Targeting Radiation Resistance in Glioblastoma Stem Cells

描述(申请人提供)：放射抵抗仍然是治疗多形性胶质母细胞瘤(GBM)的一个重大临床挑战。GBM最初可能对放射治疗有反应，但随后的局部复发是普遍的，这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，可能是推动放射治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GBM细胞对辐射的抵抗力更强。在连续移植中，数百个GBM干细胞通常足以重新填充GBM异种移植瘤，而非干细胞GBM干细胞的数量高出几个数量级，无法做到这一点，这表明需要足够的GBM干细胞来延缓或防止肿瘤复发。然而，在理解保护GBM干细胞免受辐射的具体机制方面仍有相当大的差距。也缺乏有效的放射增敏策略，可以显著提高GSC对放射治疗的反应。申请者研究计划的长期目标是确定创新和变革性的治疗策略，以改进对GBM和其他人类癌症的放射治疗。这项申请中提出的研究的目的是阐明和研究GSC特异性信号与GBM的辐射抗性之间的机制联系。中心假设是，在GSCs中观察到的辐射抵抗表型在很大程度上是由于Notch调节的生存信号网络。这一假设是根据申请人实验室提供的初步数据提出的。这项研究的基本原理是，对Notch调控的信号网络有更好的理解，有可能通过组合抑制该信号网络的多个关键点来实现创新和有效的放射增敏方法。在初步数据的指导下，这一假说将通过追求两个具体目标来检验：1)通过基因救援实验和药理学方法的互补组合来描绘GSCs中Notch调控的生存信号网络；以及2)严格测试一种药物组合，该药物组合协同靶向该Notch调控的信号网络，并有效地抑制GSCs在体外和体内的致瘤性和辐射抗性。预计拟议的研究，如果得到充分开发和成功完成，将对GBM中观察到的抗辐射表型的当前范例产生新的见解，并最终导致GBM的新的放射增敏方法。

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.