Biomarkers such as the epidermal growth factor receptors EGFR and HER2/Neu and gastrin-releasing peptide (GRP) receptors (GRPRs) are highly expressed in various diseases such as breast and prostate cancers and play important roles in disease progression and survival. They are also major drug targets for targeted therapy. There is an urgent need to develop non-invasive and accurate methods for diagnosis and selection of patients and to monitor biomarker levels/distribution and their changes upon treatment by targeted drugs. Molecular imaging of cancer biomarkers using MRI potentially improves our understanding of the disease and drug activity during preclinical and clinical drug treatment. However, lack of desired MRI contrast agents capable of enhancing the contrast between normal tissues and tumors with high relaxivity, tumor targeting, high intratumoral distribution and no toxicity is one of the major barriers for the application of MRI to assess specific biomarkers for diagnosis and monitor drug effect. The goals of this research are to develop protein-based MRI contrast agents for future clinical application with further improved relaxivity, targeting capability and reduced toxicity to enable accurate monitoring of the expression level and distribution of two biomarkers (HER2/Neu and EGFR) in different types of cancers, and to monitor tumor response to treatment using targeted therapeutics with significantly reduced metal toxicity.
Aim 1 is to further increase relaxivity by varying structural arrangements in inner coordination shell and optimizing relaxation properties in outer sphere coordination.
Aim 2 is to develop targeted contrast agents to monitor the expression and distribution of HER2 and EGFR during cancer progression and treatment.
Aim 3 is to study the safety profiles for biostability and toxicity in preclinical models. In addition to improving our understanding of the relaxation theory, our proposed study to improve the relaxivity, targeting capability, and good tumor tissue distribution of the designed contrast agents has potential to overcome the major barriers in the clinical application of molecular imaging by MRI to assess specific disease markers. Detecting the temporal and spatial changes of a set of related disease biomarkers such as HER2 and EGFR sharing the same signaling pathway will allow for earlier disease diagnosis, monitoring disease progression and the synergistic treatment by targeted therapy, aiding in patient selection, and development of novel targeted therapies for clinical applications.

Public Health Relevance

The epidermal growth factor receptors EGFR and HER2/Neu are highly expressed as biomarkers in various cancers and play important roles in cancer progression and survival. They are also the major drug targets. Our proposed studies meet the urgent need to develop non-invasive and accurate MRI contrast agents for diagnosis and to monitor biomarker levels and their changes upon treatment by targeted drugs in cancer patients.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
5R01EB007268-06
Application #
8444430
Study Section
Clinical Molecular Imaging and Probe Development (CMIP)
Program Officer
Liu, Christina
Project Start
2006-12-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
6
Fiscal Year
2013
Total Cost
$408,245
Indirect Cost
$93,583
Name
Georgia State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
837322494
City
Atlanta
State
GA
Country
United States
Zip Code
30302
Zhang, Chen; Zhang, Tuo; Zou, Juan et al. (2016) Structural basis for regulation of human calcium-sensing receptor by magnesium ions and an unexpected tryptophan derivative co-agonist. Sci Adv 2:e1600241
Turaga, Ravi Chakra; Yin, Lu; Yang, Jenny J et al. (2016) Rational design of a protein that binds integrin αvβ3 outside the ligand binding site. Nat Commun 7:11675
Gorkhali, Rakshya; Huang, Kenneth; Kirberger, Michael et al. (2016) Defining potential roles of Pb(2+) in neurotoxicity from a calciomics approach. Metallomics 8:563-78
Pu, Fan; Qiao, Jingjuan; Xue, Shenghui et al. (2015) GRPR-targeted Protein Contrast Agents for Molecular Imaging of Receptor Expression in Cancers by MRI. Sci Rep 5:16214
Tang, Shen; Reddish, Florence; Zhuo, You et al. (2015) Fast kinetics of calcium signaling and sensor design. Curr Opin Chem Biol 27:90-7
Zhuo, You; Solntsev, Kyril M; Reddish, Florence et al. (2015) Effect of Ca²⁺ on the steady-state and time-resolved emission properties of the genetically encoded fluorescent sensor CatchER. J Phys Chem B 119:2103-11
Zhang, Chen; Miller, Cassandra Lynn; Brown, Edward M et al. (2015) The calcium sensing receptor: from calcium sensing to signaling. Sci China Life Sci 58:14-27
Xue, Shenghui; Yang, Hua; Qiao, Jingjuan et al. (2015) Protein MRI contrast agent with unprecedented metal selectivity and sensitivity for liver cancer imaging. Proc Natl Acad Sci U S A 112:6607-12
Chen, Yanyi; Xue, Shenghui; Zou, Juan et al. (2014) Myoplasmic resting Ca2+ regulation by ryanodine receptors is under the control of a novel Ca2+-binding region of the receptor. Biochem J 460:261-71
Zhang, Chen; Mulpuri, Nagaraju; Hannan, Fadil M et al. (2014) Role of Ca2+ and L-Phe in regulating functional cooperativity of disease-associated ""toggle"" calcium-sensing receptor mutations. PLoS One 9:e113622

Showing the most recent 10 out of 30 publications