TAMPA, Fla. (Dec. 19, 2012) – Researchers at Moffitt Cancer Center
, working with colleagues at The University of Arizona and Arizona State University, have developed a new combination agent approach targeting tumor receptors based on their variety of cell surface proteins. The approach, which was tested in pancreatic cancers and melanoma modeled in tumor-bearing mice, opens the possibility of developing new multivalent agents that can target unique and multiple receptor combinations in tumor cells. This is a significant improvement over current single-target strategies. The study
appeared in a recent issue of the Proceedings of the National Academy of Sciences of the United States of America
According to the authors, the concept of a “magic bullet” that targets cancer cells while leaving normal cells unaffected has been around for a long time. However, magic bullet approaches have used single — rather than a variety of — bullets to target cancer cells. Accordingly, the researchers have developed synthetic heteromultivalent ligands that target multiple receptors simultaneously. A ligand is a signaling and triggering molecule that binds to a site on a protein.
“The synthetic heteromultivalent ligands developed in this study are relatively small, highly active binders that display tumor selectivity due to the multivalent effect,” said study senior author Robert J. Gillies
, Ph.D., chair of the Department of Cancer Imaging & Metabolism
. “These findings open the possibility for developing new, multivalent agents targeted to unique receptor combinations in tumor cells with a high degree of specificity.”
The researchers noted that many of the previously developed targeted therapies showed short-term clinical success because the large size of the antibodies used reduced their specificity. The researchers found that smaller is better when designing and synthesizing a series of heteromultivalent ligands containing two different receptors.
“Selectivity was observed and quantified, showing that the small synthetic heteromultivalent ligands can distinguish target cells from control cells,” said study author Liping Xu, Ph.D., member of Moffitt’s Department of Cancer Imaging & Metabolism. “Our data provide evidence that small bivalent heteromultivalent ligands can be developed for targeting human cancers.”
According to the authors, small doses of the ligands are required to maximally exploit the multivalent binding.
“Further studies will be needed to determine circulation time of these multivalent constructs in the blood,” explained David L. Morse
, Ph.D., member of Moffitt’s Department of Cancer Imaging & Metabolism. “In addition, a better understanding of cell-surface receptor expression levels in patient tumors and normal tissues needs to be developed.”
The authors suggest that although their work was limited to targeting cancer cells, the approach could also be useful for developing therapies for other diseases.
“Our study demonstrates in vivo evidence that small bivalent heteromultivalent ligands can be used to selectively target cells that express two cell surface targets and opens the possibility that specific combinations of targets on tumors can be identified and selectively targeted,” they concluded.
The work was supported by National Institutes of Health, National Cancer Institute Grants R01 CA123547 and R01 CA097360. About Moffitt Cancer Center Located in Tampa, Moffitt is one of only 41 National Cancer Institute-designated Comprehensive Cancer Centers, a distinction that recognizes Moffitt’s excellence in research, its contributions to clinical trials, prevention and cancer control. Since 1999, Moffitt has been listed in U.S. News & World Report as one of “America’s Best Hospitals” for cancer. With more than 4,200 employees, Moffitt has an economic impact on the state of nearly $2 billion. For more information, visit MOFFITT.org, and follow the Moffitt momentum on Facebook, twitter and YouTube.
Media release by Florida Science Communications ###