Epigenetic and Genetic Vulnerabilities in Synovial Sarcoma

滑膜肉瘤的表观遗传和遗传脆弱性

基本信息

  • 批准号:
    10016099
  • 负责人:
  • 金额:
    $ 34.9万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-09-01 至 2023-08-31
  • 项目状态:
    已结题

项目摘要

ABSTRACT RP-4 focuses on synovial sarcoma, an aggressive pediatric/young adult sarcoma driven by the SS18-SSX fusion oncogene. SS18-SSX has emerged as a multi-faceted disruptor of epigenetic control that mediates genome-wide transcriptional deregulation, resulting in proliferation and aberrant or arrested differentiation. Our overall goal is to probe the basic pathobiology of synovial sarcoma so as to nominate potential therapeutic targets. We propose hypothesis-driven screening approaches, namely functional genomic screens to uncover vulnerabilities among chromatin/transcriptional regulators and among kinases, as well as targeting the oncogenic fusion itself. Based on the hypothesis that SS18-SSX causes synovial sarcoma cells to possess special “epigenetic” dependencies, we will, in Aim 1, (a) perform a broad functional genomic screen using a new CRISPR knock-out pooled library against epigenetic modulators; and (b) seek to further validate and understand mechanistically KDM2B, a dependency identified in preliminary studies, as a vulnerability in human synovial sarcoma cells. Based on the hypothesis that another effect of SS18-SSX is transcriptional deregulation of growth signaling, Aim 2 will employ three orthogonal strategies to better define targetable kinase vulnerabilities in this sarcoma. Specifically, we will (a) perform a CRISPR-based functional genomic screen against kinases in human synovial sarcoma cell lines; (b) identify activated kinases in synovial sarcoma by phospho-protein profiling of patient-derived xenografts; and (c) define the targets of pazopanib in synovial sarcoma by two complementary methods, affinity proteomics and PLATO (parallel analysis of translated ORFs). These two analyses should clarify the critical kinase targets of this multi-targeted kinase inhibitor that is active in a subset of synovial sarcoma patients. The results generated in this Aim will be integrated to form the basis for more rational targeting of critical kinases in this sarcoma. As SS18-SSX is the primary driver oncogene in synovial sarcoma, the junction point of the fusion transcript represents an rational and highly specific target for sequence-based therapeutics using new antisense oligonucleotide (ASO) approaches. Building on our promising results using gapmer ASOs to directly target other sarcoma fusions in vitro and in vivo, we will optimize and evaluate gapmer ASOs against SS18-SSX. In Aim 4, we will validate the targets identified in Aims 1-3 by confirming on-target effects and expression in human tumors, and we will perform preclinical evaluation of their potential as therapeutic targets in vitro and in vivo. The most promising targets will be validated and subjected to extensive preclinical evaluation using multiple, orthogonal, relevant in vitro and in vivo systems. The ultimate overall goal of this fundamentally translational project is to begin clinical evaluation of at least one agent based on the novel targets and strategies identified through our work in patients with this often lethal sarcoma within five years.
摘要 RP-4侧重于滑膜肉瘤,一种由SS 18-SSX驱动的侵袭性儿科/年轻成人肉瘤 融合癌基因SS 18-SSX已经成为一种多方面的表观遗传控制的破坏者, 全基因组转录失调,导致增殖和异常或停滞 分化我们的总体目标是探讨滑膜肉瘤的基本病理生物学,以提名 潜在的治疗目标。我们提出了假设驱动的筛选方法,即功能 基因组筛选,以揭示染色质/转录调节因子之间的漏洞, 激酶,以及靶向致癌融合本身。基于SS 18-SSX导致 滑膜肉瘤细胞具有特殊的“表观遗传”依赖性,我们将在目标1中,(a)进行广泛的 使用针对表观遗传调节剂的新CRISPR敲除汇集文库进行功能性基因组筛选; 以及(B)寻求进一步验证和机械地理解KDM 2 B,在 初步研究,作为人类滑膜肉瘤细胞的脆弱性。基于这样的假设, SS 18-SSX的另一个作用是生长信号传导的转录失调,Aim 2将使用三个 正交策略,以更好地定义靶向激酶的脆弱性,在这个肉瘤。具体来说,我们将 (a)在人滑膜肉瘤细胞中针对激酶进行基于CRISPR的功能性基因组筛选 (B)通过患者来源的磷酸化蛋白质谱鉴定滑膜肉瘤中的活化激酶; 异种移植物;和(c)通过两种互补方法确定帕唑帕尼在滑膜肉瘤中的靶点, 亲和蛋白质组学和PLATO(翻译ORF的平行分析)。这两个分析应该澄清 这种多靶点激酶抑制剂的关键激酶靶点,在滑液肉瘤的一个子集中具有活性 患者本目标中产生的结果将被整合,作为更合理地确定目标的基础, 关键的激酶。由于SS 18-SSX是滑膜肉瘤中的主要驱动癌基因, 融合转录物的连接点代表了基于序列的免疫反应的合理和高度特异性的靶点。 使用新的反义寡核苷酸(阿索)方法的治疗。在我们有希望的成果基础上 使用gapmer ASO直接靶向其他肉瘤融合体的体外和体内研究,我们将优化和 评估针对SS 18-SSX的缺口体ASO。在目标4中,我们将验证目标1-3中确定的目标, 确认在人类肿瘤中的靶向作用和表达,我们将进行临床前评估, 它们作为体外和体内治疗靶点的潜力。最有希望的目标将得到验证, 使用多个正交相关体外和体内试验进行广泛的临床前评价 系统.这个基本转化项目的最终总体目标是开始临床评价 至少一种药物的基础上的新的目标和战略,确定通过我们的工作,患者 这种通常致命的肉瘤。

