MET, or hepatocyte growth factor receptor is a driver and biomarker of numerous cancers. Several kinase inhibitors and extracellular antagonists targeting this signaling axis have demonstrated clinical efficacy in select MET+ patient populations. Moreover, MET overexpression is a predictor of poor prognosis. Thus, the proposed research is centered on the following hypothesis: quantitative molecular imaging of MET expression will provide an efficient means for patient stratification and prognosis by non-invasive assessment of MET levels in primary tumors and metastases. Clinical studies will be needed to appropriately evaluate this hypothesis. The proposed research is designed to generate the molecular imaging probes to enable this assessment while also providing fundamental insight into the characteristics that benefit molecular imaging of solid tumors. Objective: Engineer a sensitive, specific positron emission tomography (PET) agent for MET through protein engineering and comparative evaluation of ligand scaffold topology and biophysical parameters.
Aim 1 : Comparatively evaluate Gp2, affibody, fibronectin, and antibody synthetic ligands for PET imaging of MET expression in cancer. Synthetic, non-agonistic ligands, with low nanomolar affinities to MET, engineered from three small (5-10 kDa) protein scaffolds will be used as PET imaging agents. 64Cu- radiolabeled ligands will be evaluated in subcutaneous lung cancer xenografts by PET / computed tomography and excised tissue biodistribution. Molecular sensitivity and specificity will be compared across scaffolds and mutants as well as compared to an anti-MET antibody. Metabolite, immunogenicity, and biophysical studies will be performed on lead probes.
Aim 2 : Enhance the molecular imaging performance of lead probes towards clinical translation through modulation of ligand biophysics, use of a clinically superior radioisotope, and assessment in a more advanced mouse model. Lead imaging agents will be enhanced through the use of a more rapidly decaying radioisotope (68Ga), modified sites and chemistries for radioisotope conjugation, and modulation of ligand hydrophilicity and charge. Molecular sensitivity and specificity will be evaluated in a disseminated lung cancer model in preparation for translation.

Public Health Relevance

The proposed research aims to develop molecular positron emission tomography imaging agents for the cancer biomarker MET. In particular, small protein scaffolds - with superior biodistribution characteristics relative to antibodies - will be used to engineer synthetic ligands. Imaging agents will be optimized based on performance in several mouse models to aid translation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21EB019518-02
Application #
9024528
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Sastre, Antonio
Project Start
2015-04-01
Project End
2017-01-31
Budget Start
2016-02-01
Budget End
2017-01-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Engineering (All Types)
Type
Biomed Engr/Col Engr/Engr Sta
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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