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/文摘