Perivascular tissue models to overcome MGMT-mediated temozolomide resistance in glioblastoma

克服胶质母细胞瘤中 MGMT 介导的替莫唑胺耐药性的血管周围组织模型

• 批准号: 10818804
• 负责人: Brendan A. Harley
• 金额: $ 8.87万
• 依托单位: UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10818804
• 关键词: Acceleration; Administrative Supplement; Alkylating Agents; Animal Model; Animals; Automobile Driving; Benchmarking; Biocompatible Materials; Biomechanics; Biomedical Engineering; Blood Vessels; Brain; Cancer Center; Career Mobility; Cell Communication; Cell Line; Cell model; Cells; Chemical Engineering; Chemotherapy and/or radiation; Clinical; Coculture Techniques; Collaborations; Complex; Cues; DNA Repair; Diffuse; Dimensions; Disease Progression; Drug resistance; Engineering; Evaluation; Evolution; Excision; Female; Glioblastoma; Glioma; Goals; Hydrogels; Hypoxia; Illinois; Infiltration; Invaded; Libraries; Link; Malignant Neoplasms; Malignant neoplasm of brain; Mediating; Mentors; Mentorship; Meta-Analysis; Methyltransferase; Modeling; Monitor; Neurites; Neurons; Operative Surgical Procedures; Outcome; Paracrine Communication; Parents; Patients; Pattern; Peripheral; Play; Process; Proliferating; Proteins; Radiation; Radiation therapy; Recurrence; Research; Research Assistant; Research Personnel; Research Project Grants; Resistance; Role; Surgical margins; Survival Rate; Therapeutic Intervention; Tissue Engineering; Tissue Model; Tissues; Training; Training Programs; Training Support; Tumor Cell Invasion; Universities; Variant; anti-cancer; antitumor effect; bioelectricity; brain tissue; career; chemotherapy; cytotoxic; extracellular; in vivo; innovation; miniaturize; mortality; neoplastic cell; neurovascular; novel; novel therapeutics; parent grant; professor; programs; radiation response; response; standard of care; stem; temozolomide; tool; treatment response; tumor; tumor growth; tumor microenvironment; tumor progression

ABSTRACT This application is being submitted in response to PA-21-071. Glioblastoma (GBM) is the most common and lethal form of brain cancer. Standard of care is surgical resection followed by treatment with the alkylating agent temozolomide (TMZ). Resection removes the tumor bulk, and TMZ provides some benefit to many patients. The parent Cancer Tissue Engineering Collaborative project (R01 CA256481) is developing tissue engineering approach to accelerate the evaluation of new anticancer compounds that overcome TMZ resistance. This project is developing processes to create engineered models of the perivascular niches (PVNs) that extend from the tumor into the surrounding parenchyma and which are believed to play a dominant role in invasion, recurrence, TMZ resistance, and poor survival. Conventional bulk hydrogels, even miniaturized variants, do not provide an avenue to tailor, or trace the evolution of, the local microenvironment surrounding unique cell subpopulations. The objective of this NCI Diversity Administrative supplement is to support a female Research Assistant Professor within a chemical engineering department to develop a fully independent research program developing hierarchical models of neuron–glioma connectivity within the glioblastoma tumor microenvironment and after therapeutic intervention. The unique microenvironment established in the tumor edge is responsible for neuronal hyperexcitability, tumor invasion and recurrence after therapeutic intervention. This project will evaluate the hypothesis that neuronal input is a key factor for tumor progression. To do this, this project will first \inspect neuron–glioma connectivity as the main driver of tumor growth using engineered hydrogel models of the brain microenvironment (Aim S1). We will subsequently determine the repercussions of therapeutic intervention on the neuron-glioma unit (Aim S2). This proposed supplement will enable a junior female investigator to develop a fully independent research program as a Research Assistant Professor at the University of Illinois at Urbana- Champaign. Through this independent research as well as interactions within the host department, the campus Cancer Center at Illinois, and external senior mentors, we have identified a complementary but independent research trajectory as well as mentoring programs to support the full independence of an exemplary junior investigator.

抽象的 本申请是针对 PA-21-071 提交的，胶质母细胞瘤 (GBM) 是最常见且最常见的肿瘤。 致命的脑癌治疗标准是手术切除，然后用烷化剂治疗。 替莫唑胺 (TMZ) 切除可去除肿瘤块，替莫唑胺为许多患者带来一些好处。 母体癌症组织工程合作项目（R01 CA256481）正在开发组织工程 该项目旨在加速评估克服 TMZ 耐药性的新型抗癌化合物。 正在开发流程来创建从血管周围延伸的血管周围生态位（PVN）的工程模型 肿瘤侵入周围实质，被认为在侵袭、复发、 传统的块状水凝胶，即使是小型水凝胶，也无法提供 TMZ 耐药性和存活率。 定制或追踪独特细胞亚群周围局部微环境的进化途径。 该 NCI 多样性行政补充文件的目的是支持女性研究助理 化学工程系教授开发完全独立的研究项目 胶质母细胞瘤肿瘤微环境内及之后的神经元-胶质瘤连接的分层模型 在肿瘤边缘建立的独特的微环境治疗负责神经元的干预。 该项目将评估治疗干预后的过度兴奋、肿瘤侵袭和复发。 假设神经输入是肿瘤进展的关键因素，为此，该项目将首先“检查”。 使用大脑工程水凝胶模型，神经元-神经胶质瘤连接是肿瘤生长的主要驱动力 我们随后将确定治疗干预对微环境的影响。 神经元神经胶质瘤单元（目标 S2）。 作为伊利诺伊大学厄巴纳分校研究助理教授，完全独立的研究项目 通过这种独立研究以及主办部门、校园内的互动。 伊利诺伊州癌症中心和外部高级导师，我们已经确定了一个互补但独立的团队 研究轨迹以及指导计划，以支持模范大三学生的完全独立 研究者。