Office: 234A Schweitzer Hall
117 Schweitzer Hall
University of Missouri
Columbia, MO 65211
|BS||University of Miami||Miami, Fla.||Biochemistry|
|PhD||St. Louis University||St. Louis, Mo.||Molecular Virology|
We have established a research program to develop radiolabeled peptides and proteins as tumor specific diagnostic and therapeutic agents. Combinatorial peptide and antibody fragment libraries are being employed to identify molecules that preferentially bind tumor antigens. The tumor-avid peptides and antibody fragments are subsequently engineered to bind the medically important radionuclides into their structures. Finally, the radiolabeled peptides and proteins are investigated for their abilities to target tumor cells in vitro and in vivo.
Radiolabeled α-MSH Peptide Analogs: The goal of this project is to design radiolabeled alpha-melanocyte stimulating hormone (α-MSH) analogs for melanoma imaging and therapy. α-MSH is a small tridecapeptide hormone that is involved in control of skin coloration. α-MSH receptors have been identified on human and mouse melanoma cells making them attractive targets for the development of new peptide imaging and/or therapeutic radiopharmaceuticals. We have developed an α-MSH analog (CCMSH) that is cyclized via site-specific Tc-99m, Re, or Re-188 metal coordination. The metal-cyclized CCMSH analog is radiochemically stable and retains α-MSH receptor affinity and specificity. In vivo, the Tc-99m-CCMSH complex was effective in imaging melanoma in both murine and human melanoma mouse tumor model systems. The Tc-99m-CCMSH complex exhibited high tumor uptake and retention values coupled with rapid whole body clearance kinetics. Similar biodistribution results were obtained for the Re-188-CCMSH complex in tumor bearing mice. We are currently evaluating the melanoma therapeutic efficacy of the Re-188-CCMSH and Pb-212-DOTA-ReCCMSH in vivo.
Tumor Binding Peptides Selected from Bacteriophage Display Libraries: A combinatorial approach is being used to search for small polypeptides that bind the cancer associated Thomsen-Friedenreich (T) glycoantigen and ErbB-2 receptor with high affinities and specificities. Random peptide bacteriophage display libraries were screened for molecules that bound T-antigen and ErbB-2. Two T-antigen binding peptide sequences, P30 and P10, have been shown to bind free T-antigen in solution, T-antigen displaying proteins, and breast carcinoma cells displaying T antigen on their surfaces. The P30 peptide has be shown to inhibit T-antigen mediated tumor cell adhesion between malignant melanoma cells and adhesion between tumor cells and endothelial cells. Bacteriophage libraries have also been employed to identify peptide sequences that bind the ErbB-2 receptor. The ErbB-2 receptor is upregulated in a number of cancers, including breast and prostate. A six amino acid peptide, p6.1, has been identified that binds the extracellular domain of ErbB-2. The p6.1 peptide is capable of distinguishing between tumor cells and normal cells. We are continuing to explore the molecular recognition properties and the biological activities of the T antigen and ErbB-2 binding peptides.
Hoffman TJ, Quinn TP, Volkert, WA. Development of Receptor-Avid Peptide Radiotracers for Targeting for Human Cancers. In: Targeted Molecular Imaging; Eds Welch and Eckelman, CRC Press. pp 337-357 (2012).
Calzada V, Zhang X, Fernadez M, Diaz-Miqueli A, Iznaga-Escobar N, Deutscher SL, Balter H, Quinn TP, Cabral P. A potential theranostic agent for EGF-R expression tumors: 177LuDOTA-Nimotuzumab. Curr. Radiopharm. 5: 318-24 (2012).
Zhang X, Yue Z, Lu BY, Vazquez-Flores GJ, Yuen J, Figueroa SD, Gallazzi F, Cutler C, Quinn TP, Lacy JL. Copper-62 labeled ReCCMSH peptide analogs for melanoma PET imaging. Curr. Radiopharm. 5: 329-35 (2012).
Gambini, JP, Cabral P, Alonso O, Savio E, Figueroa SD, Zhang X, Ma L, Deutscher SL, and Quinn TP. Evaluation of 99mTc-glucarate as a breast cancer imaging agent in an xenograft animal model. Nucl. Med. Biol. 38: 255-260 (2011).
Deutscher SL, Dickerson M, Gui G, Newton J, Holm JE, Vogeltanz-Holm N, Kliethermes B, Hewett JE, Kumar SR, Quinn TP, Sauter ER. Carbohydrate antigens in nipple aspirate fluid predict the presence of atypia and cancer in women requiring diagnostic breast biopsy. BMC Cancer. 10 :519 (2010).
Wei K, Zhang X, Gallazzi F, Miao Y, Jin Y, Brechbiel MW, Xu H, Clifford T, Welch MJ, Lewis JS, Quinn TP. Melanoma imaging using 111In-, 86Y- and 68Ga-labeled CHX-A″-Re(Arg11)CCMSH. Nucl. Med. Biol. 36:345-354 (2009).