关键的代谢依赖性 顺铂耐药的 HNSCC，确定有效代谢抑制的机会并提高我们的理解 顺铂耐药性的获得与肿瘤免疫调节之间的相互作用 微环境。项目 2 将探索维持基因组和转录组重编程所需的 伴随耐药性发展的代谢变化并询问 Nrf-2 依赖性和 独立的信号传导通过内在的细胞机制驱动耐药性并增强远处转移 以及肿瘤细胞和肾上腺素能神经元之间的旁分泌信号传导。项目3将测试新陈代谢是否 项目 1 中概述的重编程可通过非侵入性成像（超极化磁共振 成像）以及项目 2 中概述的由于克隆灭绝和扩张引起的生物变化是否可以 使用 CTC 分析在接受顺铂治疗的患者中检测到。 H-CARR 有潜力通过识别获得顺铂来实现顺铂的全部临床效用 在治疗早期发现耐药性，并开发克服这种耐药性和相关表型的方法，例如 如远处转移增强。成功完成所提出的实验将产生新的 顺铂在 HNSCC 及相关上皮细胞临床应用的精准肿瘤学方法临床标准 肺癌和食管的呼吸消化道癌，因此对癌症生存有重大影响 全世界。