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
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
Qiao, Jingjuan; Xue, Shenghui; Pu, Fan et al. (2014) Molecular imaging of EGFR/HER2 cancer biomarkers by protein MRI contrast agents. J Biol Inorg Chem 19:259-70
Zou, Juan; Salarian, Mani; Chen, Yanyi et al. (2014) Gap junction regulation by calmodulin. FEBS Lett 588:1430-8
Zhang, Chen; Huang, Yun; Jiang, Yusheng et al. (2014) Identification of an L-phenylalanine binding site enhancing the cooperative responses of the calcium-sensing receptor to calcium. J Biol Chem 289:5296-309
Xue, Shenghui; Qiao, Jingjuan; Jiang, Jie et al. (2014) Design of ProCAs (protein-based Gd(3+) MRI contrast agents) with high dose efficiency and capability for molecular imaging of cancer biomarkers. Med Res Rev 34:1070-99
Kirberger, Michael; Wong, Hing C; Jiang, Jie et al. (2013) Metal toxicity and opportunistic binding of Pb(2+) in proteins. J Inorg Biochem 125:40-9
Xue, Shenghui; Qiao, Jingjuan; Pu, Fan et al. (2013) Design of a novel class of protein-based magnetic resonance imaging contrast agents for the molecular imaging of cancer biomarkers. Wiley Interdiscip Rev Nanomed Nanobiotechnol 5:163-79
Li, Shunyi; Jiang, Jie; Zou, Jin et al. (2012) PEGylation of protein-based MRI contrast agents improves relaxivities and biocompatibilities. J Inorg Biochem 107:111-8
Wang, Zhong-Min; Tang, Shen; Messi, Maria Laura et al. (2012) Residual sarcoplasmic reticulum Ca2+ concentration after Ca2+ release in skeletal myofibers from young adult and old mice. Pflugers Arch 463:615-24
Wei, Lixia; Li, Shunyi; Yang, Jianhua et al. (2011) Protein-based MRI contrast agents for molecular imaging of prostate cancer. Mol Imaging Biol 13:416-23

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