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

基本信息

批准号：
9750641
负责人：
Patrick Paddison
金额：
$ 39.42万
依托单位：
FRED HUTCHINSON CANCER RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9750641
关键词：
3&apos 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 Operative Surgical Procedures Patients Pharmaceutical Preparations Process Production Property Proteins Public Health Publishing RNA Splicing Radiation 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 individualized medicine inhibitor/antagonist knock-down mRNA Precursor melanoma neoplastic cell nerve stem cell novel preclinical trial programs prospective public health relevance recruit small molecule standard of care stem-like cell targeted treatment therapeutic target tumor tumor heterogeneity tumor xenograft validation studies

项目摘要

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，不幸的是，即使采用化疗、放疗和手术等标准护理疗法，90% 的 GBM 患者也会在两年内死亡。大多数 GBM 靶向治疗策略将无法改善患者的长期生存，因为肿瘤异质性和致癌信号通路冗余或正常组织中意外的毒性引起肿瘤耐药。是在关键癌症分子过程中引发“多向性”扰动的因素，肿瘤更难以解决，我们的研究小组最近通过功能性遗传筛查在前 mRNA 3' 剪接位点 (ss) 识别中发现了一种此类多向性 GBM 特异性漏洞。 GBM 干细胞样细胞 (GSC) 和非转化神经干细胞 (NSC) 中的癌症致死基因 3' ss 识别的敲除或部分化学抑制触发了数百个特异性的产生。仅在 GSC 中的必需基因中发生错误剪接事件（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 CiSSR，因为癌症诱导的 3' 剪接位点识别缺陷可能会在多个 CiSSR 中触发。人类 GBM 分离株和亚型，当在体内触发时，人类化身 GBM 肿瘤会显着消退，从而显着提高生存率。这项资助的目的是揭示 GBM 特异性的潜在机制。 CiSSR 并围绕它们制定针对 GBM 和其他癌症的可行治疗策略。如果成功，这笔拨款将确立 3' ss 为 GBM 和可能的其他癌症的可行治疗靶点，同时提供切实可行的治疗策略，以检验有关的竞争假设。潜在的 CiSSR 生物学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，目标 2 检查特定表观遗传调节剂“缓冲”3' 丢失的新发现。 Aim 3 验证了 GBM 中的 ss 识别，并涉及最近关于 BRD4 抑制的 MYC 合成致死性报告，并在 GBM 分离株中测试了剪接抑制剂苏德霉素 D6，在体内验证了 CiSSR 生物学和药物组合，并将鉴定直接在成人中触发 CiSSR 的新先导化合物。总之，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结合起来。与剪接、剪接调节剂、神经胶质瘤肿瘤模型和小分子发现方面的领先研究人员合作，最终目标是在未来 5-10 年内赞助正在进行的临床试验。