MDM2 ONCOGENE AS A TARGET FOR MODULATING CANCER THERAPY

mdm2致癌基因已被证明在人类癌症中被放大或过度表达，约50%的乳腺癌，40- 60%的骨肉瘤，30%的软组织肉瘤和60%的胶质瘤。也有研究表明，mdm2水平与几种人类癌症的不良预后有关。mdm2癌蛋白与p53肿瘤抑制蛋白结合，并作为p53的负调控因子。p53肿瘤抑制因子在癌症治疗中也有重要作用，p53介导的细胞凋亡是许多临床使用的癌症化疗药物和放射治疗的主要作用机制。因此，mdm2对p53的负调控可能会限制DNA损伤剂对p53的激活程度，从而限制其治疗效果。研究者推测，通过抑制mdm2的表达，mdm2癌蛋白水平降低，mdm2对p53的负反馈抑制减弱，导致功能性p53水平显著升高，从而调节p53介导的治疗效果。这项拨款申请的总体目标是研究mdm2致癌基因在肿瘤生长中的功能，以及mdm2作为癌症治疗药物靶点的潜在价值。以下具体目标将被审查：1)。通过抑制人体内肿瘤模型中mdm2的表达，确定mdm2在肿瘤生长中的作用；2）. 研究mdm2抑制是否激活p53并诱导细胞凋亡，以及这些作用是否导致体内肿瘤生长抑制；3）. 确定mdm2抑制剂与DNA损伤剂之间是否存在体内协同治疗作用；和4)。确定mdm2抑制是否对关键宿主组织具有特异性作用，这些组织通常是癌症化疗诱导的毒性部位。当这些特定目标完成后，将有可能在未来的研究中调查mdm2在人类肿瘤发展中的作用，并最终确定mdm2作为人类癌症治疗新药设计靶点的实用性。

The mdm2 oncogene has been shown to be amplified or overexpressed in human cancers, about 50 percent of breast cancers, 40-60 percent of osteosarcomas, 30 percent of soft tissue sarcomas, and 60 percent of gliomas. It also has been suggested that mdm2 levels are associated with poor prognosis of several human cancers. The mdm2 oncoprotein binds to the p53 tumor suppressor protein and serves as a negative regulator of p53. The p53 tumor suppressor also has an important role in cancer therapy, with p53-mediated apoptosis being a major mechanism of action for many clinically used cancer chemotherapeutic agents and radiation therapy. Therefore, the negative regulation of p53 by mdm2 may limit the magnitude of p53 activation by DNA damaging agents, thereby limiting their therapeutic effectiveness. The investigators hypothesize that, by inhibiting mdm2 expression, the mdm2 oncoprotein level will be reduced and the mdm2 negative feed-back inhibition of p53 will be diminished, resulting in a significant increase of functional p53 levels that will modulate p53-mediated therapeutic effects. The overall objective of this grant application is to investigate the functions of mdm2 oncogene in tumor growth and the potential value of mdm2 as a drug target for cancer therapy. The following Specific Aims will be examined: 1). To determine the role of mdm2 in tumor growth by inhibiting mdm2 expression in in vivo models of human cancers; 2). To determine whether mdm2 inhibition activates p53 and induces apoptosis and whether these effects result in tumor growth inhibition in vivo; 3). To determine whether there are in vivo synergistically therapeutic effects between mdm2 inhibition and DNA damaging agents; and 4). To determine whether mdm2 inhibition has specific effects on key host tissues that are often sites of toxicity induced by cancer chemotherapy. When these specific aims have been accomplished, it will be possible in future studies to investigate the role of mdm2 in tumor development in humans and, ultimately, determine the usefulness of mdm2 as a target for new drug design for human cancer therapy.