Here we propose examining the mechanisms of erbB family signaling in osteosarcoma, defining the role of Ras within this signaling cascade and assessing the therapeutic potential for osteosarcoma of inhibiting erbB and/or Ras, as a means of developing my scientific career. I am an Assistant Professor of Pediatrics at the University of Texas MD Anderson Cancer Center, with a strong background in laboratory-based scientific investigation from prior experiences with basic immunology and immunotherapy, but I began investigating tumor biology and cell signaling only recently. We have defined the expression of the erbB family members (EGFR, Her-2 and Her-4) in osteosarcoma cells, and showed that these proteins are constitutively phosphorylated, or activated, in osteosarcoma. Here we propose exploiting a new technology - tissue lysate protein arrays - to screen rapidly the entire set of second messenger proteins that may lie downstream of erbB and Ras in osteosarcoma, in the presence of constitutive erbB signaling and during inhibition of erbB, Ras or both. We will then pursue more detailed analyses, using western blot and RNAi approaches, to confirm the roles identified for these second messengers. With these studies we will determine which second messengers provide essential survival and growth signals in osteosarcoma, identifying potential targets for therapy. Finally, we will assess the possibility for osteosarcoma treatment of using small molecule inhibitors to block signaling from erbB or Ras, using the well-characterized LM7 osteosarcoma xenograft model. In pursuing these investigations, I will become adept in the experimental techniques and body of knowledge particular to the field of signal transduction, enabling me to apply these approaches to the field of sarcoma research while drawing on the strengths of my prior experience. I plan a career as a physician-scientist, spending the majority of my time in translational laboratory-based investigations of promising new treatments for sarcomas, combined with a limited (20% or less) effort in clinical work, focusing on the care of children with sarcomas, especially boney tumors. This award, in combination with the support and environment of M.D. Anderson Cancer Center, will provide the ideal vehicle for establishing my career and aiding me in becoming a successful laboratory investigator who is competitive for funding from national sources. ? ? Relevance: Osteosarcoma is the third most common cancer in adolescents and the most common malignancy of bone. Currently 30 to 40 percent of osteosarcoma patients die from their disease despite aggressive chemotherapy and surgery, which has generated tremendous interest in identifying markers of prognostic and therapeutic significance. The proposed studies will define the potential role of small molecule inhibitors of signal transduction, from erbB and from downstream protein targets, in treating osteosarcoma, which will also serve as the model system for determining this role in other solid tumors of childhood. ? ? ?
