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.

Public Health Relevance

Using a novel mouse model of colon cancer, we will perform the first systematic analysis of a suite of noninvasive imaging probes to monitor tumor progression and predict response to targeted therapeutics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA095103-13
Application #
8726908
Study Section
Special Emphasis Panel (ZCA1-RPRB-M)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
13
Fiscal Year
2014
Total Cost
$579,443
Indirect Cost
$466,028
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
004413456
City
Nashville
State
TN
Country
United States
Zip Code
37212
Zhu, Shoumin; Soutto, Mohammed; Chen, Zheng et al. (2016) Helicobacter pylori-induced cell death is counteracted by NF-κB-mediated transcription of DARPP-32. Gut :
Parang, B; Bradley, A M; Mittal, M K et al. (2016) Myeloid translocation genes differentially regulate colorectal cancer programs. Oncogene 35:6341-6349
Hong, Jun; Chen, Zheng; Peng, Dunfa et al. (2016) APE1-mediated DNA damage repair provides survival advantage for esophageal adenocarcinoma cells in response to acidic bile salts. Oncotarget 7:16688-702
McKenzie, Andrew J; Hoshino, Daisuke; Hong, Nan Hyung et al. (2016) KRAS-MEK Signaling Controls Ago2 Sorting into Exosomes. Cell Rep 15:978-87
Hardbower, Dana M; Singh, Kshipra; Asim, Mohammad et al. (2016) EGFR regulates macrophage activation and function in bacterial infection. J Clin Invest 126:3296-312
Zhao, Yue; Liu, Qi; Acharya, Pankaj et al. (2016) High-Resolution Mapping of RNA Polymerases Identifies Mechanisms of Sensitivity and Resistance to BET Inhibitors in t(8;21) AML. Cell Rep 16:2003-16
Yu, Huapeng H; Dohn, Michael R; Markham, Nicholas O et al. (2016) p120-catenin controls contractility along the vertical axis of epithelial lateral membranes. J Cell Sci 129:80-94
Schulte, Michael L; Khodadadi, Alexandra B; Cuthbertson, Madison L et al. (2016) 2-Amino-4-bis(aryloxybenzyl)aminobutanoic acids: A novel scaffold for inhibition of ASCT2-mediated glutamine transport. Bioorg Med Chem Lett 26:1044-7
Sievers, Chelsie K; Leystra, Alyssa A; Clipson, Linda et al. (2016) Understanding Intratumoral Heterogeneity: Lessons from the Analysis of At-Risk Tissue and Premalignant Lesions in the Colon. Cancer Prev Res (Phila) 9:638-41
Harris, Kelly L; Pulliam, Stephanie R; Okoro, Emmanuel et al. (2016) Western diet enhances benzo(a)pyrene-induced colon tumorigenesis in a polyposis in rat coli (PIRC) rat model of colon cancer. Oncotarget 7:28947-60

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