Ras-mediated erbB signaling in Osteosarcoma

描述（由申请人提供）：项目摘要：在这里，我们建议检查骨肉瘤中erbB家族信号传导的机制，定义Ras在该信号级联中的作用，并评估抑制erbB和/或Ras对骨肉瘤的治疗潜力，作为发展我的科学事业的一种手段。我是德克萨斯大学MD安德森癌症中心的儿科助理教授，在实验室基础科学研究方面有很强的背景，以前有基础免疫学和免疫疗法的经验，但我最近才开始研究肿瘤生物学和细胞信号传导。我们已经确定了erbB家族成员（EGFR，Her-2和Her-4）在骨肉瘤细胞中的表达，并表明这些蛋白质在骨肉瘤中是组成性磷酸化或激活的。在这里，我们建议利用一种新的技术-组织裂解物蛋白阵列-快速筛选的第二信使蛋白，可能位于下游的erbB和Ras在骨肉瘤中，在组成性erbB信号的存在下，并在抑制erbB，Ras或两者。然后，我们将使用蛋白质印迹和RNAi方法进行更详细的分析，以确认这些第二信使的作用。通过这些研究，我们将确定哪些第二信使在骨肉瘤中提供重要的生存和生长信号，确定潜在的治疗靶点。最后，我们将使用充分表征的LM 7骨肉瘤异种移植模型，评估使用小分子抑制剂阻断erbB或Ras信号传导治疗骨肉瘤的可能性。在进行这些研究时，我将熟练掌握信号转导领域的实验技术和知识体系，使我能够将这些方法应用于肉瘤研究领域，同时利用我以前的经验。我计划作为一名医生科学家的职业生涯，花费我的大部分时间在转化实验室为基础的研究有前途的新疗法肉瘤，结合有限的（20%或更少）的临床工作的努力，专注于儿童肉瘤的护理，特别是骨肿瘤。这个奖项，结合支持和环境的医学博士。安德森癌症中心，将提供理想的工具，建立我的职业生涯，并帮助我成为一个成功的实验室研究员谁是竞争力的资金从国家来源。 相关性：骨肉瘤是青少年中第三常见的癌症，也是最常见的骨恶性肿瘤。目前，尽管进行了积极的化疗和手术，仍有30%至40%的骨肉瘤患者死于这种疾病，这引起了人们对确定具有预后和治疗意义的标志物的极大兴趣。拟议的研究将确定信号转导的小分子抑制剂的潜在作用，从erbB和下游蛋白质的目标，在治疗骨肉瘤，这也将作为模型系统，以确定这种作用在其他实体瘤的儿童。

DESCRIPTION (provided by applicant): Project Summary: 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.