MYC-dependent loss of splicing fidelity in Glioblastoma multiforme

多形性胶质母细胞瘤中 MYC 依赖性剪接保真度损失

• 批准号: 9313844
• 负责人: Patrick Paddison
• 金额: $ 44万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9313844
• 关键词: 3' Splice Site; Adult; Adult Glioblastoma; Adult Glioma; Affect; Automobile Driving; Azacitidine; Biological Assay; Biology; Brain Neoplasms; Buffers; Cell Cycle Arrest; Cell Death; Cell Survival; Chemicals; Chemosensitization; Child; Childhood Brain Neoplasm; Childhood Glioblastoma; Childhood Glioma; Chromatin; Cis-Acting Sequence; Clinical; Clinical Trials; Collaborations; Complex; DNA Modification Methylases; DNA-Directed RNA Polymerase; Defect; Development; Drug Combinations; Drug Delivery Systems; Epigenetic Process; Essential Genes; Event; Funding; Genes; Genetic Screening; Genomics; Glioblastoma; Glioma; Goals; Grant; Histones; Human; Introns; Investigational Drugs; Knowledge; Lead; Lethal Genes; Malignant Neoplasms; Melanoma Cell; Modeling; Molecular; Names; Normal tissue morphology; Oncogenic; Patients; Pharmaceutical Preparations; Process; Production; Property; Proteins; Public Health; Publishing; RNA Splicing; Radiosurgery; Recruitment Activity; Reporter; Reporting; Research Personnel; Resistance; Sampling; Screening for cancer; Signal Pathway; Site; Spices; Spliceosomes; Sum; Testing; Therapeutic; Toxic effect; Tumor Markers; United States National Institutes of Health; Validation; Work; Xenograft Model; Xenograft procedure; cancer therapy; chemotherapy; design; exon skipping; experimental study; improved; in vivo; inhibitor/antagonist; knock-down; mRNA Precursor; melanoma; neoplastic cell; nerve stem cell; novel; overexpression; pre-clinical trial; programs; prospective; public health relevance; small molecule; standard of care; stem-like cell; targeted treatment; therapeutic target; tumor; tumor heterogeneity; tumor xenograft; validation studies

 DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most invasive and aggressive brain tumor in adults and children. Even with standard of care therapies such as chemotherapy, radiation and surgery 90% of GBM patients die within two years. Unfortunately, most targeted therapeutic strategies for GBM will fail to improve long-term patient survival due to tumor resistance arising from tumor heterogeneity and redundancy in oncogenic signaling pathways or to unanticipated toxicities in normal tissues. Among alternative strategies are ones that trigger "pleotropic" perturbations in key cancer molecular processes, more difficult for tumors to work around. Our group recently found one such pleotropic GBM-specific vulnerability in pre-mRNA 3' splice site (ss) recognition, from functional genetic screening for cancer-lethal genes in GBM stem-like cells (GSCs) and non- transformed neural stem cells (NSCs). Knockdown or partial chemical inhibition of 3' ss recognition triggered production of 100s of specific missplicing events (either intron retention or exon skipping) in essential genes only in GSCs, leading to cell cycle arrest and cell death. We have named these missplicing events CiSSRs for Cancer-induced 3' Splice Site Recognition defects. CiSSRs could be triggered in multiple human GBM isolates and subtypes, and when triggered in vivo profoundly regressed a human avatar GBM tumor, dramatically improving survival. The purpose of this grant is to reveal the underlying mechanism of GBM-specific CiSSRs and to develop actionable therapeutic strategies around them for GBM and other cancers. If successful, this grant will establish 3' ss recognition as a viable therapeutic target for GBM and likely other cancers, while delivering tangible therapeutic strategies. Aim 1 examines competing hypotheses regarding the underlying CiSSR biology, which will inform studies in tumors and clinical samples, including the possibility of finding prospective splicing tumor biomarkers. Aim 2 examines the novel finding that specific epigenetic regulators "buffer" loss of 3' ss recognition in GBM and speaks to recent reports of MYC synthetic lethality with BRD4 inhibition and also tests splicing inhibitor sudemycin D6 in GBM isolates. Aim 3 validates CiSSR biology and drug combinations in vivo and will identify new lead compounds that trigger CiSSRs in directly in adult and pediatric brain tumor isolates. In sum, this grant offers a GBM therapeutic program focused on splicing. The program interweaves mechanistic studies with pre-clinical trials and collaborations with leading researchers in splicing, splicing modulators, glioma tumor models, and small molecule discovery. One end- goal is to have sponsored clinical trials underway within the next 5-10 years.

 描述(申请人提供)：多形性胶质母细胞瘤(GBM)是成人和儿童中侵袭性最强的脑肿瘤。即使在化疗、放射治疗和手术等标准护理治疗下，90%的GBM患者也会在两年内死亡。不幸的是，大多数针对GBM的靶向治疗策略将无法改善患者的长期生存，原因是肿瘤的异质性和致癌信号通路中的冗余或正常组织中的意外毒性引起的肿瘤耐药性。在可供选择的策略中，有一些策略会在关键的癌症分子过程中引发“多发性”扰动，这对肿瘤来说更难绕过。我们的团队最近在前mRNA3‘剪接位点(Ss)识别中发现了一个这样的多效性GBM特异性漏洞，这是从GBM干细胞(GSCs)和未转化的神经干细胞(NSCs)中对致癌基因的功能性遗传筛选中发现的。3‘s识别的敲除或部分化学抑制仅在GSC的必需基因中引发了100个特定的错接事件(内含子保留或外显子跳跃)，导致细胞周期停滞和细胞死亡。我们将这些错误剪接事件命名为癌症诱导的3‘剪接位点识别缺陷的CiSSRs。CiSSRs可以在多种人类GBM分离株和亚型中被触发，当在体内被触发时，可以深刻地退化人类头像GBM肿瘤，显著提高存活率。这笔赠款的目的是揭示GBM特异性CiSSRs的潜在机制，并围绕它们开发针对GBM和其他癌症的可行治疗策略。如果成功，这笔赠款将在提供切实的治疗策略的同时，确立3‘s公司对GBM和可能的其他癌症的可行治疗目标的认可。目的1检查关于潜在的CiSSR生物学的相互竞争的假设，这将为肿瘤和临床样本的研究提供信息，包括发现预期的剪接肿瘤生物标记物的可能性。目的2研究新发现的特异性表观遗传调节因子3‘s识别在GBM中的“缓冲”丢失，以及最近关于BRD4抑制的MYC合成致死性的报道，并在GBM分离株中测试剪接抑制剂sudemycin D6。目的3在体内验证CiSSR生物学和药物组合，并将在成人和儿童脑瘤分离株中鉴定直接触发CiSSR的新的先导化合物。总而言之，这笔赠款提供了一个专注于剪接的GBM治疗计划。该计划将机制研究与临床前试验交织在一起，并与剪接、剪接调节剂、胶质瘤肿瘤模型和小分子发现方面的领先研究人员合作。一个最终目标是在未来5-10年内赞助正在进行的临床试验。