R01CA267721

In vivo imaging of mitochondria structure and function in therapy-resistant lung tumors - Abstract (30 lines):

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 initial 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 as an in vivo biomarker of mitochondrial membrane potential and OXPHOS in lung tumors. 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.

Los Angeles University Of California

NOT APPLICABLE

93.394 - Cancer Detection and Diagnosis Research

National Cancer Institute (NCI) [HHS - NIH]

Los Angeles, California 90095 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)

Amendment Since initial award the total obligations have increased 464% from $535,514 to $3,022,622.