In vivo imaging of mitochondria structure and function in therapy resistant lung tumors

治疗耐药性肺肿瘤线粒体结构和功能的体内成像

基本信息

批准号：
10866660
负责人：
David B Shackelford
金额：
$ 7.29万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-07-01 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10866660
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

项目摘要

Abstract (30 line): 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（30行）：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改善非小细胞肺癌（NSCLC）患者的总体存活率。我们建议调查极性发射断层扫描（PET）示踪剂，18F-BNTP作为一种新型代谢诊断，并发展基于代谢的理论策略，靶向抗治疗中的氧化线粒体代谢 KRAS/LKB1和EGFR突变肺肿瘤。 NSCLC将于2021年在美国夺取约130,000的生命。肺肿瘤经常具有高突变伯嫩，通常会构成靶向致癌的单药疗法驾驶员突变失败。此外，肺腺癌的代谢活性子集（LUADS） KRAS和LKB1或EGFR中的轴承突变通常对免疫疗法方法具有抗性。然而，不管检查点抑制剂或有针对性疗法受益的缩写如何，大多数患者都将最终会产生对治疗的抵抗力。我们合理化一种克服治疗抗性的不同方法在NSCLC中 - 即通过其代谢特征对肿瘤进行分类。在这里，肿瘤分组，由它们的代谢依赖性而不是仅仅由它们的遗传改变。 NSCLC是代谢异质性疾病和肿瘤利用糖酵解和氧化性线粒体代谢生长。线粒体是细胞生物能和氧化磷酸化（Oxphos）的位置，是必不可少的用于肺部肿瘤的启动和维护。由于缺乏体内成像问题，我们的知识存在差距在NSCLC中如何调节线粒体生物能力的物理和机械水平。解决这个差距，我们使用PET成像示踪剂18F-BNTP在肺肿瘤中功能成像的线粒体活性并证明它发挥了线粒体膜电位（Δψ）和氧化的体内生物标志物肺肿瘤中的磷酸化（OXPHOS）3。重要的是，通过使用18F-BNTP PET成像我们能够在OXPHOS依赖性和独立的肺肿瘤之间不同。从治疗上，我们已经证明了 18F-BNTP阳性，依赖Oxphos的LUAD对线粒体复合物I抑制剂敏感。我们假设18F-BNTP PET成像可以在功能上介绍线粒体生物能和耐治疗的肺部肿瘤中的自适应氧化物代谢，以指导OXPHOS抑制剂治疗。在 AIM 1我们将在耐治疗的LUADS中对线粒体生物能学进行体内解剖。在目标2中我们将对抗治疗的自适应氧化代谢进行体内和功能性分析 KRAS/LKB1和EGFR突变体。在AIM 3中，我们将在Luad中纵向介绍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，我们建议 18F-BNTP PET成像引导的靶向和氧化代谢代表了一种新的治疗策略克服KRAS/LKB1和EGFR突变肿瘤患者的耐药性。