Sundaram Ramakrishnan, Ph.D.
Professor of Surgery
Description of Research
Angiogenesis is important in tissue remodeling and repair. However, in diseases such as cancer and age-related macular degeneration, inhibition of angiogenesis is clinically relevant. To improve the therapeutic efficacy of anti-angiogenic molecules Dr. Ramakrishnan’s lab are using genetic approaches to improve vascular homing and bioavailability.
Tumor hypoxia drives peritoneal seeding and metastasis of ovarian cancer cells. Hypoxia creates a niche for cancer initiating stem cells and confers chemoresistance. Their studies have identified a network of microRNA-mediated changes in cancer cells and tumor vascular endothelium. Micro-RNA network was found to fine-tune the stabilization of hypoxia inducible factor 1 (HIF-1). Endothelial cells specifically upregulate miR-424, which destabilized E3 ligase complex assembly by targeting the scaffolding protein, CUL-2. At the same time, tumor cells downregulated miR-199a in hypoxia. They have identified a reciprocal regulatory loop involving the GTPase, Dynamin and miR-199a which is encoded from the opposite strand of an intron in Dynamin gene. As Dynamin regulates endocytosis and iron uptake, they investigated the regulation of iron in in the tumor microenvironment. A novel strategy to dysregulate iron homeostasis is developed their laboratory. Cell permeable iron was found to inhibit tumor angiogenesis and chemosensitize cancer cells to DNA damaging drugs. Dr. Ramakrishnan’s is currently investigating the effect of cell permeable iron in preclinical models of ovarian and pancreatic cancers.
Superantigen-based cancer vaccines: Tumor microenvironment is immunosuppressive. their laboratory has genetically engineered the T-cell receptor binding domain of a superantigen, Toxic Shock Syndrome Toxin-1, to activate the tumor infiltrating immune cells. Cancer cells coated with self-anchoring superantigens are investigated in preclinical models either alone or in combination with antibodies to immune check-point inhibitors and chemotherapy.
- Genetically Engineered Anti-angiogenic molecules. Discovered mutation P125A improves biological activity of human endostatin. US patent 6,825,167, Genetic Modification of Endostatin
- Discovered that Cell permeable iron can be used to inhibit tumor angiogenesis and potentiate the effects of DNA damaging cancer chemotherapeutics. Therapeutic composition and application of cell permeable iron - US patent Application Number 62/183,801 and Confirmation Number 7809. June 24th, 2016.
Selected Cancer-Related Publications
Collaborating in the Multidisciplinary Research Program(s):