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

基本信息

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
项目类别：
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

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

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项目摘要

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）是针对胶质母细胞瘤（GBM）的护理标准的组成部分。仅在手术中添加RT在手术中增加了手术可显着延长患者的存活 GBM的患者最终屈服于该疾病，生存时间不可接受。到目前为止，在手术中添加有针对性或非靶向疗法的RT限制了成功并表明需要针对这种疾病的新型策略。有足够的证据支持GBM的异质性和一个小的存在胶质母细胞瘤干细胞（GSCS）的群体，对RT和化学疗法的抗性能够再生肿瘤。一起，耐药的GSC，超越癌细胞的分散可见的肿瘤，大面积缺氧和血脑屏障（BBB）增加了挑战 GBM进行癌症治疗。我们以前已经证明辐射会重新激活导致细胞的干细胞程序多能力和可塑性，然后获得诱导的GSC状态。重要的是，我们表明这一过程可以针对目标，并且防止GSC的诱导导致 GBM动物模型的生存提高。我们现在已经开发了新颖的化合物越过BBB并防止辐射引起的GSC产生。此外，我们的初步数据表明，可以利用辐射诱导的多能状态来允许 GBM细胞的末端分化。本申请中提出的研究基于这些调查结果并将研究计划带入这个令人兴奋的新方向，以利用这种诱发的多元状态用于改变GBM的辐射响应。