Chandan Guha, M.B.,B.S., Ph.D.

A)    Cell Transplantation to repair radiation injury. The radiation biology laboratory is investigating the molecular pathways of radiation-induced normal tissue injury. In a rodent model of radiation-induced liver damage, our group has demonstrated that intrasplenic or intraportal transplantation of hepatocytes can ameliorate the histopathological manifestations of hepatic radiation injury and significantly improve survival in rodents. We have extended this strategy and are examining whether intestinal stem cell growth factors, such as, R-spondin 1 and endothelial cell transplantation would ameliorate radiation-induced gastrointestinal tract injury.

B)    Preparative Irradiation to facilitate liver cell repopulation and stem cell engraftment in vivo. We were the first to use liver irradiation as a preparative regimen for liver cell transplantation. The long-term goal of this project is to develop liver cell transplantation as an alternative to orthotopic liver transplantation for patients with terminal liver diseases. We are examining whether a preparative regimen of focal irradiation, delivered by stereotactic radiosurgery (SRS), could ablate parenchymal cells in various organs and create a microenvironment that promotes the engraftment, growth and differentiation of progenitor / stem cell in vivo. 

C)    Immunomodulation of radiation therapy: Radiation-enhanced tumor vaccines. Irradiated tumors can potentially serve as a source of tumor antigens in vivo, where dying tumor cells would release various tumor antigens slowly over time. The long-term goal is to design novel tumor vaccines and amplify the immune response to such vaccines with primary tumor irradiation. Upon completion of these preclinical studies, we have designed a proof-of-principle clinical trial that will examine whether a combination of a pancreatic vaccine (PANVAC – vaccinia virus vectors expressing CEA and MUC1) and conventional 5-FU based chemo-radiation therapy would improve overall survival and induce strong tumor-specific immunity in patients with unresectable pancreatic cancer. We are also investigating whether High Frequency Ultrasound (HIFU) can augment the immune response to prostate cancer tumor vaccines.

D)    Development of novel radiosensitizers: ATM and polo-like kinase 1 as a target. Our long-term goal is to screen for drugs that can radiosensitize tumor cells without having undue normal tissue toxicity. Since, majority of tumor cells have aberrant G1 checkpoint, irradiated tumor cells depend upon the G2 checkpoint for survival. In order to increase the intrinsic radiosensitivity of tumor cells, novel drugs are being designed that target the cell cycle checkpoints, especially the G2 checkpoint.Molecular targets include proteins that participate in the DNA damage surveillance pathway, such as, ATM and Plk1.