PROJECT 2: Cell surface receptors comprise an important class of membrane molecules that form communication links between the extracellular milieu and the cell's interior. In addition, a number of cell surface receptors have been shown to play a significant role in imparting specific phenotypes to transformed cells, for example growth factor independence and metastatic behavior. Non-invasive imaging of receptor activity dynamically in live cells and mouse models would significantly enhance our understanding of the role of these receptors in the etiology of cancer and the response of tumors to therapeutic agents directed against these receptors. For the purpose of this proposal we will focus on three distinct receptors. The epidermal growth factor receptor (EGFR) is often over-expressed and activated in tumors in a ligand independent manner, while the hepatocyte growth factor receptor (Met) is activated in an autocrine manner in that tumor cells express the ligand (HGF) and the receptor (Met) simultaneously thus constitutively activating intracellular signaling cascades. The CXCR7 receptor is activated in a paracrine manner in that specific organs such as bone marrow, lung and liver express SDF, the ligand which through CXCR7 activation results in the spread and growth of metastasis to these sites. In Project 2, we propose to develop molecular imaging strategies to image activity of three receptors that contribute significantly to the transformed phenotype. The proposal is organized in three aims, one for each of the above three receptors. In each of the aims we will develop two independent approaches to image the receptor and the one with the best signal to noise and specificity will be used in further in-vitro validation studies to demonstrate that the reporter faithfully reports on the appropriate molecular events. Lastly, in each of the aims, the appropriate receptor will be used to investigate the efficacy of novel therapies directed against each receptor in a live mouse model and the efficacy of the therapy will be correlated with molecular imaging as a non-invasive surrogate for receptor activity. Public Health: The studies proposed here will result in the development of imaging based mouse models that will facilitate the development and testing of anti-cancer therapies directed against key receptor molecules.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA093990-10
Application #
8330943
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2011-09-01
Budget End
2012-08-31
Support Year
10
Fiscal Year
2011
Total Cost
$374,695
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Type
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Keith, Lauren; Ross, Brian D; Galbán, Craig J et al. (2016) Semiautomated Workflow for Clinically Streamlined Glioma Parametric Response Mapping. Tomography 2:267-275
Nyati, Shyam; Chator, Areeb; Schinske, Katerina et al. (2016) A Requirement for ZAK Kinase Activity in Canonical TGF-? Signaling. Transl Oncol 9:473-481
Joshi, Bishnu P; Pant, Asha; Duan, Xiyu et al. (2016) Multimodal Video Colonoscope for Targeted Wide-Field Detection of Nonpolypoid Colorectal Neoplasia. Gastroenterology 150:1084-1086
Al-Dujaili, Saja A; Koh, Amy J; Dang, Ming et al. (2016) Calcium Sensing Receptor Function Supports Osteoblast Survival and Acts as a Co-Factor in PTH Anabolic Actions in Bone. J Cell Biochem 117:1556-67
Stacer, A C; Fenner, J; Cavnar, S P et al. (2016) Endothelial CXCR7 regulates breast cancer metastasis. Oncogene 35:1716-24
Luker, K E; Pata, P; Shemiakina, I I et al. (2015) Comparative study reveals better far-red fluorescent protein for whole body imaging. Sci Rep 5:10332
Chang, S Laura; Cavnar, Stephen P; Takayama, Shuichi et al. (2015) Cell, isoform, and environment factors shape gradients and modulate chemotaxis. PLoS One 10:e0123450
Stacer, Amanda C; Wang, Hanxiao; Fenner, Joseph et al. (2015) Imaging Reporters for Proteasome Activity Identify Tumor- and Metastasis-Initiating Cells. Mol Imaging 14:414-28
Van Dort, Marcian E; Galbán, Stefanie; Wang, Hanxiao et al. (2015) Dual inhibition of allosteric mitogen-activated protein kinase (MEK) and phosphatidylinositol 3-kinase (PI3K) oncogenic targets with a bifunctional inhibitor. Bioorg Med Chem 23:1386-94
Wang, Lizhong; Liu, Runhua; Ye, Peiying et al. (2015) Intracellular CD24 disrupts the ARF-NPM interaction and enables mutational and viral oncogene-mediated p53 inactivation. Nat Commun 6:5909

Showing the most recent 10 out of 161 publications