Quantitative Imaging of OXPHOS in Pancreatic Cancer

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PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive cancers. Leveraging clinical and basic science expertise in PDAC and quantitative positron emission tomography (PET), we propose to evaluate a PET tracer to quantify a targetable and potentially prognostic feature of PDAC, oxidative phosphorylation (OXPHOS), in preclinical studies. Ring Finger Protein 43, RNF43, encodes for an E3 ubiquitin ligase commonly mutated in PDAC and high- risk pancreatic precursor lesions, including intraductal papillary mucinous neoplasms (IPMNs). At MD Anderson, we have developed a genetically engineered mouse model of PDAC with pancreas-specific mutant Kras expression and bi-allelic loss of Rnf43 (Kras;Rnf43 mice). Single-cell RNA sequencing of Kras;Rnf43 pancreata reveals a striking enrichment for mitochondrial genes, including dramatically increased OXPHOS. In Preliminary Studies, we have demonstrated that an inhibitor of OXPHOS activity extends the survival of Kras;Rnf43 mice compared to vehicle-treated control. Quantitative relationships between pancreatic OXPHOS activity and progression of precursor lesions to PDAC, as well as OXPHOS activity and response to OXPHOS inhibition, is unknown, motivating our proposed studies. Here, we propose to quantify OXPHOS activity in vivo using a PET tracer targeting mitochondrial membrane potential. While not previously evaluated in PDAC, a PET tracer of mitochondrial membrane potential, 18F-fluorobenzyl triphenylphosphonium (18F-BnTP), has shown utility for quantifying OXPHOS activity in mouse models of lung cancer. We will leverage the elevated OXPHOS activity in tumors arising in Kras;Rnf43 mice, as well as orthotopic allografts derived from these mice and human PDX models, to test two hypotheses, (1) that elevated accumulation of 18F-BnTP is a property of Rnf43 mutation in PDAC and (2) that PET with 18F-BnTP serves as a pharmacodynamic biomarker of response to an OXPHOS inhibitor. We propose three Specific Aims. Aim 1: To evaluate tumor accumulation of 18F-BnTP in Kras;Rnf43 mice and Kras;p53-mutant (KPC) mice. Aim 2: To longitudinally evaluate 18F-BnTP accumulation in the pancreata of Kras;Rnf43 mice during multistep progression to PDAC. Aim 3: To evaluate 18F-BnTP PET as a pharmacodynamic (PD) biomarker of OXPHOS inhibition. Translational Relevance. We will evaluate a clinically-translatable PET tracer in mice and patient- derived tissues that may enable the prioritization of patients with PDAC for OXPHOS-inhibitor therapy and allow optimization of therapeutic regimens targeting OXPHOS activity.