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

这是一个基于我们在ErbB信号和分子成像方面的综合专业知识的新项目。我们已经发现Lrigl1是一种泛erbb抑制剂，标志着一种新的、大部分处于静止状态的结肠干细胞群。使用Lrig1-CreERT2;Apcflox/+小鼠，我们已经开发了一个强大的，高度可处理的，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BRAF CRC细胞通过ras介导的P13K信号激活来抵抗BRAF抑制。联合抑制BRAF和PI3K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。我们提出三项具体目标来推进这项工作。

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.