Targeting FAK and integrin signaling in preclinical models of Ewing sarcoma

尤文肉瘤临床前模型中针对 FAK 和整合素信号传导

基本信息

  • 批准号:
    8967409
  • 负责人:
  • 金额:
    $ 17.71万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2015
  • 资助国家:
    美国
  • 起止时间:
    2015-07-07 至 2020-06-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Research: Ewing sarcoma is the second most common bone malignancy of childhood. Treatment regimens are highly toxic and patients with metastatic disease are rarely cured. Efforts to utilize targeted therapies for patients with Ewing sarcoma have been limited due to an insufficient number of validated clinical targets. To this end, I performed a kinome profiling screen of Ewing sarcoma cell lines that identified focal adhesion kinase (FAK) as highly active. I demonstrated that activated FAK is expressed in tumors and downregulation of this target impairs growth, survival, and tumor proliferation in this disease. However, it is currently unknown how FAK is activated in Ewing sarcoma, whether FAK is necessary for the development of metastasis as seen in other cancers, and how to best utilize FAK inhibitors in the clinic for patients with Ewing sarcoma. In a recent screening effort to identify non-kinase molecular vulnerabilities in Ewing sarcoma, I found that Ewing sarcoma cell lines are dependent on a number of integrins, a class of transmembrane receptors known to activate FAK and play a role in cancer metastasis. Based on additional preliminary data, I now propose to demonstrate that Ewing sarcoma is dependent on one of these integrins, ITGB2, for growth, survival, tumor progression, and FAK activation. I also propose to show that ITGB2 and FAK are necessary for the development of metastasis in this disease. Finally, in a large-scale screening effort to identify therapeutic combinations for use with FAK inhibitors, I found that Aurora kinase inhibitors synergized with FAK inhibition in a Ewing sarcoma cell line. Therefore, I propose to validate the preliminary finding that Aurora B kinase inhibitors in combination with FAK inhibition is an efficacious combination and a candidate for testing in second-generation clinical trials for patients with Ewing sarcoma. Candidate Career Goals: The time period encompassed by this career development award will be the final critical training phase of my career prior to transition to independence. During this time I will gain the knowledge, laboratory skills, writing experience, and maturity necessary to apply for a tenure-track physician-scientist position in academic pediatric oncology. In the long- term, my goal is to be a leading expert in the identification of new therapeutic strategies for pediatric sarcomas through the use of innovative approaches in the lab. The research proposed in this application will be performed under the mentorship of Dr. Kimberly Stegmaier at Dana- Farber Cancer Institute and Dr. Todd Golub at the Broad Institute with guidance of a scientific advisory committee composed of leading experts in cancer biology. Environment: The Dana-Farber Cancer Institute houses internationally recognized research programs in cancer biology and translational discovery. The Division of Pediatric Oncology has a distinguished record of training young physician-scientists for leadership roles in pediatric cancer research. Graduates from this training have gone on to make transformative discoveries that continue to shape the future of clinical care for pediatric cancer patients.
 描述(由申请人提供):研究:尤文肉瘤是第二个最常见的骨恶性肿瘤的儿童。治疗方案具有高毒性,并且患有转移性疾病的患者很少治愈。由于经验证的临床靶点数量不足,尤文肉瘤患者的靶向治疗受到限制。为此,我进行了尤文肉瘤细胞系的激酶组分析筛选,确定黏着斑激酶(FAK)为高活性。我证明了活化的FAK在肿瘤中表达,并且该靶点的下调损害了这种疾病中的生长、存活和肿瘤增殖。然而,目前尚不清楚FAK在尤文肉瘤中是如何被激活的,FAK是否是其他癌症中所见的转移发展所必需的,以及如何在尤文肉瘤患者的临床中最好地利用FAK抑制剂。在最近的筛选工作,以确定非激酶分子的尤文肉瘤的弱点,我发现,尤文肉瘤细胞系依赖于一些整合素,一类跨膜受体已知激活FAK,并在癌症转移中发挥作用。基于额外的初步数据,我现在建议证明尤文肉瘤依赖于这些整合素之一,ITGB 2,生长,生存,肿瘤进展和FAK激活。我还建议表明,ITGB 2和FAK是必要的发展转移,在这种疾病。最后,在一项大规模的筛选工作中,我发现Aurora激酶抑制剂与FAK抑制剂在尤文肉瘤细胞系中有协同作用。因此,我建议验证初步发现,极光B激酶抑制剂与FAK抑制剂的组合是一种有效的组合,并在尤文肉瘤患者的第二代临床试验中进行测试的候选人。候选人职业目标:这一职业发展奖所涵盖的时间段将是我职业生涯过渡到独立之前的最后一个关键培训阶段。在此期间,我将获得必要的知识,实验室技能,写作经验和成熟度,以申请学术儿科肿瘤学的终身制医生-科学家职位。从长远来看,我的目标是通过在实验室中使用创新方法,成为确定儿科肉瘤新治疗策略的领先专家。本申请中提出的研究将在Dana- Farber癌症研究所的Kimberly Stegmaier博士和Broad研究所的托德戈卢布博士的指导下进行,并由癌症生物学领域的领先专家组成的科学咨询委员会指导。丹娜-法伯癌症研究所拥有国际公认的癌症生物学和转化发现研究项目。儿科肿瘤学部门在培训年轻的医生科学家在儿科癌症研究中发挥领导作用方面有着杰出的记录。从这次培训的毕业生已经继续进行变革性的发现,继续塑造儿科癌症患者的临床护理的未来。

项目成果

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Brian Crompton其他文献

Brian Crompton的其他文献

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{{ truncateString('Brian Crompton', 18)}}的其他基金

PROJECT 3: Applying Liquid Biopsy Technologies to Detect Clinical Response and Mechanisms of Resistance in the Treatment of LMS
项目 3:应用液体活检技术检测 LMS 治疗的临床反应和耐药机制
  • 批准号:
    10493631
  • 财政年份:
    2022
  • 资助金额:
    $ 17.71万
  • 项目类别:
PROJECT 3: Applying Liquid Biopsy Technologies to Detect Clinical Response and Mechanisms of Resistance in the Treatment of LMS
项目 3:应用液体活检技术检测 LMS 治疗的临床反应和耐药机制
  • 批准号:
    10705742
  • 财政年份:
    2022
  • 资助金额:
    $ 17.71万
  • 项目类别:
Liquid biopsy approaches to inform osteosarcoma prognosis and tumor evolution
液体活检方法可告知骨肉瘤预后和肿瘤演变
  • 批准号:
    10668427
  • 财政年份:
    2020
  • 资助金额:
    $ 17.71万
  • 项目类别:
Liquid biopsy approaches to inform osteosarcoma prognosis and tumor evolution
液体活检方法可告知骨肉瘤预后和肿瘤演变
  • 批准号:
    10202511
  • 财政年份:
    2020
  • 资助金额:
    $ 17.71万
  • 项目类别:
Liquid biopsy approaches to inform osteosarcoma prognosis and tumor evolution
液体活检方法可告知骨肉瘤预后和肿瘤演变
  • 批准号:
    10426209
  • 财政年份:
    2020
  • 资助金额:
    $ 17.71万
  • 项目类别:
Targeting FAK and integrin signaling in preclinical models of Ewing sarcoma
尤文肉瘤临床前模型中针对 FAK 和整合素信号传导
  • 批准号:
    9512891
  • 财政年份:
    2015
  • 资助金额:
    $ 17.71万
  • 项目类别:

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