My primary research focus involves the role of DNA repair, specifically a protein called O6-methylguanine DNA methyltransferase (MGMT), in anticancer drug resistance. We are investigating several strategies to down-regulate MGMT activity in various human tumor cell types. We are also interested in using gene therapy approaches, as well as molecular targeting of drug delivery, to enhance chemotherapy treatment in animal models.
My research is directed toward biochemical and molecular approaches to enhance anticancer chemotherapy. We are interested in understanding the mechanisms of anticancer drug resistance, the biological alterations that occur during carcinogenesis, as well as pharmacological approaches to improve drug actions.
Currently, we are investigating the DNA repair protein O6-methylguanine DNA methyltransferase (MGMT), which repairs DNA lesions induced by several alkylating anticancer drugs including chloroethylnitrosoureas (CENUs), temozolamide and others. We are studying several approaches to modulate MGMT activity such as catalytic ribozymes and short-interfering RNAs, which target mRNA, as well as the reagent, O6-benzylguanine (BG), a potent biochemical inhibitor of MGMT. We have shown that inhibition of MGMT reverses drug resistance in various human tumors, and that BG significantly enhances CENU antitumor therapy in an animal model.
The dose-limiting toxicity of this and many other chemotherapy treatments is acute myelosuppression. Hence, another aim of my research is to use gene therapy strategies to protect bone marrow cells against anticancer agents. We have developed a bone marrow transplantation model to study hematopoietic protection using transduced human and murine stem cells. We have shown that gene transfer of DNA repair proteins protects bone marrow cells against anticancer chemotherapy drugs and improves animal survival. In collaboration with other laboratories, we are also investigating the use of hematopoietic stem cell gene transfer to improve anticancer treatments in human patients.
