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

这是一个新的项目，建立在我们在ErbB信号和分子成像的综合专业知识。我们发现Lrigl1是一种泛ErbB抑制剂，标志着结肠干细胞的一种新的、基本上静止的群体。使用Lrig1-CreERT2; Apcflox/+小鼠，我们已经开发了一种稳健的、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[18 F]-FLT PET和[18 F]-FDG PET，我们在体内发现突变型BRAF CRC细胞通过RAS介导的P13 K信号转导激活抵抗BRAF抑制。BRAF和PI3K的联合抑制在这种情况下是非常有效的。我们建议在我们的Lrig1-Cre驱动小鼠模型中评估一套创新的生物正交成像生物标志物，以监测肿瘤的发生、进展和对靶向治疗的反应。我们提出三个具体目标来推进这项工作。 目标1.利用TSPO配体PET成像评估新型Wnt抑制剂在临床相关的干细胞衍生的结肠癌小鼠模型中的疗效。在Lrig1-CreERT2/+; Apcflox/+小鼠中结肠镜检查证实的肿瘤中，将评价TSPO配体PET作为预测对VU-WS 113（一种CK1 α的变构激活剂）的临床和组织病理学反应的指标。我们预测，Wnt通路抑制将导致治疗效果，可以通过非侵入性成像定量预测。 目标2.采用多模式成像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/+小鼠将用作引入人CRC中常见的其他遗传事件（突变型BRAF、KRAS和p53缺失）的平台。将随时间推移比较报告肿瘤细胞燃料（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，结果与遗传事件、肿瘤分级和分期以及对靶向治疗的反应相关。 目标3。在BRAF突变型CRC患者中联合使用BRAF和PI3K抑制剂的临床试验中，利用分子成像预测治疗反应。患者将通过范德比尔特的个性化癌症医学倡议（PCMI）提供的SNaPshot基因分型进行鉴定。将在治疗开始前和治疗第15天评价系列[18 F]-FLT PET，并将这些结果与标准RECIST标准进行比较。

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.