Metabolic adaptation enables cisplatin resistance and inhibits tumor immunity

代谢适应使顺铂耐药并抑制肿瘤免疫

• 批准号: 10942977
• 负责人: VLAD C SANDULACHE
• 金额: $ 16.2万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10942977
• 关键词: ATP Citrate (pro-S)-Lyase; Acetates; Acetyl Coenzyme A; Acetylation; Adrenergic Agents; Aspartoacylase; Award; Biological; Biological Markers; Cancer Etiology; Carbon; Cell Nucleus; Cells; Cessation of life; Cisplatin; Citrates; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Coenzyme A; Coenzyme A Ligases; Collaborations; Cytoprotection; Cytosol; DNA Damage; DNA Maintenance; Dependence; Development; Dimensions; Distant Metastasis; Early Diagnosis; Extinction; Fatty Acids; Fostering; Genes; Genetic; Genome; Genomics; Glucose; Goals; Growth; Head and Neck Squamous Cell Carcinoma; Histone Acetylation; Histones; Human Papillomavirus; Hypoxia; Image; Institution; Knock-out; Knowledge; Ligation; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Mammalian Cell; Measurement; Medicine; Metabolic; Metabolism; Mitochondria; Modeling; Molecular; Myelin; Nerve; Nervous System; Neurons; Normal tissue morphology; Nuclear; Oligodendroglia; Oxaloacetates; Paracrine Communication; Patients; Pharmaceutical Preparations; Phenotype; Physiological; Pre-Clinical Model; Process; Production; Protein Isoforms; Pyruvate; Pyruvate Dehydrogenase Complex; Reaction; Research; Research Personnel; Resistance; Resistance development; Role; Schwann Cells; Solid Neoplasm; Source; Stress; Testing; Therapeutic; Toxic effect; Treatment Failure; Tumor Immunity; University of Texas M D Anderson Cancer Center; Upper aerodigestive tract cancer; antitumor effect; cancer cell; cancer survival; chemotherapeutic agent; chemotherapy; cholesterol biosynthesis; clinical biomarkers; clinical practice; college; experimental study; improved; lipid biosynthesis; metabolomics; multidisciplinary; neoplastic cell; nerve supply; neurotransmission; non-invasive imaging; novel; optogenetics; pharmacologic; pre-clinical; precision oncology; response; small molecule; transcriptomics; tumor; tumor microenvironment; tumor-immune system interactions

Head and neck squamous cell carcinoma (HNSCC) remains a leading cause of cancer death 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 the Houston Center for Acquired Resistance Research (H-CARR) is to develop a robust biological understanding of the key drivers of cisplatin resistance in HNSCC, which will lead to the development of novel means of early detection of resistant tumors and treatment. We previously showed that acetate metabolism and neuronal signaling are essential to organizing the metabolic response to cisplatin-generated stress. H-CARR will bring together our biological and metabolic models of cisplatin resistance to provide a comprehensive window into its acquisition, as outlined in the projects listed below. 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 crosstalk 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 that accompany the development of resistance 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 by CTC analysis in patients undergoing cisplatin-based treatment. In the proposed supplement, we aim to foster new collaborations and deepen our understanding of the neuron-dependent metabolic shifts that drive cisplatin resistance in HNSCC. These studies will increase the overall impact of Projects 1 and 2 within the original scope by identifying actionable paracrine signaling between tumor cells and the neurons associated with metabolic changes and cisplatin resistance. H-CARR has the potential to realize the full clinical utility of cisplatin by identifying resistance early in treatment and developing the means to overcome resistance and phenotypes associated with resistance, such as enhanced distant metastasis. Successful completion of the proposed experiments will generate the new clinical standard for precision oncology approaches to the clinical utilization of cisplatin in HNSCC and related upper-aerodigestive tract cancers; therefore, it will have a major impact on cancer survival worldwide.

头部和颈部鳞状细胞癌（HNSCC）仍然是全球癌症死亡的主要原因，每年约50万例。顺铂是HNSCC的黄金标准系统剂。在临床前模型中已经描述了固有和获得的顺铂耐药性，并且在临床实践中经常遇到。当发生时，它是致命的。休斯顿获得的抵抗力研究中心（H-CARR）的总体目标是对HNSCC中顺铂耐药性的关键驱动因素有强有力的生物学理解，这将导致新的耐药性肿瘤和治疗的新型手段发展。我们先前表明，乙酸代谢和神经元信号传导对于组织对顺铂产生的应激的代谢反应至关重要。 H-Carr将汇集我们的顺铂耐药性生物学和代谢模型，以提供全面的收购窗口，如下所述的项目中所述。项目1将使用最先进的代谢组学研究来确定顺铂耐药的HNSCC的关键代谢依赖性，确定有效代谢抑制的机会，并提高我们对获得顺铂抵抗和调节肿瘤免疫微环境之间串扰的理解。项目2将探索通过固有细胞机制和肿瘤细胞和肾上腺素能神经元之间的固有细胞机制和旁分泌信号传导伴随抗药性发展所需的基因组和转录重编程。项目3将测试项目1中概述的代谢重编程是否可以通过非侵入性成像（超极化磁共振成像）以及是否可以通过基于Cisplatin治疗的患者的CTC分析来检测到项目2中概述的生物学转移。在拟议的补充剂中，我们旨在促进新的合作，并加深对神经元依赖性代谢转变的理解，这些转变驱动HNSCC中的顺铂耐药性。这些研究将通过鉴定肿瘤细胞之间可起作用的旁分泌信号传导以及与代谢变化和顺铂耐药性相关的神经元之间可起作用的旁分泌信号传导，从而增加项目1和2在原始范围内的总体影响。 H-CARR有可能通过在治疗早期鉴定耐药性并开发克服与抗药性相关的耐药性和表型（例如增强的远处转移）来实现顺铂的全部临床实用性。提出的实验的成功完成将生成新的临床标准，用于精确肿瘤学方法，用于在HNSCC和相关的高消化道癌中顺铂的临床利用。因此，它将对全球癌症生存产生重大影响。