Targeting the OLIG2 Transcription Factor

靶向 OLIG2 转录因子

• 批准号: 8588494
• 负责人: Charles D Stiles
• 金额: $ 28.86万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-19 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588494
• 关键词: Address; Adjuvant; Age-Years; Attenuated; Biological; Biological Assay; Biological Process; Biometry; Brain; Brain Neoplasms; CDKN2A gene; Cancer Etiology; Cancer Patient; Cause of Death; Cell Count; Cell Culture Techniques; Cells; Cessation of life; Clinical Investigator; Clinical Trials; Controlled Study; Core Facility; DNA Sequence Analysis; Dana-Farber Cancer Institute; Data; Development; Doctor of Philosophy; Doxycycline; Enrollment; Genes; Genetic; Genetic Suppression; Glioblastoma; Glioma; Histone Deacetylase Inhibitor; Human; Immunohistochemistry; Implant; Laboratories; Lead; MDM2 gene; Malignant Glioma; Mediating; Minority; Modality; Modeling; Molecular; Mus; Mutation; Nude Mice; Pathology; Patients; Pharmaceutical Preparations; Phase II Clinical Trials; Population; RNA Interference; Radiation; Radiation Oncologist; Radiation therapy; Radiation-Sensitizing Agents; Radio; Recurrence; Recurrent tumor; Resected; Resistance; Resolution; Sampling; Scientist; Signal Transduction; Solvents; Specimen; Students; TP53 gene; Testing; Tetanus Helper Peptide; Therapeutic; Therapeutic Clinical Trial; Time; Tissues; Vorinostat; Woman; Work; attenuation; cancer genome; clinical material; in vivo; inhibitor/antagonist; interest; irradiation; member; men; middle age; nerve stem cell; novel; response; skills; small hairpin RNA; small molecule; standard of care; stemness; temozolomide; therapeutic target; transcription factor; tumor; vector

Glioblastomas are notoriously insensitive to radiation and genotoxic drugs. Paradoxically, the p53 gene is structurally intact in the majority (-75%) of ttiese tumors. Resistance to genotoxic modalities in p53-intact gliomas has been attributed to attenuation of p53 functions by other mutations within a p53 signaling axis that includes CDKN2A(p14^'^), MDM2 and ATM. In preliminary studies, we have generated an alternative and potentially actionable resolution to the p53 paradox. Put briefly, we have shown that the gliogenic transcription factor 0LIG2 suppresses p53-mediated responses to genotoxic damage in glioblastoma cells. Against this backdrop, the broad objective of studies proposed in this SPORE project is to use clinical materials to test the hypothesis that small molecule inhibitors of OLIG2 could serve as targeted therapeutics for glioblastoma - either as stand alone modalities or (more likely) as adjuvants to radiotherapy and genotoxic drugs. This hypothesis makes four testable predictions: Our first specific aim is to test the prediction that current standard of care (radiation and Temozolomide) actually enriches for OLIG2-positive cells within p53-positive glioblastomas. Our second specific aim is to test the prediction that one current class of radiosensifizing drugs - the HDAC inhibitors - actually work by suppressing 0L1G2 expression in cancer patients. Our third specific aim is to test the prediction that genetic suppression of 0L1G2 can sensitize p53-positive human gliomas to radiotherapy in vivo. Our fourth specific aim is to test the prediction that shRNA-mediated knockdown of genes essential to 0L1G2 function (e.g. HDACs) will be synthetic lethal to irradiation in p53 positive gliomas. The basic scientist on this project (CD Stiles, PhD) is a molecular biologist and the clinical investigator (JS Loeffler) is a radiation oncologist. Dr Stiles and his students initially cloned the OLIG genes and defined their biological functions in brain development and malignant glioma. Dr Loeffier is a leader in the field of brain tumor irradiation with a special interest in glioblastomas. Together they have the skill sets required for successful completion ofthe study plan. The work they propose will be supported by dedicated SPORE core facilities for Pathology and Biostatistics. If the work described here supports the view that 0LIG2 is a viable target for glioma therapeutics, clinical trials of 0L1G2 antagonists (e.g. HDAC inhibitors) as an adjuvant to radiotherapy can be initiated within a five-year period of time.

众所周知，胶质母细胞瘤对辐射和基因毒性药物不敏感。p53基因是 在大多数（~75%）这种肿瘤中结构完整。p53完整基因对遗传毒性方式的抗性 神经胶质瘤归因于p53信号传导轴内的其他突变导致p53功能减弱 包括CDKN2A（p14）、MDM2和ATM。在初步研究中，我们已经产生了一种替代方案， 以及解决p53悖论的可行方案。简而言之，我们已经证明， 转录因子OLIG2抑制胶质母细胞瘤细胞中p53介导的对遗传毒性损伤的反应。 在此背景下，SPORE项目中提出的研究的广泛目标是使用临床 材料来测试OLIG2的小分子抑制剂可以作为靶向治疗剂的假设 对于胶质母细胞瘤-无论是作为独立的方式或（更可能）作为辅助放疗， 基因毒性药物这一假设提出了四个可检验的预测：我们的第一个具体目标是检验 预测目前的护理标准（放射和替莫唑胺）实际上富集了OLIG2阳性 p53阳性胶质母细胞瘤中的细胞。我们的第二个具体目标是测试当前一个预测 一类放射增敏药物-HDAC抑制剂-实际上是通过抑制0L1G2表达而起作用的。 癌症患者。我们的第三个具体目标是检验0L1G2的遗传抑制可以 p53阳性人脑胶质瘤对放射治疗的敏感性。我们的第四个具体目标是测试 预测shRNA介导的对0L1G2功能必需的基因（例如HDAC）的敲低将是 p53阳性胶质瘤的放射合成致死率 该项目的基础科学家（CD Stiles，PhD）是分子生物学家和临床研究者 (JS Loeffler）是一名放射肿瘤学家。斯泰尔斯博士和他的学生最初克隆了OLIG基因， 它们在脑发育和恶性胶质瘤中的生物学功能。Loeffier博士是该领域的领导者， 脑肿瘤放射治疗，特别关注胶质母细胞瘤。他们一起拥有所需的技能， 顺利完成学习计划。他们提出的工作将得到专用的SPORE核心的支持 病理学和生物统计学设施。如果这里描述的工作支持0LIG2是可行的观点， 作为神经胶质瘤治疗剂的靶点，OL1G2拮抗剂（例如HDAC抑制剂）作为佐剂的临床试验， 放射治疗可以在五年内开始。