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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：
Professor Dr. Carsten Müller-Tidow
金额：
--
依托单位：
Klinik für Hämatologie, Onkologie und Rheumatologie
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：
https://gepris.dfg.de/gepris/projekt/278765452?language=en
关键词：
Genomics epigenomics approaches characterize novel

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（ES）是一种高度恶性的骨和软组织肿瘤，主要发生于儿童和年轻人的骨盆和长骨，早期转移至肺和骨。近年来，儿科恶性肿瘤的预期生存率有所提高。然而，目前只有三分之二的无转移 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。从遗传学上讲，ES 是由平衡染色体 EWS/ETS 易位定义的，它会产生目前不可靶向的致癌嵌合转录因子 (EWS-ETS)。与疾病发展有关的其他体细胞突变仅以低频率观察到。最近，我们发现 EZH2 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。我们鉴定了几个低频反复突变的基因。有趣的是，FGFR1 的激活点突变、该基因座在原发性肿瘤中的频繁扩增（31.7%）以及广泛的表达增加表明显着的 FGFR1 活性是该疾病的一个重要属性。 FGFR1 激活的各种机制以及与 EZH2 相关的表观遗传机制表明 ES 中表观遗传和遗传驱动改变的结合。因此，本提案的主要目的是描述 ES 中相关驱动机制的治疗机会。我们将在致死率筛选中将通过基因编辑产生的特定基因敲除与基于 CRISP/Cas9 的系统结合起来，并在 ES 细胞系中结合不同亚致死剂量的 Ponatinib。此外，我们将结合先前确定的 ES 转移关键参与者的基因敲除来筛选合成致死性基因缺陷。有前景的候选组合将与基因组、表观遗传学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成药性。我们期望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式。