Sundaram Ramakrishnan, Ph.D.
Professor of Pharmacology
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Publications |
Research Interests
Angiogenesis is critical for the growth and metastasis of solid tumors. Tumor cells produce a number of growth factors (angiogenic factors) to activate pre-existing vasculature to form new blood vessels. Angiogenesis modulates the rate of tumor growth, supply matching the demand. Therefore, angiogenesis inhibitors can be used to complement surgery and chemotherapy of cancer. In the recent past we identified and characterized a mutant form of endostatin (P125A-endostatin) which was more potent than the native protein. The P125A-endostatin was further modified to improve its localization to tumor vasculature. As tumor vasculature overexpress alpha V beta 3/beta 5 integrins, endostatin was modified to incorporate R-G-D sequence either at the amino or carboxyl terminus. RGD modification improved tumor localization of endostatin and decreased microvessel density in tumors of treated animals. Adeno associated virus (AAV) constructs were made to study the effect of gene therapy on cancer growth in preclinical models. A single intramuscular injection of AAV-P125A-endostatin resulted in sustained expression of the protein for more than three months. There was a dose dependent change in endostatin levels in the serum. Higher doses of AAV-P125A-endo elicited potent inhibition of angiogenesis. Recent studies suggest that AAV-mediated expression of mutant endostatin can synergize with chemotherapy to inhibit ovarian and breast cancer in transgenic mice. |
