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

摘要(30行)： 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 肿瘤常常有很高的突变负担，常常导致针对致癌基因的单剂治疗。 驱动程序突变不成功。此外，肺腺癌代谢活性亚群(LUAD) 携带KRAS和LKB1或EGFR突变的患者经常对免疫治疗方法产生耐药性。然而， 不管检查点抑制剂或靶向治疗最初的益处如何，大多数患者都会 最终会对治疗产生抵抗力。我们合理化了一种克服治疗阻力的不同方法。 在非小细胞肺癌中-即根据肿瘤的代谢特征对肿瘤进行分类。在这里，肿瘤被分组并 以他们的新陈代谢依赖性为目标，而不仅仅是他们的基因变化。非小细胞肺癌是一种新陈代谢 异质性疾病和肿瘤利用糖酵解和氧化线粒体代谢来生长。这个 线粒体是细胞生物能和氧化磷酸化(OXPHOS)的场所，是必不可少的 用于肺癌的启动和维持。由于缺乏活体成像探测器，我们的知识存在差距 在生理和机制水平上，线粒体生物能量学在非小细胞肺癌中是如何被调节的。致信地址 在这个缺口中，我们使用18F-BnTP PET成像示踪剂对肺肿瘤中的线粒体活性进行了功能成像 并证明它是体内线粒体膜电位(ΔΨ)和氧化的生物标志物 肺肿瘤中的磷酸化(OXPHOS)。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。在治疗上，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成像可用于功能分析线粒体生物能量学和 耐药肺肿瘤的适应性氧化代谢指导OXPHOS抑制剂的治疗。在……里面 目的1我们将在体内解剖治疗难治性LUAD患者的线粒体生物能量学。在AIM 2 我们将在体内对耐药的适应性氧化代谢进行结构和功能分析 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。

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.