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.

项目概要： 癌症需要代谢适应来支持驱动肿瘤生长的无节制增殖。突变 在许多癌症中观察到线粒体基因组（mtDNA）中的突变，但这些突变在塑造癌症中的作用 对细胞代谢和肿瘤生长的认识还不完全。线粒体DNA突变损害了 电子传递链（ETC）似乎在大多数形式的癌症中被选择性地对抗。许特尔细胞癌 甲状腺癌（HTC）是一种临床上具有侵袭性的癌症，在甲状腺癌中富含功能丧失的mtDNA突变。 我们认为HTC代表了一个理想的疾病离群值，其中 询问mtDNA改变和ETC功能在癌症中的作用。在这份提案中，我们采用了独特的， 高度互补的方法来表征线粒体DNA突变在HTC和其他 甲状腺癌和肾癌。首先，我们开发了一种临床方案， 在手术患者中使用稳定同位素示踪（目的1）。第二，我们已经确定了一种合成的致命相互作用 编码的复合物I突变，并确定了一个有前途的小分子治疗，使用患者来源的 模型（目标2）。最后，我们已经开发了新的GEMM，从中询问复合物I的作用， 在甲状腺肿瘤发生中的作用（目的3）。这些方法是高度互补和协同的，但 每个人都独立地准备弥合关键的知识差距，并导致对代谢调节的新见解 在癌症中。本提案的总体目标是描述代谢适应所必需的特征， 在接受甲状腺手术的患者中，直接在HTC中的复合物I损失，以识别和靶向代谢负债 作为复合物I损失下游的代谢重新布线的结果，并确定复合物I损失是否起作用， 促进或改变小鼠甲状腺肿瘤的形成。这些发现将直接和直接相关， 甲状腺癌患者，提供了与其他携带mtDNA突变的肿瘤相关的新见解， 通过对ETC在癌症中的功能提供新的见解，对癌症类型产生广泛的影响。