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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

基本信息

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
项目类别：
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

项目摘要

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