In Vivo Imaging of Mitochondria Structure and Function in Therapy Resistant Lung Tumors

难治性肺肿瘤线粒体结构和功能的体内成像

• 批准号: 10747207
• 负责人: David B Shackelford
• 金额: $ 4.07万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10747207
• 关键词: 3-Dimensional; Address; American; Area; Biguanides; Bioenergetics; Biological Markers; Biopsy; Cancer Patient; Cell Line; Cell Respiration; Classification; Clinical; Complex; Data; Dependence; Diagnosis; Diagnostic; Disease; Disease Resistance; Dissection; Electron Transport; Epidermal Growth Factor Receptor; Exhibits; Functional Imaging; Gene Expression Profiling; Genetically Engineered Mouse; Goals; Health; Human; Immuno-Chemotherapy; Immunotherapy; KRAS2 gene; Knowledge; Lung Adenocarcinoma; Lung Neoplasms; Maintenance; Malignant neoplasm of lung; Measures; Membrane Potentials; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenic; Oxidative Phosphorylation; Patients; Phenotype; Phosphorylation Inhibition; Physiological; Positron-Emission Tomography; Rationalization; Research; Resistance; Resistance development; STK11 gene; Site; Spirometry; Structure; Survival Rate; Testing; Therapeutic; Time; Tracer; Tyrosine Kinase Inhibitor; Work; advanced disease; cancer therapy; checkpoint therapy; diagnostic strategy; driver mutation; fluorodeoxyglucose; image guided; imaging probe; improved; in vivo; in vivo imaging; inhibitor; metabolic profile; mitochondrial membrane; mitochondrial metabolism; mutant; nano-string; neoplastic cell; novel; novel diagnostics; novel strategies; novel therapeutic intervention; novel therapeutics; patient derived xenograft model; stem; superresolution microscopy; targeted treatment; therapy development; therapy resistant; treatment response; tumor; tumor initiation; tumor metabolism; uptake

Abstract The overarching goal of this study is to identify effective metabolic based diagnostic and therapeutic strategies to improve the overall survival of patients with Non-small cell lung cancer (NSCLC). We propose to investigate the positron emission tomography (PET) tracer, 18F-BnTP as a novel metabolic diagnostic and to develop metabolic based therapeutic strategies targeting oxidative mitochondrial metabolism in therapy resistant KRAS/LKB1 and EGFR mutant lung tumors. NSCLC will claim the lives of ~130,000 in the US in 2021. Lung tumors frequently possess a high mutational burden, often rendering single agent therapies targeting oncogenic driver mutations unsuccessful. Furthermore, metabolically active subsets of lung adenocarcinomas (LUADs) bearing mutations in KRAS and LKB1 or EGFR are frequently resistant to immunotherapy approaches. However, regardless of the initials benefits from checkpoint inhibitors or targeted therapies, the majority of patients will eventually develop resistance to therapy. We rationalize a different approach to overcoming therapy resistance in NSCLC – namely the classification of tumors by their metabolic signature. Here, tumors are grouped and targeted by their metabolic dependencies rather than solely by their genetic alterations. NSCLC is a metabolically heterogeneous disease and tumors utilize both glycolytic and oxidative mitochondrial metabolism to grow. The mitochondria are the site of cellular bioenergetics and oxidative phosphorylation (OXPHOS) and are essential for lung tumor initiation and maintenance. Due to a lack of in vivo imaging probes there is a gap in our knowledge at a physiological and mechanistic level of how mitochondrial bioenergetics are regulated in NSCLC. To address this gap, we functionally imaged mitochondrial activity in lung tumors utilizing the PET imaging tracer 18F-BnTP and demonstrate that it functions an in vivo biomarker of mitochondrial membrane potential (ΔΨ) and oxidative phosphorylation (OXPHOS) in lung tumors3. Importantly, by using 18F-BnTP PET imaging we are able to distinguish between OXPHOS dependent and independent lung tumors. Therapeutically, we have demonstrated that 18F-BnTP positive, OXPHOS-dependent LUADs are sensitive to mitochondrial complex I inhibitors. We hypothesize that 18F-BnTP PET imaging can be utilized to functionally profile mitochondrial bioenergetics and adaptive oxidative metabolism in therapy-resistant lung tumors to guide treatment with OXPHOS inhibitors. In aim 1 we will perform an in vivo dissection of mitochondrial bioenergetics in therapy-resistant LUADs. In aim 2 we will perform a structural and functional in vivo analysis of adaptive oxidative metabolism in therapy-resistant KRAS/LKB1 and EGFR mutant LUADs. In Aim 3 we will longitudinally profile oxidative metabolism in LUAD patients with advanced disease. The proposed work has relevance to human health in which we propose that 18F-BnTP PET imaging guided targeting and oxidative metabolism represents a new therapeutic strategy to overcome therapy resistance in patients with KRAS/LKB1 and EGFR mutant tumors.

