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Project 1: Molecular Imaging & Targeted Therapeutics of Stem Cell-Derived Colon Cancer

This project builds upon our combined expertise in ErbB signaling and molecular imaging. We have discovered that Lrig1, a pan-ErbB inhibitor, marks a novel, largely quiescent population of colonic stem cells. Using Lrig1-CreERT2/+;Apcflox/+ mice, we have developed a robust, clinically relevant mouse model of colon cancer. These mice develop multiple distal colonic tumors within 50 days following tamoxifen induction of Cre activity. Tumors arising in Lrig1-CreERT2/+;Apcflox/+ mice overexpress translocator protein (TSPO); we have also observed increased levels of TSPO in human colorectal cancer (CRC) tissue, underscoring the translational relevance of this model. Using novel TSPO positron emission tomography (PET) ligands, we detect small colonic tumors in Lrig1-CreERT2/+;Apcflox/+ mice. Using this model, we present proof-of-principle in vivo efficacy of a novel small molecule Wnt inhibitor developed during the previous grant cycle. During this cycle, we also gained clinical insight into the molecular information provided by [18F]-FLT PET, an imaging biomarker that measures DNA replication via thymidine salvage. Through combined use of [18F]-FLT PET and [18F]-FDG PET, we discovered that mutant BRAF CRC cells resist BRAF inhibition through RAS-mediated activation of PI3K signaling. Further molecular characterization of CRC cells resistant to BRAF inhibition have led us to propose development of a molecular imaging assay of glutamine uptake in this project.

Building upon these accomplishments, we propose to use Lrig1-CreERT2/+;Apcflox/+ mice as a platform for introducing additional genetic events that occur during progression of CRC. CRC progression from cell-oforigin to metastasis is a multistep process driven by the accumulation of distinct genetic events. Expression of driver genes (e.g., KRAS) and/or deletion of tumor suppressor genes (e.g., APC, p53), activate core signaling pathways in tumor cells. Molecular imaging has the potential to quantitatively interrogate discrete pathways and biological processes, although this potential is largely unmet. Association of quantitative imaging readouts with activation and inhibition of core signaling pathways is severely limited because current imaging probes have not been systematically evaluated in well-controlled, clinically relevant in vivo systems. To address this, we propose to leverage our novel Lrig1-Cre driver mouse model to evaluate an innovative suite of biologically orthogonal imaging biomarkers as a function of colon cancer initiation, progression and response to targeted therapeutics. Our overall hypothesis is that molecular imaging metrics will reflect the consequences of specific genetic events associated with CRC progression. We believe that these imaging probes will predict responses to clinically relevant targeted therapy. To evaluate these hypotheses, we propose the following three Specific Aims.

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.

Aim 2. To employ multimodal imaging to assess both colon cancer progression driven by cumulative mutations 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.