Preclinical Evaluation of ERBB Family Members as Therapeutic Targets in Osteosarc

描述（申请人提供）：骨肉瘤是最常见的原发性骨癌，也是青少年中第三常见的实体瘤，在美国每年影响近1000人。这种疾病迫切需要新的治疗方法，因为近40%的确诊患者会死于这种疾病，而且这种疾病的生存率在25年多的时间里没有真正提高。来自ERBB受体酪氨酸激酶家族的信号为骨肉瘤提供了重要信号，并且pan-ERBB抑制剂在阻止骨肉瘤生长方面比选择性EGFR抑制剂或阻断EGFR或Her-2信号的抑制剂更有效。大多数骨肉瘤确实表达EGFR，并且那些表达Her-2的骨肉瘤具有更大的转移倾向。然而，Her-2和Her-4对骨肉瘤恶性行为的具体贡献在很大程度上没有文献记载。在四个ERBB家族成员中，Her-4是最不好表征的。基于与单独抑制EGFR和Her-2相比，pan ERBB抑制的体外优效性，假设Her-4对骨肉瘤病理学有独特的贡献。同样，由于Her-2与更具转移性的表型相关，因此它可能也具有独特的贡献。该提案旨在通过定义该疾病中每个家族成员的独特贡献，评估靶向ERBB受体酪氨酸激酶家族治疗骨肉瘤的科学基础。在第一个具体目标中，分子方法用于评估每个ERBB家族成员对骨肉瘤生物学的精确贡献，特别关注Her-4在细胞核中的作用及其调节其他基因表达的潜力。在第二个具体目标中，评估了一个大型骨肉瘤存档标本库中ERBB家族成员的表达，将表达与临床结果相关联。在第三个具体目标中，使用新的正畸骨肉瘤异种移植模型来评估特异性pan ERBB抑制剂PF 00299804的治疗潜力。消除个别ERBB家族成员的影响也进行了评估。当成功完成后，拟议的研究将确定每个ERBB家族成员对骨肉瘤生物学的具体贡献，了解它们在临床背景下的作用，并可能为使用泛ERBB抑制剂治疗骨肉瘤患者提供基础。如果基本假设得到证实，这些研究将为迫切需要新治疗的儿童进行新的临床试验铺平道路。

DESCRIPTION (provided by applicant): Osteosarcoma is the most common primary bone cancer, and the third most common solid tumor in adolescents, affecting nearly 1000 people per year in the United States. This disease desperately needs new therapies, since nearly 40% of those diagnosed will die of their disease, and the survival for this disease has not truly improved in more than 25 years. Signals from the ERBB family of receptor tyrosine kinases contribute essential signals to osteosarcoma, and that a pan-ERBB inhibitor is more effective at stopping the growth of osteosarcoma than is a selective EGFR inhibitor or an inhibitor that blocks signals from either EGFR or Her-2. Most osteosarcoma is do express EGFR, and that those which express Her-2 have a greater propensity to metastasize. However, the specific contributions of Her-2 and Her-4 to malignant behavior in osteosarcoma are largely undocumented. Of the four ERBB family members, Her-4 is the least well characterized. Based upon the in vitro superiority of pan ERBB inhibition compared to inhibition of EGFR and Her-2 alone, it is hypothesized that Her-4 makes unique contributions to osteosarcoma pathology. Likewise, since Her-2 is associated with a more metastatic phenotype, it is likely that it also has unique contributions. This proposal is intended to evaluate the scientific basis for therapies targeting the ERBB family of receptor tyrosine kinases for treating osteosarcoma, by defining the unique contributions of each of the family members within this disease. In the first specific aim, molecular approaches are used to evaluate the precise contributions of each ERBB family member to osteosarcoma biology, focusing particularly on the role of Her-4 in the nucleus and its potential to regulate the expression of other genes. In the second specific aim, a large bank of archival osteosarcoma specimens is evaluated for expression of members of the ERBB family, correlating expression with clinical outcome. In the third specific aim, to novel orthodontic osteosarcoma xenograft models are used to evaluate the therapeutic potential of a specific pan ERBB inhibitor, PF00299804. The effect of eliminating individual ERBB family members also is evaluated. When successfully completed, the proposed studies will define the specific contributions of each ERBB family member to osteosarcoma biology, understanding their role in a clinical context, and potentially providing the basis for using a pan ERBB inhibitor for treating patients with osteosarcoma. Should the underlying hypothesis be proven, these studies would pave the way for new clinical trials for children who desperately need new treatments.