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: 9071397
• 负责人: Jialiang Wang
• 金额: $ 32.79万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 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/9071397
• 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; Role; Signal Transduction; Stem cells; Testing; Therapeutic; Therapeutic Intervention; Transplantation; Tumorigenicity; Variant; arm; base; cancer stem cell; combinatorial; driving force; genetic approach; hypoxia inducible factor 1; improved; in vivo; inhibitor/antagonist; innovation; insight; killings; notch protein; novel; novel therapeutics; prevent; programs; public health relevance; radiation resistance; radioresistant; radiosensitizing; research study; response; secretase; stem; synergism; targeted agent; targeted treatment; 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（由申请人提供）：辐射阻力仍然是治疗多形胶质母细胞瘤（GBM）的重大临床挑战。 GBM最初可能对放射疗法有反应，但是，随后的局部复发是普遍的，表明通过辐射杀死了肿瘤细胞。新兴证据表明，具有干细胞样特征的GBM细胞（称为GBM干细胞）的亚群可能代表放疗后驱动肿瘤复发的关键决定因素。 GBM干细胞比匹配的非茎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，而非茎GBM细胞无法以高数量级的数量进行数量，这表明需要足够的GBM干细胞来延迟或预防肿瘤复发。但是，了解保护GBM干细胞免受辐射的特定机制存在很大的空白。还缺乏有效的放射敏化策略，这些策略可能会显着改善GSC对放射疗法的反应。申请人研究计划的长期目标是确定改善GBM和其他人类癌症放射疗法的创新和变革性治疗策略。该应用程序中提出的研究的目的是追求长期目标的下一步，是阐明和targt GBM的GSC特异性信号传导和放射线抗性之间的机械联系。中心假设是，在GSC中观察到的辐射表型在很大程度上归功于凹口调节的Proservival信号网络。该假设是根据申请人实验室中产生的初步数据提出的。拟议的研究的基本原理是，通过组合抑制该信号网络的多个关键点，可以更好地理解对缺口调节的信号网络的潜力。在初步数据的指导下，该假设将通过追求两个具体的目的来检验：1）通过遗传救援实验和药理方法的补充组合来描述GSC中的缺口调节的Provival信号网络； 2）严格测试该药物组合，以协同靶向该NOTCH调节的信号网络，并有效地抑制GSC在体外和体内的肿瘤性和放射性抑制。预计拟议的研究（F充分开发和成功完成）将对GBM中观察到的辐射抗性表型的当前范式产生新颖的见解，并最终导致GBM的新放射激素化方法。