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

摘要/摘要 放射治疗(RT)是治疗胶质母细胞瘤(GBM)标准中不可或缺的一部分。 虽然与单纯手术相比，在手术中增加RT可以显著延长患者的生存时间，但所有 患有GBM的患者最终会死于这种疾病，生存时间低得令人无法接受。 到目前为止，在手术和放疗中增加靶向或非靶向治疗的效果有限。 这项工作取得了成功，并表明需要采取新的战略来防治这种疾病。 有充分的证据支持基底膜的异质性和小的 胶质母细胞瘤干细胞(GSCs)群体，对RT和化疗相对耐药，以及 能够使肿瘤再生。一起，治疗耐药的GSCs，癌细胞的扩散超出 可见的肿瘤、大面积的缺氧和血脑屏障(BBB)增加了挑战 GBM介绍了癌症治疗。 我们之前已经证明，辐射会重新激活干细胞程序，导致细胞 多能性和可塑性，随后获得诱导的GSC状态。重要的是，我们 表明这一进程是有针对性的，防止诱导GSC导致 提高GBM动物模型的存活率。我们现在已经开发出新的化合物， 跨越血脑屏障，防止辐射诱导的GSCs的产生。此外，我们的 初步数据表明，辐射诱导的多效态可以用于 GBM细胞的终末分化。本申请中提出的研究建立在这些基础上 并将研究计划带入这一令人兴奋的新方向，以利用这一诱导 改变GBM辐射响应的多能态。

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.