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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：
10247701
负责人：
Marc Ladanyi
金额：
$ 34.47万
依托单位：
SLOAN-KETTERING INST CAN RESEARCH
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：
https://reporter.nih.gov/project-details/10247701
关键词：
Affect Affinity Antisense Oligonucleotides Base Sequence Binding Proteins CRISPR/Cas technology Cell Line Cell Proliferation Cell Survival Child Childhood Chromatin Clinical Clinical Trials Clustered Regularly Interspaced Short Palindromic Repeats Dependence Disease Engineering Epigenetic Process Genes Genetic Predisposition to Disease Genetic Transcription Goals Growth Human Impairment In Vitro Investigation Knock-out Lead Libraries Malignant Neoplasms Mediating Methods Modeling Oncogenes Oncogenic Open Reading Frames Patients Pharmaceutical Preparations Phase Phosphoproteins Phosphotransferases Preclinical Drug Evaluation Proteins Proteomics Sampling Signal Transduction Soft tissue sarcoma Specimen System Therapeutic Therapeutic Uses Transcript Translating Tyrosine Kinase Inhibitor Validation Work Xenograft procedure base functional genomics gene product genome-wide in vivo in vivo Model in vivo evaluation inhibitor/antagonist kinase inhibitor knock-down novel patient derived xenograft model patient subsets preclinical evaluation research clinical testing sarcoma screening small hairpin RNA synovial sarcoma targeted treatment therapeutic candidate therapeutic target treatment strategy tumor young 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