Utilizing Radiation-Induced Multi-potency to Increase the Efficacy of Radiotherapy

总结/摘要 放射治疗（RT）是针对胶质母细胞瘤（GBM）的标准治疗的组成部分。 虽然在手术中加入RT比单独手术显著提高了患者生存率，但所有 患有GBM的患者最终死于该疾病，并且存活时间低得不可接受。 到目前为止，在手术和RT中添加靶向或非靶向治疗的效果有限 成功，并表明需要新的战略来对付这种疾病。 有足够的证据支持GBM的异质性和存在小的 胶质母细胞瘤干细胞（GSC）群体），对RT和化疗相对耐受，以及 使肿瘤再生。总之，治疗抗性GSC，癌细胞的分散超过 可见的肿瘤、大面积缺氧和血脑屏障（BBB）增加了挑战 GBM呈现于癌症治疗。 我们以前已经证明，辐射重新激活干细胞程序， 多能性和可塑性，随后获得诱导的GSC状态。重要的是我们 表明这一过程可以靶向，阻止GSC的诱导导致 改善GBM动物模型的存活率。我们现在已经开发出了新的化合物， 穿过血脑屏障并阻止辐射诱导的GSC的产生。而且我们的 初步数据表明，辐射诱导的多能态可以用来允许 GBM细胞的终末分化。本申请中提出的研究建立在这些 研究结果，并采取研究计划进入这个令人兴奋的新方向，利用这种诱导 多能状态改变GBM的辐射反应。

SUMMARY/ABSTRACT Radiation therapy (RT) is an integral part of the standard-of-care against glioblastoma (GBM). While the addition of RT to surgery over surgery alone significantly prolongs patient survival, all patients with GBM ultimately succumb to the disease and survival times are unacceptably low. So far, the addition of targeted or non-targeted therapies to surgery and RT have had limited success and indicate the need for novel strategies against this disease. There is ample evidence supporting the heterogeneity of GBM and the existence of a small population of glioblastoma stem cells (GSCs)), relatively resistant to RT and chemotherapy, and able to regrow the tumor. Together, treatment resistant GSCs, dispersion of cancer cells beyond the visible tumor, large areas of hypoxia and the blood-brain-barrier (BBB) add to the challenge GBM presents to cancer therapy. We have previously demonstrated that radiation reactivates stem cell programs causing cellular multipotency and plasticity, followed by the acquisition of an induced GSC state. Importantly, we showed that this process could be targeted and that preventing the induction of GSCs led to improved survival in animal models of GBM. We have now developed novel compounds that cross the BBB and prevent the radiation-induced generation of GSCs. Furthermore, our preliminary data indicate that a radiation-induced multipotent state can be utilized to allow for terminal differentiation of GBM cells. The studies proposed in this application build on these findings and take the research program into this exciting new direction to utilize this induced multipotent state for altering the radiation responses of GBM.