Dr. Pieper's research program is divided into two components. The first component focuses on cell signaling and the influence of cell-cycle regulation on chemotherapeutic response of gliomas to the methylating agent temozolomide (TMZ). Work in Dr. Pieper's laboratory has identified pathways involving the DNA damage sensors Chk1 and p38 that lead to drug resistance to TMZ and that might serve as targets for sensitization of tumors to this important chemotherapeutic agent. The second program in Dr. Pieper's laboratory involves trying to understand the genetic events important in the formation of human brain tumors. It is known that single defined genetic alterations can result in the transformation of rodent cells, likely because these alterations lead to genomic instability and a variety of other genetic changes. Dr. Pieper's laboratory has identified four key pathways critical in controlling glioma development, and is further examining how disregulation of these pathways leads to glioma formation. Of particular note is the recent observation from Dr. Pieper's laboratory that some of the same pathways that contribute to astrocytic transformation also suppress the ability of cells to be eliminated by apoptosis-inducing agents such as TRAIL, and perhaps by the immune system itself. These observations are expected to lead to new ways to suppress both drug resistance and tumorigenicity in human gliomas.