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: 10707142
• 负责人: Jeffrey Nicholas Myers
• 金额: $ 117.47万
• 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/10707142
• 关键词: 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; FADH2; GPX2 gene; Generations; Genomics; Genotoxic Stress; Glutathione; Glycolysis; Goals; Head and Neck Squamous Cell Carcinoma; Human; Human Papillomavirus; Image; Immune checkpoint inhibitor; Individual; Infiltration; Infrastructure; Institution; 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; 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.

总结 头颈部鳞状细胞癌（HNSCC）仍然是全球癌症死亡的主要原因 约500,000箱/年。顺铂是HNSCC的黄金标准系统剂。顺铂耐药性 固有的和获得的，已在临床前模型中进行了描述，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大的生物学理解 HNSCC中顺铂耐药性的主要驱动因素，并开发了开发早期检测的手段 并克服它一旦出现。我们先前表明：1）为顺铂产生的细胞加工 代谢应激是灵敏度和/或抗性的关键驱动力，以及2）协调的基因组（TP53突变） 和转录组（NRF-2激活）重编程对于组织代谢反应至关重要 产生的压力。 H-Carr汇集了我们的生物学和代谢模型的顺铂耐药性和我们的生物学模型 转化能力以非侵入性图像肿瘤代谢，并使用循环检测生物学转移 如在 下面列出的项目，由组织为3个核心的强大行政和分析基础设施的支持。 项目1将使用艺术状态代谢组学研究来确定关键的代谢依赖性 抗顺铂的HNSCC，确定有效代谢抑制的机会并提高我们的理解 顺铂耐药性的获取与肿瘤免疫的调节之间的串扰 微环境。项目2将探讨维持所需的基因组和转录组重编程 代谢转变伴随着抵抗的发展并询问NRF-2如何依赖和 独立的信号传导通过内在的细胞机制驱动电阻和增强的远处转移 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将测试是否代谢 可以通过非侵入性成像（超极化磁共振成像）检测到项目1中概述的重编程 成像）以及由于克隆灭绝和扩张而导致项目2中概述的生物学转移是否可以是 在接受顺铂治疗的患者中使用CTC分析检测。 H-Carr有可能通过识别获得顺铂的全部临床实用性 治疗期间的早期抵抗力并开发了克服这种和相关表型的手段 作为增强的遥远转移。成功完成拟议的实验将产生新的 精确肿瘤学方法的临床标准，用于HNSCC和相关上层的临床利用 肺和食道的机动消化道癌，因此对癌症存活产生了重大影响 全世界。