Targeting Radiation Resistance in Glioblastoma Stem Cells

描述（由申请人提供）：放射耐药仍然是治疗多形性胶质母细胞瘤（GBM）的重要临床挑战。GBM最初可能对放疗有反应，然而，随后的局部复发是普遍的，这表明放疗不足以杀死致瘤细胞。新出现的证据表明，具有干细胞样特征的GBM细胞亚群，被称为GBM干细胞，可能是驱动放疗后肿瘤复发的关键决定因素。GBM干细胞比匹配的非干细胞对辐射的抵抗力更强。在连续移植中，几百个GBM干细胞通常足以重新填充GBM异种移植肿瘤，而非干细胞的GBM细胞在数个数量级以上时不能这样做，这表明需要充分根除GBM干细胞来延迟或预防肿瘤复发。然而，在了解保护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，可以显著改善GSCs对放射治疗的反应。申请人研究项目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目标是阐明和瞄准gsc特异性信号传导与GBM辐射抗性之间的机制联系，这是追求长期目标的下一步。核心假设是，在GSCs中观察到的耐辐射表型在很大程度上是由于Notch调节的促生存信号网络。这一假设是根据申请人实验室产生的初步数据制定的。提出的研究的基本原理是，更好地理解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，导致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验证：1)通过遗传拯救实验和药理学方法的互补组合来描述Notch调控的促生存信号网络；2)严格测试一种药物组合，协同靶向notch调节的信号网络，并在体外和体内有效抑制GSCs的致瘤性和辐射耐药。预计，如果充分发展和成功完成拟议的研究，将对目前在GBM中观察到的放射抗性表型范式产生新的见解，并最终导致新的GBM放射增敏方法。

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.