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
- 来源:
- 关键词:AffectAffinityAntisense OligonucleotidesBase SequenceBinding ProteinsCRISPR/Cas technologyCell LineCell ProliferationCell SurvivalChildChildhoodChromatinClinicalClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsDependenceDiseaseEngineeringEpigenetic ProcessGenesGenetic Predisposition to DiseaseGenetic TranscriptionGoalsGrowthHumanImpairmentIn VitroInvestigationKnock-outLeadLibrariesMalignant NeoplasmsMediatingMethodsModelingOncogenesOncogenicOpen Reading FramesPatientsPharmaceutical PreparationsPhasePhosphoproteinsPhosphotransferasesPreclinical Drug EvaluationProteinsProteomicsSamplingSignal TransductionSoft tissue sarcomaSpecimenSystemTherapeuticTherapeutic UsesTranscriptTranslatingTyrosine Kinase InhibitorValidationWorkXenograft procedurebasefunctional genomicsgene productgenome-widein vivoin vivo Modelin vivo evaluationinhibitor/antagonistkinase inhibitorknock-downnovelpatient subsetspreclinical evaluationprofiles in patientsresearch clinical testingsarcomascreeningsmall hairpin RNAsynovial sarcomatargeted treatmenttherapeutic candidatetherapeutic targettreatment strategytumoryoung adult
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主要研究滑膜肉瘤,这是一种由SS18-SSX驱动的儿童/年轻人侵袭性肉瘤
融合癌基因。SS18-SSX已成为表观遗传控制的多方面破坏者,介导
全基因组转录失控,导致增殖异常或停滞
差异化。我们的总体目标是探索滑膜肉瘤的基本病理生物学,从而提名
潜在的治疗靶点。我们提出了假设驱动的筛选方法,即泛函
基因组筛查以发现染色质/转录调控因子和
激酶,以及靶向致癌融合本身。基于SS18-SSX引起的假设
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
利用新的CRISPR基因敲除文库对表观遗传调节子进行功能基因组筛选
和(B)寻求进一步机械地确认和理解Kdm2b,这是#年确定的一种依赖
初步研究,认为这是人类滑膜肉瘤细胞的一种脆弱性。基于这样的假设
SS18-SSX的另一个作用是转录上解除了对生长信号的调控,Aim 2将使用三个
正交策略,以更好地确定该肉瘤中的靶向激酶脆弱性。具体来说,我们将
(A)在人滑膜肉瘤细胞中进行基于CRISPR的针对蛋白激酶的功能性基因组筛选
(B)通过患者来源的磷酸化蛋白图谱鉴定滑膜肉瘤中的活化蛋白。
以及(C)通过两种互补的方法确定帕佐帕尼在滑膜肉瘤中的靶点,
亲和蛋白质组学和柏拉图(翻译的ORF的平行分析)。这两个分析应该会澄清
在滑膜肉瘤亚群中发挥活性的这种多靶点激酶抑制物的关键激酶靶点
病人。在这一目标中产生的结果将被综合起来,形成更合理的目标确定基础
肉瘤中的关键蛋白激酶。由于SS18-SSX是滑膜肉瘤的主要致癌基因,因此
融合转录本的连接点代表了基于序列的合理和高度特异的靶点
使用新的反义寡核苷酸(ASO)方法的治疗。在我们令人振奋的结果的基础上
使用Gapmer ASOS在体外和体内直接靶向其他肉瘤融合,我们将优化和
对照SS18-SSX评估Gapmer ASO。在目标4中,我们将通过以下方式确认目标1-3中确定的目标
确认靶向效应和在人类肿瘤中的表达,我们将进行临床前评估
它们在体外和体内作为治疗靶点的潜力。最有希望的目标将得到验证和
使用多个、正交、相关的体外和体内试验进行广泛的临床前评估
系统。这个从根本上翻译的项目的最终总体目标是开始临床评估
根据我们的工作确定的新靶点和策略至少使用一种药物治疗慢性阻塞性肺疾病
这往往是五年内致命的肉瘤。
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
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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:
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:
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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