My main research focus is tumor and normal tissue radiobiology. These studies are designed to improve tumor eradication by maximizing tumor radiation response while minimizing toxicity of normal tissue. On-going studies include modulating the tumor microenvironment to improve treatment response of non-small-cell lung cancer with the central hypothesis that radiation fractionation can be used to control tumor microenvironment and reduce tumor growth and recurrence. Pre-clinical studies using head and neck xenografts are underway to improve survival of tobacco-associated squamous cancers, using radiation in combination with molecular-targeted chemotherapy agents against growth pathways specific to head and neck cancers. Other cell culture and xenograft studies are investigating the pattern of radiation delivery as a mechanism to exploit dose-dependent ATM-mediated DNA damage response pathways to improve the treatment of glioblastoma.
Complementary studies are examining radiation-induced normal tissue sequelae. We have recently shown that kidney irradiation induces loss of sphingomyelin-phosphodiesterase-acid-like-3b (SMPDL3b) expression in cultured podocytes, and alters podocyte sphingolipid homeostasis inducing loss of filopodia. After irradiation, we discovered that the actin-binding protein ezrin relocated from the podocyte plasma membrane to the cytosol, promoting cytoskeletal remodeling. Irradiation triggered a time-dependent loss of SMPDL3b and coincident elevation in ceramide levels, and reductions in sphingosine, sphingosine-1 phosphate and ceramide-1-phosphate. From these observations, we identified a novel lipid-based molecular pathway mediating radiation-induced podocyte injury that allowed the mitigation of long-term functional renal injury after kidney-targeted irradiation using a preclinical model.