The EGFR contributes to the pathogenesis of many human cancers, including colorectal cancer (CRC), which is the third most commonly diagnosed cancer and the third leading cause of cancer deaths in the US for both men and women. The EGFR has become a major therapeutic target in many cancers. The EGFR neutralizing monoclonal antibody, cetuximab, is approved for the treatment of advanced CRCs that contain wild-type KRAS; however, only 15% of individuals with wild-type KRAS CRC respond to cetuximab, and individuals with mutant KRAS CRC do not respond to cetuximab. The challenge in cancer research I propose to address is: why has EGFR blockade in CRC (and other solid tumors) had such modest clinical benefit. I propose that the inability to more effectively block the EGFR in CRC is due, at least in part, to three issues: 1) an incomplete understanding of the complexity of EGFR signaling triggered by its seven mammalian ligands; 2) inadequate predictive preclinical models and 3) the emergence of drug resistance. By addressing each of these three issues, the overall goal of this revised application is to significantly advance the diagnosis, treatment and monitoring of individuals with CRC. Our focus is CRC, viewed from the perspective of membrane-proximal EGFR-related events. We anticipate that advances we make will be applicable to other solid tumors in which EGFR signaling plays a prominent role. Based on our recent finding that the Egfr inhibitor, Lrig1, marks a distinct population of colonic stem cells and acts as a tumor suppressor, along with the use of unique reporter mice (Lrig1-Apple, Egfr-EmGFP), we propose to link key events in colonic neoplasia to stem cells and Egfr- related events. Our lab has developed a robust model of colonic neoplasia: within 50 days of inducing loss of one Apc allele in Lrig1-expressing colonic stem cells, multiple, highly dysplastic colonic adenomas arise that can be monitored by colonoscopy and novel PET imaging probes. These mice will be treated with the first available mouse Egfr neutralizing antibody. Findings in mouse adenomas will be related to human adenomas. Using MulltiOmyx and DISSECT, we will examine the tumor landscape at single cell resolution and deconstruct tumor heterogeneity. Using a newly developed 3D culture system, we have discovered a novel mode of cetuximab resistance via increased WNT signaling due to marked upregulation of a long con-coding RNA not previously linked to CRC. We will further elucidate the mechanism of this resistance and advance these findings clinically. We will further examine a new mode of signaling by EGFR and its ligands via exosomes and test whether EGFR-containing exosomes act as a decoy to reduce the amount of EGFR antibody delivered to tumors. We will harness the tools and resources at Vanderbilt University, Vanderbilt-Ingram Cancer Center and Vanderbilt's GI Specialized Programs of Research Excellence (SPORE) to advance this work.

Public Health Relevance

We propose that the modest impact of EGFR blockade in CRC (and other solid tumors) is due to 1) an incomplete understanding of the complexity of EGFR signaling triggered by its seven mammalian ligands, 2) inadequate predictive preclinical models and 3) the emergence of drug resistance. By addressing each of these three issues, the overall goal of this revised application is to significantly advance the diagnosis, treatment and monitoring of individuals with CRC. Clinical implementation of advances made will be accelerated through Vanderbilt's GI Specialized Programs of Research Excellence that is focused on CRC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Unknown (R35)
Project #
5R35CA197570-03
Application #
9673679
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Salnikow, Konstantin
Project Start
2017-04-01
Project End
2024-03-31
Budget Start
2019-04-01
Budget End
2020-03-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Vanderbilt University Medical Center
Department
Type
DUNS #
079917897
City
Nashville
State
TN
Country
United States
Zip Code
37232
Zhang, Qin; Jeppesen, Dennis K; Higginbotham, James N et al. (2018) Mutant KRAS Exosomes Alter the Metabolic State of Recipient Colonic Epithelial Cells. Cell Mol Gastroenterol Hepatol 5:627-629.e6
Saito-Diaz, Kenyi; Benchabane, Hassina; Tiwari, Ajit et al. (2018) APC Inhibits Ligand-Independent Wnt Signaling by the Clathrin Endocytic Pathway. Dev Cell 44:566-581.e8
Liu, Qi; Herring, Charles A; Sheng, Quanhu et al. (2018) Quantitative assessment of cell population diversity in single-cell landscapes. PLoS Biol 16:e2006687
Means, Anna L; Freeman, Tanner J; Zhu, Jing et al. (2018) Epithelial Smad4 Deletion Up-Regulates Inflammation and Promotes Inflammation-Associated Cancer. Cell Mol Gastroenterol Hepatol 6:257-276
Herring, Charles A; Banerjee, Amrita; McKinley, Eliot T et al. (2018) Unsupervised Trajectory Analysis of Single-Cell RNA-Seq and Imaging Data Reveals Alternative Tuft Cell Origins in the Gut. Cell Syst 6:37-51.e9
Hinger, Scott A; Cha, Diana J; Franklin, Jeffrey L et al. (2018) Diverse Long RNAs Are Differentially Sorted into Extracellular Vesicles Secreted by Colorectal Cancer Cells. Cell Rep 25:715-725.e4
Schulte, Michael L; Fu, Allie; Zhao, Ping et al. (2018) Pharmacological blockade of ASCT2-dependent glutamine transport leads to antitumor efficacy in preclinical models. Nat Med 24:194-202
Banerjee, Amrita; McKinley, Eliot T; von Moltke, Jakob et al. (2018) Interpreting heterogeneity in intestinal tuft cell structure and function. J Clin Invest 128:1711-1719
Choi, Eunyoung; Lantz, Tyler L; Vlacich, Gregory et al. (2018) Lrig1+ gastric isthmal progenitor cells restore normal gastric lineage cells during damage recovery in adult mouse stomach. Gut 67:1595-1605
Lu, Yuanyuan; Zhao, Xiaodi; Liu, Qi et al. (2017) lncRNA MIR100HG-derived miR-100 and miR-125b mediate cetuximab resistance via Wnt/?-catenin signaling. Nat Med 23:1331-1341

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