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

利用辐射诱导的多效性来提高放射治疗的功效

• 批准号: 10705985
• 负责人: Frank Pajonk
• 金额: $ 50.79万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-01 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10705985
• 关键词: Affect; Animal Model; Area; Blood - brain barrier anatomy; Cell Differentiation process; Cell Line; Cells; Chemotherapy and/or radiation; Chromatin; Clonal Evolution; Data; Development; Disease; Exhibits; Generations; Genotoxic Stress; Glioblastoma; Glioma; Goals; Heterogeneity; Hypoxia; Malignant Neoplasms; Neurons; Operative Surgical Procedures; Pathway interactions; Patients; Phenotype; Population; Process; Promoter Regions; Public Health; Radiation; Radiation therapy; Recurrence; Research; Resistance; Role; Solid; Testing; Treatment Failure; Xenograft procedure; blood-brain barrier crossing; cancer cell; cancer therapy; chemotherapy; differentiation protocol; improved; in vivo; inhibitor; mouse model; neuronal circuitry; novel; novel strategies; prevent; programs; radiation response; radioresistant; standard of care; stem cells; stemness; success; therapy outcome; transcription factor; tumor

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.

摘要/摘要 放射治疗 (RT) 是胶质母细胞瘤 (GBM) 治疗标准的一个组成部分。 虽然与单纯手术相比，在手术中加入放疗可以显着延长患者的生存期，但所有 GBM 患者最终死于该疾病，且生存时间短得令人无法接受。 到目前为止，在手术和放疗的基础上添加靶向或非靶向疗法的效果有限。 成功并表明需要针对这种疾病的新策略。 有充分的证据支持 GBM 的异质性和小群体的存在 胶质母细胞瘤干细胞 (GSC) 群体），对 RT 和化疗相对耐药，并且 能够使肿瘤再生。总之，治疗耐药的 GSC、癌细胞的扩散超出了 可见的肿瘤、大面积缺氧和血脑屏障（BBB）增加了挑战 GBM 提出了癌症治疗。 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，然后获得诱导的 GSC 状态。重要的是，我们 表明这个过程可以是有针对性的，并且阻止 GSC 的诱导会导致 改善 GBM 动物模型的存活率。我们现在已经开发出新的化合物 穿过 BBB 并防止辐射诱导的 GSC 生成。此外，我们的 初步数据表明，可以利用辐射诱导的多能态来允许 GBM细胞的终末分化。本申请中提出的研究建立在这些基础上 发现并将研究计划带入这个令人兴奋的新方向，以利用这种诱导 改变 GBM 辐射反应的多能状态。