Molecular Imaging & Targeted Therapeutics of Stem Cell-Derived Colon Cancer

分子成像

• 批准号: 8867155
• 负责人: Robert J. Coffey
• 金额: $ 28.81万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-24 至 2016-04-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8867155
• 关键词: BRAF gene; Cells; Clinical; Clinical Trials; Colon Carcinoma; Colonoscopy; DNA biosynthesis; Event; Genetic; Genotype; Glucose; Glutamine; Human; Image; KRAS2 gene; Ligands; Malignant Neoplasms; Mediating; Medicine; Molecular Target; Monitor; Multimodal Imaging; Mus; Mutation; Pathway interactions; Patients; Population; Positron-Emission Tomography; Reporting; Signal Transduction; Staging; Stem cells; Steroid biosynthesis; Therapeutic; Time; Treatment Efficacy; Work; clinically relevant; fluorodeoxyglucose positron emission tomography; imaging biomarker; imaging probe; in vivo; inhibitor/antagonist; innovation; molecular imaging; mouse model; mutant; neoplastic cell; non-invasive imaging; novel; response; therapeutic target; thymidine kinase 1; tumor; tumor initiation; tumor progression; uptake

This is a new project that builds upon our combined expertise in ErbB signaling and molecular imaging. We have discovered that Lrigl1 a pan-ErbB inhibitor, marks a novel, largely quiescent population of colonic stem cells. Using Lrig1-CreERT2;Apcflox/+ mice, we have developed a robust, highly tractable, clinically relevant, stem cell-derived mouse model of colon cancer. Through combined use of [18F]-FLT PET and [18F]-FDG PET, we discovered in vivo that mutant BRAF CRC cells resist BRAF inhibition through RAS-mediated activation of P13K signaling. Combined inhibition of BRAF and PI3K is highly efficacious in this setting. We propose to evaluate an innovative suite of biologically orthogonal imaging biomarkers to monitor tumor initiation, progression and response to targeted therapeutics in our Lrig1-Cre driver mouse model. We propose three Specific Aims to advance this work. Aim 1. To utilize TSPO ligand PET imaging to assess the efficacy of a novel Wnt inhibitor in a clinically relevant, stem cell-derived mouse model of colon cancer. In colonoscopy-confirmed tumors in Lrig1-CreERT2/+;Apcflox/+ mice, TSPO ligand PET will be evaluated as a metric for predicting clinical and histopathological response to VU-WS113, an allosteric activator of CK1alpha. We predict that Wnt pathway inhibition will result in therapeutic efficacy that can be predicted quantitatively by non-invasive imaging. Aim 2. To employ multimodal imaging to assess both colon cancer progression driven by cumulative mutations and responses to targeted therapeutics. The Lrig1-CreERT2/+;Apcflox/+ mouse will be used as a platform to introduce additional genetic events that commonly occur in human CRC (mutant BRAF, KRAS and loss of p53). Imaging metrics that report tumor cell fueling (glucose/glutamine uptake), steroidogenesis (TSPO expression), and DNA replication (thymidine kinase 1 (TK1) expression) will be compared over time and the results correlated to genetic events, tumor grade and stage, and responses to targeted therapeutics. Aim 3. To utilize molecular imaging to predict therapeutic response in a clinical trial that combines BRAF and PI3K inhibitors in patients with mutant BRAF CRC. Patients will be identified by SNaPshot genotyping provided through Vanderbilt's Personalized Cancer Medicine Initiative (PCMI). Serial [18F]-FLT PET will be evaluated prior to the initiation of therapy and day 15 of therapy, and these results will be compared to standard RECIST criteria.

这是一个新项目，建立在我们在 ErbB 信号传导和分子成像方面的综合专业知识之上。我们发现 Lrigl1 是一种泛 ErbB 抑制剂，标志着一种新型的、基本上处于静止状态的结肠干细胞群。使用 Lrig1-CreERT2;Apcflox/+ 小鼠，我们开发了一种稳健的、高度易处理的、临床相关的、干细胞衍生的结肠癌小鼠模型。通过联合使用[18F]-FLT PET和[18F]-FDG PET，我们在体内发现突变型BRAF CRC细胞通过RAS介导的P13K信号传导激活来抵抗BRAF抑制。在这种情况下，联合抑制 BRAF 和 PI3K 非常有效。我们建议评估一套创新的生物正交成像生物标志物，以监测 Lrig1-Cre 驱动小鼠模型中肿瘤的发生、进展和对靶向治疗的反应。我们提出了三个具体目标来推进这项工作。 目标 1. 利用 TSPO 配体 PET 成像来评估新型 Wnt 抑制剂在临床相关的干细胞衍生小鼠结肠癌模型中的功效。在结肠镜检查证实的 Lrig1-CreERT2/+；Apcflox/+ 小鼠肿瘤中，TSPO 配体 PET 将作为预测对 VU-WS113（一种 CK1α 变构激活剂）临床和组织病理学反应的指标进行评估。我们预测 Wnt 通路抑制将产生可通过非侵入性成像定量预测的治疗效果。 目标 2. 采用多模态成像来评估累积突变驱动的结肠癌进展和对靶向治疗的反应。 Lrig1-CreERT2/+;Apcflox/+ 小鼠将用作平台来引入人类 CRC 中常见的其他遗传事件（突变 BRAF、KRAS 和 p53 缺失）。报告肿瘤细胞燃料（葡萄糖/谷氨酰胺摄取）、类固醇生成（TSPO 表达）和 DNA 复制（胸苷激酶 1 (TK1) 表达）的成像指标将随着时间的推移进行比较，并将结果与​​遗传事件、肿瘤分级和阶段以及对靶向治疗的反应相关。 目标 3. 在针对突变 BRAF CRC 患者联合使用 BRAF 和 PI3K 抑制剂的临床试验中，利用分子成像预测治疗反应。将通过范德堡大学个性化癌症医学计划 (PCMI) 提供的 SNaPshot 基因分型来识别患者。将在治疗开始前和治疗第 15 天之前对系列 [18F]-FLT PET 进行评估，并将这些结果与标准 RECIST 标准进行比较。