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

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2023 · $72,857

## Abstract

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 oxidat...

## Key facts

- **NIH application ID:** 10866660
- **Project number:** 3R01CA267721-02S1
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** David B Shackelford
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $72,857
- **Award type:** 3
- **Project period:** 2022-07-01 → 2027-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10866660

## Citation

> US National Institutes of Health, RePORTER application 10866660, In vivo imaging of mitochondria structure and function in therapy resistant lung tumors (3R01CA267721-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10866660. Licensed CC0.

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