Genomics and epigenomics approaches to characterize novel therapy targets in Ewing sarcoma
基因组学和表观基因组学方法来表征尤文肉瘤的新治疗靶点
基本信息
- 批准号:278765452
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:德国
- 项目类别:Research Grants
- 财政年份:2015
- 资助国家:德国
- 起止时间:2014-12-31 至 2018-12-31
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
Ewing sarcoma (ES) is a highly malignant bone and soft tissue neoplasm that arises predominantly in the pelvis and long bones in children and young adults with early metastasis to lung and bone. Survival expectancy increased for pediatric malignancies in recent years. However, only two thirds of ES patients without metastases currently achieve long lasting remissions by multimodal therapy approaches. Moreover, advanced ES has an even worse prognosis. Genetically, ES is defined by balanced chromosomal EWS/ETS translocations, which give rise to oncogenic chimeric transcription factors (EWS-ETS) that are currently not targetable. Other contributing somatic mutations involved in disease development have only been observed at low frequency. Recently, we identified EZH2 as an important driver for metastasis development in ES. Also, we have performed whole exome and genome sequencing in primary ES. We identified several recurrently mutated genes at low frequency. Of interest, activating point mutations of FGFR1, frequent amplification of this locus (31.7%) in primary tumors and widespread increased expression suggested significant FGFR1 activity as an important attribute of this disease. The various mechanisms of FGFR1 activation and the epigenetic mechanisms associated with EZH2 point towards a combination of epigenetic and genetic driver alterations in ES. The main aim of this proposal is therefore to characterize the therapeutic opportunities of relevant driver mechanisms in ES. We will combine specific gene knock outs generated via gene editing with a CRISP/Cas9-based system in a lethality screen together with different sublethal doses of Ponatinib in ES cell lines. Furthermore, we will combine gene knock-outs of previously identified key players of ES metastasis in such a screen for synthetic lethality gene defects. Promising candidate combinations will be evaluated together with genomic, epigenetic and clinical data and their potential druggability will be tested in preclinical model systems. We anticipate a better comprehension of key malignant mechanisms that help to improve therapy for ES, and to develop new therapeutic treatment modalities for cancer in general.
尤文肉瘤是一种高度恶性的骨和软组织肿瘤,主要发生在儿童和年轻人的骨盆和长骨,早期转移到肺和骨。近年来,儿童恶性肿瘤的生存预期增加。然而,目前只有三分之二的无转移的ES患者通过多模式治疗方法实现长期缓解。此外,晚期ES的预后更差。在遗传学上,ES由平衡的染色体EWS/ETS易位定义,其产生目前不可靶向的致癌嵌合转录因子(EWS-ETS)。其他参与疾病发展的体细胞突变仅以低频率观察到。最近,我们确定EZH 2是ES转移发展的重要驱动因素。此外,我们还在初级ES中进行了全外显子组和基因组测序。我们发现了几个低频率的重复突变基因。值得关注的是,FGFR 1的激活点突变、原发性肿瘤中该基因座的频繁扩增(31.7%)和广泛的表达增加表明FGFR 1活性是该疾病的重要属性。FGFR 1激活的各种机制和与EZH 2相关的表观遗传机制指向ES中表观遗传和遗传驱动改变的组合。因此,本提案的主要目的是表征ES中相关驱动机制的治疗机会。我们将在致死性筛选中将通过基因编辑产生的联合收割机特异性基因敲除与基于CRISP/Cas9的系统以及ES细胞系中不同亚致死剂量的Ponatinib结合。此外,我们将结合联合收割机基因敲除先前确定的关键球员的ES转移,在这样的合成致死基因缺陷的屏幕。有希望的候选组合将与基因组,表观遗传和临床数据一起进行评估,并将在临床前模型系统中测试其潜在的可药用性。我们预计将更好地理解关键的恶性机制,这有助于改善ES的治疗,并开发新的癌症治疗方法。
项目成果
期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Deep Sequencing in Conjunction with Expression and Functional Analyses Reveals Activation of FGFR1 in Ewing Sarcoma
- DOI:10.1158/1078-0432.ccr-14-2744
- 发表时间:2015-11-01
- 期刊:
- 影响因子:11.5
- 作者:Agelopoulos, Konstantin;Richter, Guenther H. S.;Mueller-Tidow, Carsten
- 通讯作者:Mueller-Tidow, Carsten
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Professor Dr. Carsten Müller-Tidow其他文献
Professor Dr. Carsten Müller-Tidow的其他文献
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{{ truncateString('Professor Dr. Carsten Müller-Tidow', 18)}}的其他基金
The relevance of EZH2 dependent Stemness mechanisms for Therapy Response and Resistance in Acute Myeloid Leukemia
EZH2 依赖性干细胞机制与急性髓系白血病治疗反应和耐药性的相关性
- 批准号:
415522939 - 财政年份:2018
- 资助金额:
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Research Grants
Mechanisms of DNMT3A-mutation induced sensitization for 5-Azacytidine in AML
DNMT3A 突变诱导 AML 中 5-氮杂胞苷致敏的机制
- 批准号:
280661318 - 财政年份:2015
- 资助金额:
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Research Grants
The significance of DNA Methyltransferase inhibition and DNA Methylation for therapy response in Acute Myeloid Leukemia
DNA 甲基转移酶抑制和 DNA 甲基化对急性髓系白血病治疗反应的意义
- 批准号:
171434580 - 财政年份:2010
- 资助金额:
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Priority Programmes
Die Bedeutung altersabhängiger genomweiter DNA-Methylierungsmuster bei der Akuten Myeloischen Leukämie / Kennwort: Biologie der AML im Alter
年龄依赖性全基因组 DNA 甲基化模式在急性髓系白血病中的意义 / 关键词:老年 AML 生物学
- 批准号:
125973759 - 财政年份:2009
- 资助金额:
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Research Grants
Die Bedeutung von INCA1 als Zellzyklusregulator und Tumorsuppressor bei der Akuten Myeloischen Leukämie / Kennwort: INCA1 bei AML
INCA1 作为细胞周期调节因子和肿瘤抑制因子在急性髓系白血病中的重要性 / 关键词:INCA1 在 AML 中
- 批准号:
63444431 - 财政年份:2008
- 资助金额:
-- - 项目类别:
Research Grants
The role of receptor tyrosine kinases in the metastatic process of early stage non-small cell lung cancer
受体酪氨酸激酶在早期非小细胞肺癌转移过程中的作用
- 批准号:
5453047 - 财政年份:2005
- 资助金额:
-- - 项目类别:
Research Grants
Chromatin-Modifikation durch chromosomale Translokation in der Pathogenese der Akuten Myeloischen Leukämie
急性髓系白血病发病机制中染色体易位引起的染色质修饰
- 批准号:
5434662 - 财政年份:2004
- 资助金额:
-- - 项目类别:
Heisenberg Fellowships
The role of the organspecific cyclin A1 gene in hemotopoiesis and pathogeneses acute myeloid leukemia
器官特异性细胞周期蛋白A1基因在急性髓性白血病造血和发病机制中的作用
- 批准号:
5195566 - 财政年份:1999
- 资助金额:
-- - 项目类别:
Research Grants
Signaling properties of driver mutations in clonal hematopoiesis of indeterminate potential (CHIP) as targets for diagnostics and therapeutic intervention
不确定潜力克隆造血 (CHIP) 驱动突变的信号传导特性作为诊断和治疗干预的目标
- 批准号:
508481183 - 财政年份:
- 资助金额:
-- - 项目类别:
Research Grants
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