Identifying metabolic dependencies in Hurthle cell carcinoma of the thyroid-Res 1

鉴定甲状腺 Hurthle 细胞癌的代谢依赖性-Res 1

• 批准号: 10734983
• 负责人: David Glenn McFadden
• 金额: $ 52.96万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-27 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734983
• 关键词: Aerobic; Alleles; Biological Models; CRISPR screen; Cancer Patient; Carbon; Cell Line; Cells; Clinical; Clinical Protocols; Complex; Data; Defect; Dependence; Disease; Electron Transport; Environment; Enzymes; Evaluation; Event; Fermentation; Fresh Tissue; Functional disorder; Genetic; Genetically Engineered Mouse; Genotype; Glucose; Glycolysis; Goals; Histology; Human; Immunocompetent; Impairment; Infusion procedures; Isotopes; Knowledge; Label; Lactate Dehydrogenase; Malignant Neoplasms; Malignant neoplasm of thyroid; Metabolic; Metabolism; Mitochondria; Mitochondrial DNA; Modeling; Monitor; Mus; Mutation; NADH dehydrogenase (ubiquinone); Nuclear; Operative Surgical Procedures; Papillary thyroid carcinoma; Patients; Proliferating; Regulation; Renal carcinoma; Resistance; Respiration; Role; Shapes; Therapeutic; Therapeutic Uses; Thyroid Gland; Thyroid Hurthle Cell Carcinoma; Tissues; Trace Elements Nutrition; University Hospitals; Variant; Xenograft Model; anaplastic thyroid cancer; cancer type; exome sequencing; inhibitor; insight; loss of function; metabolic phenotype; mitochondrial DNA alteration; mitochondrial DNA mutation; mitochondrial genome; mutant; neoplastic; novel; participant enrollment; patient derived xenograft model; patient subsets; preclinical evaluation; preclinical study; response; restoration; small molecule inhibitor; small molecule therapeutics; stable isotope; synthetic lethal interaction; therapeutic target; thyroid neoplasm; treatment response; tumor; tumor growth; tumor metabolism; tumorigenesis; whole genome

Project Summary: Cancers require metabolic adaptations to support the unbridled proliferation that drives tumor growth. Mutations in the mitochondrial genome (mtDNA) are observed in many cancers, but the role of these mutations in shaping cellular metabolism and tumor growth is incompletely understood. mtDNA mutations that impair components of the electron transport chain (ETC) appear to be selected against in most forms of cancer. Hürthle cell carcinoma of the thyroid (HTC) is clinically aggressive cancer uniquely enriched for loss-of-function mtDNA mutations in components of complex I of the ETC. We propose that HTC represents an ideal disease outlier in which to interrogate the role of mtDNA alterations and ETC function in cancer. In this proposal, we employ unique and highly complementary approaches to characterize the metabolic impact of mtDNA mutations in HTC and other forms of thyroid and kidney cancer. First, we have developed a clinical protocol to monitor central carbon directly in surgical patients using stable isotope tracing (Aim 1). Second, we have identified a synthetic lethal interaction encoded by complex I mutation and identified a promising small molecule therapeutic using patient-derived models (Aim 2). Finally, we have developed novel GEMMs from which to interrogate the role of complex I function in thyroid tumorigenesis (Aim 3). These approaches are highly complementary and synergistic, yet each is independently poised to bridge key knowledge gaps and lead to new insights into metabolic regulation in cancer. The overall goals of this proposal are to characterize the metabolic adaptations necessitated by complex I loss in HTC directly in patients undergoing thyroid surgery, to identify and target metabolic liabilities as a result of metabolic re-wiring downstream of complex I loss, and to determine whether complex I loss acts to promote or alter thyroid tumor formation in mice. These findings will be of immediate and direct relevance to thyroid cancer patients, provide new insights relevant to other tumors harboring mtDNA mutations and have broad implications across cancer types by providing new insights into ETC function in cancer.

项目摘要： 癌症需要代谢适应来支持驱动肿瘤生长的无限增殖。突变 在许多癌症中观察到线粒体基因组（mtDNA），但是这些突变在塑造中的作用 细胞代谢和肿瘤生长尚不完全了解。损害成分的mtDNA突变 电子传输链（ETC）似乎是在大多数形式的癌症中选择的。 Hürthle细胞癌 甲状腺（HTC）的临床侵略性癌症独特地富集了功能丧失mtDNA突变 i的复杂i的组成部分。我们建议HTC代表一个理想疾病的离群值 询问mtDNA改变和等在癌症中的作用。在此提案中，我们采用独特和 高度完善的方法来表征MTDNA突变在HTC和其他其他方面的代谢影响 甲状腺和肾癌的形式。首先，我们开发了一种临床方案，可以直接监测中央碳 在手术患者中，使用稳定的同位素跟踪（AIM 1）。其次，我们已经确定了合成的致命相互作用 用复合物I突变编码，并确定了使用患者来源的诺言小分子治疗 模型（AIM 2）。最后，我们开发了新颖的宝石，从中询问复杂的作用 甲状腺肿瘤发生的功能（AIM 3）。这些方法是高度互补和协同的，但是 每个人都被中毒以弥合关键知识差距并导致对代谢法规的新见解 在癌症中。该提案的总体目标是表征由 在接受甲状腺手术的患者中，HTC中的复合物I损失，以识别和靶向代谢负债 由于复杂I损失的代谢重新向下重新代谢，并确定复杂的I损失行为是否 促进或改变小鼠的甲状腺肿瘤形成。这些发现将与 甲状腺癌患者，提供与携带mtDNA突变的其他肿瘤相关的新见解，并具有 通过在癌症中提供新的见解，对癌症类型的广泛含义。