Use of CTEP portfolio compounds to counteract phenotype conversion in GBM

使用 CTEP 组合化合物来抵消 GBM 中的表型转换

基本信息

批准号：
10544037
负责人：
Frank Pajonk
金额：
$ 45.34万
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：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10544037
关键词：
3-Dimensional Affect Basic Science Biological Assay Biological Markers Biology Cancer Therapy Evaluation Program Cell Differentiation process Cells Cholesterol Clinical Clinical Trials Clonal Evolution Combination Drug Therapy Combined Modality Therapy Data Disease Dose Drug Interactions Drug Kinetics Electromagnetic Energy Fatty Acids Gene Expression Profiling Generations Glioblastoma Glioma Goals Hypoxia In Vitro Level of Evidence Literature Malignant Neoplasms Malignant neoplasm of brain Metabolic Modality Modeling Nitric Oxide Pathway interactions Patient-Focused Outcomes Patients Pharmaceutical Preparations Phenotype Population Process Publishing Radiation Radiation Dose Unit Radiation Oncology Radiation therapy Recurrence Reporting Resources Scheme Specimen Surgical Oncology Testing Time Toxic effect Transgenic Mice Treatment Failure United States National Institutes of Health biomarker identification biomarker validation blood-brain barrier crossing cancer cell cancer stem cell chemotherapeutic agent cholesterol biosynthesis disorder control drug development effective therapy imaging system improved in vivo induced pluripotent stem cell inhibitor innovation malignant breast neoplasm mevalonate mouse model neoplastic cell nerve stem cell nestin protein neurogenesis novel patient derived xenograft model prevent radiation resistance radioresistant responders and non-responders self-renewal standard of care stem cells synergism targeted agent targeted treatment temozolomide therapy outcome therapy resistant tool trait tumor tumor initiation

项目摘要

SUMMARY/ABSTRACT Despite a tremendous effort in basic science, clinical trials, drug development, and technical advances in surgery and radiation oncology, glioblastoma remains incurable and improvements in overall survival have been marginal. While radiotherapy is still one of the most effective treatment options for glioblastoma, it cannot control the disease over time. This suggests that novel combination therapies are desperately needed to improve radiation treatment outcome for patients suffering from this disease. The studies outlined in this proposal are based on a hypothesis that is backed by our extensive preliminary data and rigorous published data in the literature. The overall hypothesis is that biomarker-based drug selection predicts synergistic lethality of combination therapies in GICs and glioblastoma bulk tumor cell populations, prevents radiation-induced GBM phenotype conversion and allows for individualized optimization of radiotherapy. The three aims of this study will address this aspect of glioma biology using an innovative tool to track GICs and their progeny, while leveraging the unique resources and expertise available at UCLA and the NIH/NCI CTEP portfolio of drugs. Aim 1 will identify compounds in the NCI CTEP portfolio that interfere with radiation-induced phenotype conversion in glioblastoma and develop biomarker profiles predictive of synergistic lethality in combination with radiation. Studies in Aim 2 will optimize combination therapies in vivo. Finally, Aim 3, will use patient avatar studies to validate biomarker-based drug selection in PDX models of glioblastoma.

摘要/摘要尽管在基础科学，临床试验，药物开发和技术进步方面做出了巨大努力手术和辐射肿瘤学，胶质母细胞瘤仍然无法治愈，整体生存的改善已有是边缘。虽然放疗仍然是胶质母细胞瘤最有效的治疗方法之一，但不能随着时间的流逝控制疾病。这表明迫切需要新颖的组合疗法改善患有这种疾病的患者的辐射治疗结果。其中概述了提案基于一个假设，该假设得到了我们广泛的初步数据和严格发布的支持文献中的数据。总体假设是基于生物标志物的药物选择预测了协同杀伤力 GIC和胶质母细胞瘤大体肿瘤细胞种群中的组合疗法，可防止辐射诱导 GBM表型转化率，并允许对放射疗法进行个性化优化。这三个目标研究将使用创新的工具来跟踪GIC及其后代，以解决神经胶质瘤生物学的这一方面，而利用UCLA和NIH/NCI CTEP药物组合提供的独特资源和专业知识。 AIM 1将在NCI CTEP投资组合中识别干扰辐射诱导表型的化合物胶质母细胞瘤的转化并发展出生物标志物谱，可预测协同杀伤性与结合辐射。 AIM 2中的研究将优化体内组合疗法。最后，AIM 3将使用患者头像在PDX模型的胶质母细胞瘤模型中验证基于生物标志物的药物选择的研究。