Quantitative Imaging of OXPHOS in Pancreatic Cancer

胰腺癌中 OXPHOS 的定量成像

基本信息

批准号：
10649885
负责人：
Henry Charles Manning
金额：
$ 18.93万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-07 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649885
关键词：
ATP Synthesis Pathway Age Allografting Basic Science Biological Models Biological Process Clinical Sciences Clinical Trials Complex Data Disease Dose Drug Targeting Early Diagnosis Future Genes Genetic Genetically Engineered Mouse Histopathology Human Incidence Intervention KPC model Label Lesion Loss of Heterozygosity Maintenance Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of pancreas Measures Membrane Potentials Mitochondria Modeling Molecular Mucinous Neoplasm Mus Mutate Mutation Operative Surgical Procedures Oxidative Phosphorylation Pancreas Pancreatic Ductal Adenocarcinoma Papillary Pathology Patients Pharmacodynamics Phenotype Phosphorylation Inhibition Physicians Positron-Emission Tomography Prediction of Response to Therapy Process Property Proteins Regimen Ring Finger Domain Survival Rate TP53 gene Testing Therapeutic Tissues Tracer Translations adjudication clinical translation drug development high risk improved in vivo in vivo Model inhibitor inhibitor therapy innovation mitochondrial membrane mouse model mutant new therapeutic target pancreatic ductal adenocarcinoma model patient derived xenograft model pharmacodynamic biomarker pharmacokinetic model potential biomarker precision medicine preclinical study premalignant prognostic quantitative imaging response response biomarker single-cell RNA sequencing support tools therapeutic target tumor tumor microenvironment ubiquitin-protein ligase

项目摘要

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.

项目摘要/摘要胰腺导管腺癌（PDAC）是最具侵略性的癌症之一。利用临床和基本 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 示踪剂量化PDAC的可靶向且潜在的预后特征，氧化磷酸化（OXPHOS），在临床前研究中。环手指蛋白43，RNF43编码通常在PDAC和高 - 高的E3泛素连接酶风险胰腺前体病变，包括导管内乳头状粘液性肿瘤（IPMNS）。在MD Anderson，我们已经开发了具有胰腺特异性突变体KRAS的PDAC的基因工程小鼠模型 RNF43（KRAS; RNF43小鼠）的表达和双行损失。 KRAS的单细胞RNA测序; RNF43 Pancreata 揭示了线粒体基因的惊人富集，包括大量增加的Oxphos。在初步研究，我们已经证明了Oxphos活性的抑制剂扩展了KRAS的存活； RNF43小鼠的生存率与车辆处理的对照相比。胰Oxphos活性与前体病变向PDAC以及OXPHOS活性和对OXPHOS抑制的反应的进展未知，激励我们提出的研究。在这里，我们建议使用靶向线粒体的宠物示踪剂在体内定量OXPHOS活性膜电位。虽然先前未在PDAC（线粒体膜电位的宠物示踪剂）中进行评估，但 18F氟苯基三苯基磷芬（18F-BNTP）已显示用于量化小鼠Oxphos活性的实用性肺癌的模型。我们将利用KRAS; RNF43小鼠的肿瘤中的Oxphos活性升高，AS 以及从这些小鼠和人类PDX模型中得出的原位同种异体移植物，以检验两个假设，（1） 18F-BNTP的积累升高是PDAC中RNF43突变的特性，（2）用18F-BNTP pet 用作对OXPHOS抑制剂的反应的药效生物标志物。我们提出了三个具体目标。目的1：评估KRAS中18F-BNTP的肿瘤积累； RNF43小鼠和KRAS; p53-突变（KPC）小鼠。目的 2：纵向评估在Multistep期间KRAS胰腺中的18F-BNTP积累发展为PDAC。目标3：评估18F-BNTP PET作为Oxphos的药效学（PD）生物标志物抑制。翻译相关性。我们将评估小鼠和患者的临床转换宠物示踪剂可能使PDAC患者优先进行OXPHOS抑制剂治疗的衍生组织，并允许靶向OXPHOS活性的治疗方案的优化。