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Molecular Genetic Analysis of Colorectal Cancer; Targeted Cancer Therapy ...read more
Hypoxia, a consequence of tumor cells outgrowing their blood supply, and subsequent angiogenesis are two of the hallmarks of rapidly growing solid tumors. Dr. Zhou's laboratory has been exploiting these unique pathological features for developing novel therapeutic approaches.
The hypoxic tumor compartment poses challenges for both chemo and radiation therapies as hypoxia diminishes the therapeutic effects of chemotherapeutic agents and radiation. Conversely, this tumor compartment, hypoxic and immune-privileged, provides a unique niche for anaerobic bacteria to grow. C. novyi-NT is an attenuated strain of the anaerobic bacterium Clostridium novyi. When injected intravenously, C. novyi-NT spores are not toxic to healthy animals but can selectively germinate within and colonize tumors, resulting in massive necrosis and tumor regression. In addition to direct tumor destruction by bacterial growth, the C. novyi-NT infection elicits a potent host antitumor immune response leading to long-term cures. C. novyi-NT is considered a promising anticancer agent not only for its inherent anticancer properties, but also for its capacity to enhance other cancer therapies and to serve as a tumor-specific gene therapy vector. Dr. Zhou's laboratory has combined C. novyi-NT spores with chemotherapeutic drugs, liposomal formulation of chemotherapeutic drugs, and radiation for the treatment of several experimental tumor models. The combination therapies showed marked improvement in efficacy over the therapies using individual agents. Dr. Zhou's group is currently generating engineered C. novyi-NT strains that are more potent and less toxic in several experimental tumor models.
In response to the increased demands for nutrients and oxygen, solid tumors establish their own vascular networks that are both structurally and physiologically different from the vasculature in normal tissues. These differences form the basis for a therapeutic approach Dr. Zhou's laboratory has been developing. Both biologic and chemical agents capable of inducing vascular responses akin to those observed in inflammatory processes enhance the selective accumulation of nanoparticles in tumors. For example, the proinflammatory cytokine TNF-alpha is able to increase the tumor to blood ratio of sterically stabilized liposomes by more than 20-fold compared to the liposomes alone. Consequently, the vascular-active agents dramatically improve the therapeutic effect of liposomes containing radioactive isotopes or chemotherapeutic agents. Dr. Zhou's group is investigating a variety of vascular-active agents for their ability to augment selective tumor accumulation of nanoparticles.