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，每年约有50万例。顺铂是治疗HNSCC的金标准全身用药。顺铂耐药，既有先天耐药，也有获得性耐药，已在临床前模型中描述，并在临床实践中经常遇到；当它发生时，它是致命的。休斯顿获得性耐药研究中心(H-CARR)的首要目标是对HNSCC中顺铂耐药的关键驱动因素有一个强有力的生物学理解，这将导致开发早期发现耐药肿瘤和治疗的新手段。我们以前已经证明，醋酸盐代谢和神经元信号对于组织对顺铂产生的应激的代谢反应是必不可少的。H-CARR将把我们顺铂耐药的生物和代谢模型结合在一起，为获得顺铂提供一个全面的窗口，如下所列项目所述。项目1将使用最先进的代谢组学研究来确定顺铂耐药HNSCC的关键代谢依赖关系，确定有效代谢抑制的机会，并提高我们对顺铂耐药获得和肿瘤免疫微环境调节之间的串扰的理解。项目2将探索通过肿瘤细胞和肾上腺素能神经元之间的内在细胞机制和旁分泌信号来维持伴随着耐药性发展的代谢转变所需的基因组和转录重新编程。项目3将测试项目1中概述的代谢重新编程是否可以通过非侵入性成像(超极化磁共振成像)检测到，以及项目2中概述的由于克隆消退和扩张而导致的生物移位是否可以通过接受顺铂治疗的患者的CTC分析来检测。在拟议的附录中，我们的目标是促进新的合作，并加深我们对推动HNSCC顺铂耐药的神经元依赖性代谢变化的理解。这些研究将通过确定与代谢变化和顺铂耐药相关的肿瘤细胞和神经元之间的可操作旁分泌信号，在原始范围内增加项目1和2的整体影响。H-CARR有可能通过在治疗早期识别耐药并开发克服耐药的方法以及与耐药相关的表型(如增强的远处转移)来实现顺铂的全部临床应用。拟议实验的成功完成将为顺铂在HNSCC和相关上呼吸道癌症的临床应用建立新的精确肿瘤学方法的临床标准；因此，它将对全球癌症存活率产生重大影响。