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: 9118898
• 负责人: Patrick Paddison
• 金额: $ 47.19万
• 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/9118898
• 关键词: 3' Splice Site; Adult; Adult Glioma; Affect; Automobile Driving; Azacitidine; Biological Assay; Biology; Brain Neoplasms; Buffers; Cell Cycle Arrest; Cell Death; Cell Survival; Cells; 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; Health; Histones; Human; Introns; Investigation; 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; Reporter; Reporting; Research Personnel; Resistance; Sampling; Screening for cancer; Signal Pathway; Spices; Spliceosomes; Staging; 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; improved; in vivo; inhibitor/antagonist; knock-down; mRNA Precursor; melanoma; neoplastic cell; nerve stem cell; novel; overexpression; pre-clinical trial; programs; prospective; research study; small molecule; standard of care; stem; 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（由申请人提供）：多形性胶质母细胞瘤（GBM）是成人和儿童中最具侵袭性和侵袭性的脑肿瘤。即使使用标准的治疗方法，如化疗，放疗和手术，90%的GBM患者在两年内死亡。不幸的是，大多数针对GBM的治疗策略将无法改善患者的长期生存，这是由于肿瘤异质性和致癌信号传导途径中的冗余引起的肿瘤抗性或正常组织中的意外毒性。在替代策略中，有一种是在关键的癌症分子过程中引发“多效性”扰动，这对肿瘤来说更难解决。我们的小组最近从GBM干细胞样细胞（GSC）和非转化的神经干细胞（NSC）中的癌症致死基因的功能性遗传筛选中发现了前mRNA 3'剪接位点（ss）识别中的一种这样的多效性GBM特异性脆弱性。敲低或部分化学抑制3' ss识别触发了仅在GSC中的必需基因中产生数百个特异性错剪接事件（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CiSSRs，用于癌症诱导的3'剪接位点识别缺陷。CiSSR可以在多种人类GBM分离物和亚型中被触发，并且当在体内被触发时，人类化身GBM肿瘤显著消退，显著提高存活率。这项资助的目的是揭示GBM特异性CiSSR的潜在机制，并围绕它们为GBM和其他癌症制定可行的治疗策略。如果成功的话，这项资助将建立3' ss识别作为GBM和可能的其他癌症的可行治疗靶点，同时提供切实的治疗策略。目的1检查关于基础CiSSR生物学的竞争假设，这将为肿瘤和临床样本的研究提供信息，包括寻找前瞻性剪接肿瘤生物标志物的可能性。目的2检查了特异性表观遗传调节剂“缓冲”GBM中3' ss识别的损失的新发现，并与最近报道的MYC合成致死性与BRD 4抑制有关，还测试了GBM分离株中的剪接抑制剂sudemycin D 6。目的3在体内验证CiSSR生物学和药物组合，并将鉴定直接在成人和儿童脑肿瘤分离株中触发CiSSR的新先导化合物。总而言之，这项资助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年内进行赞助的临床试验。