抽象的 这项研究的总体目标是确定有效的基于代谢的诊断和治疗策略 提高非小细胞肺癌（NSCLC）患者的总体生存率。我们建议调查 正电子发射断层扫描 (PET) 示踪剂 18F-BnTP 作为一种新型代谢诊断并开发 针对治疗耐药的氧化线粒体代谢的基于代谢的治疗策略 KRAS/LKB1 和 EGFR 突变肺肿瘤。 2021 年，非小细胞肺癌将夺走美国约 130,000 人的生命。 肺癌 肿瘤通常具有高突变负荷，通常需要单药治疗 致癌驱动突变不成功。此外，肺腺癌的代谢活跃亚型 携带 KRAS 和 LKB1 或 EGFR 突变的 (LUAD) 经常对免疫治疗产生耐药性 接近。然而，无论检查点抑制剂或靶向治疗的最初益处如何， 大多数患者最终会对治疗产生耐药性。我们合理化了一种不同的方法 克服非小细胞肺癌的治疗耐药性——即根据肿瘤的代谢特征对肿瘤进行分类。 在这里，肿瘤是根据其代谢依赖性而不是仅仅根据其遗传来分组和靶向的 变更。 NSCLC 是一种代谢异质性疾病，肿瘤同时利用糖酵解和氧化 线粒体代谢生长。线粒体是细胞生物能和氧化的场所 磷酸化（OXPHOS）对于肺肿瘤的发生和维持至关重要。由于缺乏在 体内成像探针在生理和机械层面上我们的知识存在差距 线粒体生物能在 NSCLC 中受到调节。为了解决这一差距，我们对功能进行了成像 利用 PET 成像示踪剂 18F-BnTP 检测肺部肿瘤中的线粒体活性，并证明它 是线粒体膜电位 (ΔΨ) 和氧化磷酸化的体内生物标志物 （OXPHOS）在肺部肿瘤中3。重要的是，通过使用 18F-BnTP PET 成像，我们能够区分 OXPHOS 依赖性和非依赖性肺肿瘤。在治疗上，我们已经证明 18F-BnTP 阳性、OXPHOS 依赖性 LUAD 对线粒体复合物 I 抑制剂敏感。我们假设 18F-BnTP PET 成像可用于功能性分析线粒体生物能学和适应性氧化 耐药性肺部肿瘤的代谢，以指导 OXPHOS 抑制剂的治疗。在目标 1 中，我们将 对治疗抵抗性 LUAD 中的线粒体生物能学进行体内解剖。在目标 2 中，我们将 对治疗耐药的适应性氧化代谢进行结构和功能体内分析 KRAS/LKB1 和 EGFR 突变 LUAD。在目标 3 中，我们将纵向分析 LUAD 中的氧化代谢 患有晚期疾病的患者。拟议的工作与人类健康相关，我们建议 18F-BnTP PET 成像引导靶向和氧化代谢代表了一种新的治疗策略 克服 KRAS/LKB1 和 EGFR 突变肿瘤患者的治疗耐药性。