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.

摘要 这项研究的首要目标是确定有效的基于代谢的诊断和治疗策略 目的：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作为一种新的代谢诊断和开发 针对线粒体氧化代谢的基于代谢的治疗策略在治疗耐药中的作用 KRAS/LKB1和EGFR突变型肺肿瘤。到2021年，非小细胞肺癌将夺走美国约13万人的生命。肺 肿瘤经常具有很高的突变负担，常常导致单剂靶向治疗。 致癌基因突变不成功。此外，肺腺癌的代谢活性亚群 携带KRAS和LKB1或EGFR突变的(LUADs)经常对免疫治疗产生耐药性 接近了。然而，不管检查点抑制剂或靶向治疗的首字母有何益处， 大多数患者最终会对治疗产生抵抗力。我们将一种不同的方法合理化 克服非小细胞肺癌的治疗阻力--即根据肿瘤的代谢特征对肿瘤进行分类。 在这里，肿瘤是根据它们的代谢依赖性来分组和靶向的，而不仅仅是根据它们的基因 改装。非小细胞肺癌是一种代谢异质性疾病，肿瘤同时利用糖酵解和氧化。 线粒体新陈代谢才能生长。线粒体是细胞生物能量学和氧化的场所。 磷酸化(OXPHOS)，对肺癌的启动和维持是必不可少的。由于缺少In 活体成像探头我们在生理和机制层面上的知识存在差距 线粒体生物能量学在非小细胞肺癌中受到调控。为了解决这一差距，我们在功能上 18F-BnTP显像示踪剂在肺肿瘤线粒体活性研究中的应用 线粒体膜电位(ΔΨ)和氧化磷酸化的体内生物标志物功能 (OXPHOS)在肺肿瘤中的表达。重要的是，通过使用18F-BnTP PET成像，我们能够区分 OXPHOS依赖和独立的肺肿瘤。在治疗方面，我们已经证明了18F-BnTP 阳性、依赖OXPHOS的LUAD对线粒体复合体I抑制剂敏感。我们假设 18F-BnTP PET成像可用于对线粒体生物能量学和适应性氧化进行功能分析 耐药肺肿瘤的代谢以指导OXPHOS抑制剂的治疗。在目标1中，我们将 在体内解剖耐药LUAD患者的线粒体生物能量学。在《目标2》中我们将 对耐药患者的适应性氧化代谢进行结构和功能体内分析 KRAS/LKB1和EGFR突变体LUADs。在目标3中，我们将纵向描述LUAD的氧化代谢 患有晚期疾病的患者。拟议的工作与人类健康有关，我们在其中建议 18F-BnTP PET显像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阻力。