项目成果

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Marc Ladanyi其他文献

Marc Ladanyi的其他文献

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{{ truncateString('Marc Ladanyi', 18)}}的其他基金

Epigenetic and Genetic Vulnerabilities in Synovial Sarcoma
滑膜肉瘤的表观遗传和遗传脆弱性
  • 批准号:
    10932624
  • 财政年份:
    2023
  • 资助金额:
    $ 34.9万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    10468968
  • 财政年份:
    2018
  • 资助金额:
    $ 34.9万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    10016100
  • 财政年份:
    2018
  • 资助金额:
    $ 34.9万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    10247702
  • 财政年份:
    2018
  • 资助金额:
    $ 34.9万
  • 项目类别:
Epigenetic and Genetic Vulnerabilities in Synovial Sarcoma
滑膜肉瘤的表观遗传和遗传脆弱性
  • 批准号:
    10468966
  • 财政年份:
    2018
  • 资助金额:
    $ 34.9万
  • 项目类别:
Epigenetic and Genetic Vulnerabilities in Synovial Sarcoma
滑膜肉瘤的表观遗传和遗传脆弱性
  • 批准号:
    10247701
  • 财政年份:
    2018
  • 资助金额:
    $ 34.9万
  • 项目类别:
Developmental Research Program
发展研究计划
  • 批准号:
    7976130
  • 财政年份:
    2010
  • 资助金额:
    $ 34.9万
  • 项目类别:
P4 Elucidating SYT-SSX-depend histone code alterations to guide targeted epigenet
P4 阐明 SYT-SSX 依赖的组蛋白代码改变以指导靶向表观遗传
  • 批准号:
    7976115
  • 财政年份:
    2010
  • 资助金额:
    $ 34.9万
  • 项目类别:
MSKCC Center for Translational Cancer Genomic Analysis
MSKCC 转化癌症基因组分析中心
  • 批准号:
    7942765
  • 财政年份:
    2009
  • 资助金额:
    $ 34.9万
  • 项目类别:
MSKCC Center for Translational Cancer Genomic Analysis
MSKCC 转化癌症基因组分析中心
  • 批准号:
    8543653
  • 财政年份:
    2009
  • 资助金额:
    $ 34.9万
  • 项目类别:

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