Quantitative Imaging of OXPHOS in Pancreatic Cancer

项目总结/摘要 胰腺导管腺癌（PDAC）是最具侵袭性的癌症之一。利用临床和基础 在PDAC和定量正电子发射断层扫描（PET）的科学专业知识，我们建议评估PET 示踪剂定量PDAC的靶向和潜在预后特征，氧化磷酸化（OXPHOS）， 在临床前研究中。 Ring Finger Protein 43，RNF 43，编码一种E3泛素连接酶，通常在PDAC中突变，并且高表达。 胰腺前驱病变风险，包括导管内乳头状粘液性肿瘤（IPMN）。在MD安德森， 我们已经开发了一种具有胰腺特异性突变Kras的PDAC基因工程小鼠模型， Rnf 43的表达和双等位基因丢失（Kras; Rnf 43小鼠）。胰腺Kras; Rnf 43的单细胞RNA测序 揭示了线粒体基因的显著富集，包括OXPHOS的显著增加。初步 研究表明，OXPHOS活性抑制剂延长了Kras; Rnf 43小鼠的存活时间， 与载体处理的对照相比。胰腺OXPHOS活性与 前体病变进展为PDAC，以及OXPHOS活性和对OXPHOS抑制的反应， 未知，激发我们提出的研究。 在这里，我们建议使用靶向线粒体的PET示踪剂来定量体内OXPHOS活性。 膜电位虽然以前没有在PDAC（一种线粒体膜电位的PET示踪剂）中进行评估， 18F-氟苄基三苯基鏻（18F-BnTP）已显示出用于定量小鼠中的OXPHOS活性的实用性。 肺癌的模型我们将利用Kras; Rnf 43小鼠中产生的肿瘤中升高的OXPHOS活性， 以及源自这些小鼠和人PDX模型的原位同种异体移植物，以检验两个假设，（1） 18F-BnTP蓄积升高是PDAC中Rnf 43突变的特性，（2）18F-BnTP PET 作为对OXPHOS抑制剂反应的药效学生物标志物。我们提出三个具体目标。 目的1：评价18F-BnTP在Kras; Rnf 43小鼠和Kras;p53突变（KPC）小鼠中的肿瘤蓄积。目的 2：纵向评价多步骤给药期间Kras; Rnf 43小鼠胰腺中18F-BnTP的蓄积 发展到PDAC。目的3：评价18F-BnTP PET作为OXPHOS的药效学（PD）生物标志物 抑制作用 翻译的相关性。我们将在小鼠和患者中评估临床可翻译的PET示踪剂- 来源的组织，可以使PDAC患者优先接受OXPHOS抑制剂治疗，并允许 优化靶向OXPHOS活性的治疗方案。

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.