Targeting Radiation Resistance in Glioblastoma Stem Cells

针对胶质母细胞瘤干细胞的放射抗性

• 批准号: 8502981
• 负责人: Jialiang Wang
• 金额: $ 30.98万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8502981
• 关键词: Automobile Driving; Biological Assay; Cell Death; Cells; Characteristics; Clinical; Clinical Trials; Combined Modality Therapy; Data; Development; Drug Combinations; ERBB2 gene; Epidermal Growth Factor Receptor; Failure; Farnesyl Transferase Inhibitor; Foundations; Future; Genes; Genetic; Glioblastoma; Goals; Human; In Vitro; Knowledge; Laboratories; Lead; Link; Malignant Neoplasms; Mediating; Modality; Modeling; Mus; Mutate; Outcome; PDGFRB gene; Pathway interactions; Phenotype; Play; Public Health; Publishing; Radiation; Radiation Tolerance; Radiation therapy; Radiation-Sensitizing Agents; Radioresistance; Radiosensitization; Receptor Protein-Tyrosine Kinases; Recurrence; Research; Resistance; Role; Signal Transduction; Stem cells; Testing; Therapeutic; Therapeutic Intervention; Transplantation; Tumorigenicity; Variant; arm; base; cancer stem cell; combinatorial; driving force; hypoxia inducible factor 1; improved; in vivo; inhibitor/antagonist; innovation; insight; killings; notch protein; novel; novel therapeutics; prevent; programs; public health relevance; radiation resistance; research study; response; secretase; stem; synergism; tumor; tumor xenograft; tumorigenic

DESCRIPTION (provided by applicant): Radiation resistance remains a significant clinical challenge in treatment of glioblastoma multiforme (GBM). GBM may initially respond to radiotherapy, however, subsequent local recurrence is universal, suggesting insufficient killing of tumorigenic cells by radiation. Emerging evidence suggests that a subpopulation of GBM cells with stem cell-like characteristics, referred to as GBM stem cells, may represent a critical determinant in driving tumor recurrence after radiotherapy. GBM stem cells are more resistant to radiation than matched non- stem GBM cells. Several hundred GBM stem cells are often sufficient to repopulate GBM xenograft tumors in serial transplantation, while non-stem GBM cells fail to do so at numbers several orders of magnitude higher, suggesting adequate eradication of GBM stem cells is required to delay or prevent tumor recurrence. However, there is a considerable gap in understanding the specific mechanisms that protect GBM stem cells against radiation. There is also a lack of effective radiosensitizing strategies that may significantly improve the response of GSCs to radiotherapy. The long-term goal of the research program of the applicant is to identify innovative and transformative therapeutic strategies for improving radiotherapy for GBM and other human cancers. The objective of studies proposed in this application, which is the next step in pursuit of the long-term goal, is to elucidate and targt a mechanistic link between GSC-specific signaling and radioresistance of GBM. The central hypothesis is that the radioresistant phenotype observed in GSCs is due in large part to a Notch- regulated prosurvival signaling network. This hypothesis is formulated on the basis of the preliminary data produced in the applicant's laboratory. The rationale of the proposed research is that a better understanding of the Notch-regulated signaling network has the potential leading to innovative and effective radiosensitizing approaches through combinatorial suppression of multiple pivotal points of this signaling network. Guided by the preliminary data, this hypothesis will be tested by pursuing two specific aims: 1) to delineate the Notch- regulated prosurvival signaling network in GSCs by a complementary combination of genetic rescue experiments and pharmacological approaches; and 2) to rigorously test a drug combination that synergistically targets this Notch-regulated signaling network and effectively represses the tumorigenicity and radioresistance of GSCs in vitro as well as in vivo. It is anticipated that the proposed research, f adequately developed and successfully completed, will generate novel insights into the current paradigm of the radioresistant phenotype observed in GBM and eventually lead to new radiosensitizing approaches for GBM.

描述（由申请方提供）：放射抗性仍然是治疗多形性胶质母细胞瘤（GBM）的重大临床挑战。GBM最初可能对放射治疗有反应，然而，随后的局部复发是普遍的，表明放射对致瘤细胞的杀伤不足。新出现的证据表明，具有干细胞样特征的GBM细胞亚群（称为GBM干细胞）可能是放射治疗后驱动肿瘤复发的关键决定因素。GBM干细胞比匹配的非干GBM细胞更耐辐射。几百个GBM干细胞通常足以在连续移植中重新填充GBM异种移植肿瘤，而非干GBM细胞在高出几个数量级的数量下无法做到这一点，这表明需要充分根除GBM干细胞以延迟或预防肿瘤复发。然而，在理解保护GBM干细胞免受辐射的具体机制方面存在相当大的差距。也缺乏有效的放射增敏策略，可以显着提高GSC对放射治疗的反应。申请人研究计划的长期目标是确定创新和变革性的治疗策略，以改善GBM和其他人类癌症的放射治疗。本申请中提出的研究的目的是阐明和靶向GSC特异性信号传导与GBM的辐射抗性之间的机制联系，这是追求长期目标的下一步。中心假设是在GSC中观察到的辐射抗性表型在很大程度上是由于Notch调节的促存活信号传导网络。这一假设是根据申请人实验室提供的初步数据提出的。提出的研究的基本原理是，更好地了解Notch调节的信号网络有可能通过组合抑制该信号网络的多个关键点来产生创新和有效的放射增敏方法。在初步数据的指导下，这一假设将通过追求两个具体目标来检验：1）通过遗传拯救实验和药理学方法的互补组合来描绘GSC中Notch调节的促存活信号网络;和2）严格测试协同靶向该Notch的药物组合，调控信号网络，在体内外有效抑制GSCs的致瘤性和辐射抗性。预计所提出的研究如果得到充分发展并成功完成，将对GBM中观察到的辐射抗性表型的当前范例产生新的见解，并最终导致GBM的新的辐射增敏方法。