Preclinical Evaluation of ERBB Family Members as Therapeutic Targets in Osteosarc

ERBB家族成员作为骨肉瘤治疗靶点的临床前评估

基本信息

批准号：
9040524
负责人：
Eugenie S Kleinerman
金额：
$ 6.99万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9040524
关键词：
Adolescent Adolescent and Young Adult Affect Antigens Apoptosis Behavior Binding Biology Categories Cell Line Cell Nucleus Cell Proliferation Cells Cessation of life Characteristics Child Clinical Clinical Trials Data Development Developmental Therapeutics Program Diagnosis Disease Disease model Drug usage EGFR gene EGFR inhibition ERBB2 gene Employee Strikes Epidermal Growth Factor Receptor Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor Evaluation Event Family Family member Genes Goals Growth Immunohistochemistry In Vitro Individual Knowledge Laboratories Left Malignant - descriptor Malignant Bone Neoplasm Malignant Childhood Neoplasm Malignant Neoplasms Malignant neoplasm of lung Medicine Modeling Molecular Molecular Medicine Neoplasm Metastasis Nuclear Nuclear Translocation Operative Surgical Procedures Orthodontic Outcome Pathogenesis Pathology Patients Pharmacologic Substance Phase Phenotype Phosphorylation Play Prognostic Marker Protein Array Analysis Protein Isoforms Rare Diseases Receptor Protein-Tyrosine Kinases Role Sampling Signal Transduction Solid Neoplasm Specimen Staining method Stains Techniques Therapeutic United States Xenograft Model advanced disease base bone chemotherapy clinically relevant defined contribution disability improved in vivo inhibitor/antagonist interest malignant breast neoplasm member novel osteosarcoma pre-clinical preclinical evaluation prognostic promoter receptor small molecule targeted treatment therapeutic evaluation therapeutic target

项目摘要

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.

描述（由申请人提供）：骨肉瘤是最常见的原发性骨癌，也是青少年中第三大常见的实体瘤，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% 的确诊患者将死于这种疾病，而且这种疾病的生存率在 25 年多的时间里并没有真正改善。来自受体酪氨酸激酶 ERBB 家族的信号为骨肉瘤提供重要信号，并且泛 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很大程度上没有记录。在四个 ERBB 家族成员中，Her-4 的特征最不明确。基于与单独抑制 EGFR 和 Her-2 相比，全 ERBB 抑制的体外优越性，假设 Her-4 对骨肉瘤病理学做出独特的贡献。同样，由于 Her-2 与更具转移性的表型相关，因此它很可能也具有独特的贡献。该提案旨在通过定义每个家族成员对该疾病的独特贡献，评估针对 ERBB 受体酪氨酸激酶家族治疗骨肉瘤的疗法的科学基础。在第一个具体目标中，使用分子方法评估每个 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，评估大量档案骨肉瘤标本中 ERBB 家族成员的表达，将表达与临床结果相关联。第三个具体目标是使用新型正畸骨肉瘤异种移植模型来评估特定泛 ERBB 抑制剂 PF00299804 的治疗潜力。还评估了消除个别 ERBB 家庭成员的效果。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中的作用，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。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Neuroblastoma patient outcomes, tumor differentiation, and ERK activation are correlated with expression levels of the ubiquitin ligase UBE4B.

神经母细胞瘤患者的预后、肿瘤分化和 ERK 激活与泛素连接酶 UBE4B 的表达水平相关。

DOI：
发表时间：
2016-01
期刊：
影响因子：
0
作者：
Woodfield, Sarah E;Guo, Rong Jun;Liu, Yin;Major, Angela M;Hollingsworth, Emporia Faith;Indiviglio, Sandra;Whittle, Sarah B;Mo, Qianxing;Bean, Andrew J;Ittmann, Michael;Lopez;Zage, Peter E
通讯作者：
Zage, Peter E

Improving paclitaxel delivery: in vitro and in vivo characterization of PEGylated polyphosphoester-based nanocarriers.

改善紫杉醇的递送：聚乙二醇化聚磷酸酯纳米载体的体外和体内表征。

DOI：
10.1021/ja512616s
发表时间：
2015-01-28
期刊：
Journal of the American Chemical Society
影响因子：
15
作者：
Fuwu Zhang;Shiyi Zhang;Stephanie F Pollack;Richen Li;Amelia M. Gonzalez;Jingwei Fan;J. Zou;Sarah E. Le
通讯作者：
Sarah E. Le

Bone Sarcomas in Pediatrics: Progress in Our Understanding of Tumor Biology and Implications for Therapy.

儿科骨肉瘤：我们对肿瘤生物学和治疗意义的理解的进展。

DOI：
发表时间：
2015-08
期刊：
影响因子：
0
作者：
Rivera;Zhu, Limin;Hughes, Dennis P M
通讯作者：
Hughes, Dennis P M

Triplex DNA-binding proteins are associated with clinical outcomes revealed by proteomic measurements in patients with colorectal cancer.

三链 DNA 结合蛋白与结直肠癌患者蛋白质组学测量揭示的临床结果相关。

DOI：
发表时间：
2012
期刊：
影响因子：
37.3
作者：
Nelson, Laura D;Bender, Christian;Mannsperger, Heiko;Buergy, Daniel;Kambakamba, Patryk;Mudduluru, Giridhar;Korf, Ulrike;Hughes, Dennis;Van Dyke, Michael W;Allgayer, Heike
通讯作者：
Allgayer, Heike

New, tolerable γ-secretase inhibitor takes desmoid down a notch.

新的、可耐受的γ-分泌酶抑制剂可以降低硬纤维瘤的水平。