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: 10818769
• 负责人: Brendan A. Harley
• 金额: $ 4.44万
• 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/10818769
• 关键词: Acceleration; Administrative Supplement; Alkylating Agents; Biomedical Research; Blood Vessels; Brain; Cell Proliferation; Cells; Clinical; Data; Diffuse; Drug resistance; Encapsulated; Engineering; Evaluation; Evolution; Excision; Foundations; Glioblastoma; Hydrogels; Invaded; MGMT gene; Malignant Neoplasms; Malignant neoplasm of brain; Measures; Mediating; Modeling; Operative Surgical Procedures; Outcome; Parents; Patients; Pharmaceutical Preparations; Play; Population; Process; Recurrence; Resistance; Role; Structure; System; Tissue Engineering; Tissue Model; Treatment Efficacy; Underrepresented Populations; Variant; anti-cancer; graduate student; high throughput screening; mimetics; miniaturize; nanolitre; novel; particle; response; standard of care; stem; stem cells; temozolomide; treatment response; tumor; tumor microenvironment; two-dimensional

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 novel initiative to create granular hydrogel assemblies that can mimic the multicellular tumor microenvironment yet are amenable to high-throughput screening approaches conventionally used to examine drug responses using two-dimensional culture. We have generated the technical foundation to create granular hydrogel to study GBM therapeutic response. Granular hydrogels are macroscale structures generated as jammed assemblies of microscale hydrogel particles. To date they have been predominantly used as acellular hydrogel particles with cells cultured in the voids between particles. As part of a recent administrative supplement, we developed capacity to encapsulate GBM cells in distinct nanoliter-volume hydrogel microdroplets that can be rapidly formed, have their matrix composition tailored for discrete cell populations, and be non-toxically degraded. Now, we seek to expand efforts with granular hydrogel systems to examine high-throughput response data for glioblastoma cells. To do this, this project will first measure therapeutic responses of GBM cells to brain-mimetic HA and the perivascular secretome in granular hydrogels (Aim S1). We will subsequently examine the role of multicellular aggregations on GBM cell invasion and therapeutic efficacy using both macroscale and granular hydrogel models (Aim S2). This proposed supplement will support a graduate student from a historically underrepresented group in biomedical research to develop hierarchical models of the glioblastoma tumor microenvironment. This granular hydrogel approach provides the basis to interrogate the role of glioblastoma aggregation size and relative spacing on glioblastoma stem cell activity, GBM invasion, and resistance to frontline therapies. We will show granular hydrogels can be integrated into high-throughput screening approaches to accelerate the evaluation of novel TMZ derivatives created to target diffuse GBM cells regardless of MGMT status.

抽象的 本申请是根据 PA-21-071 提交的。胶质母细胞瘤 (GBM) 是最常见且 致命的脑癌。标准护理是手术切除，然后用烷化剂治疗 替莫唑胺（TMZ）剂。切除术去除了大部分肿瘤，TMZ 为许多人带来了一些好处 患者。父癌症组织工程合作项目 (R01 CA256481) 正在开发组织 加速评估克服 TMZ 的新型抗癌化合物的工程方法 反抗。该项目正在开发创建血管周围生态位工程模型的流程 （PVN）从肿瘤延伸到周围的实质，并被认为发挥主导作用 侵袭、复发、TMZ 耐药和不良生存中的作用。传统的块状水凝胶，甚至 小型化变体，不提供定制或追踪局部微环境演变的途径 周围独特的细胞亚群。本 NCI 多样性行政补充文件的目的是 支持一项创建可以模仿多细胞肿瘤的颗粒水凝胶组件的新举措 微环境仍然适合传统用于检查的高通量筛选方法 使用二维培养的药物反应。我们已经形成了创建细粒度的技术基础 水凝胶研究 GBM 治疗反应。颗粒水凝胶是宏观结构，生成如下： 微型水凝胶颗粒的堵塞组件。迄今为止，它们主要用作非细胞 水凝胶颗粒，细胞在颗粒之间的空隙中培养。作为最近行政管理的一部分 作为补充，我们开发出了将 GBM 细胞封装在不同纳升体积水凝胶中的能力 可以快速形成的微滴，其基质成分适合离散细胞群， 并被无毒降解。现在，我们寻求扩大颗粒水凝胶系统的研究范围 胶质母细胞瘤细胞的高通量反应数据。为此，该项目将首先测量治疗效果 GBM 细胞对颗粒水凝胶中的拟脑 HA 和血管周围分泌体的反应（目标 S1）。 随后我们将研究多细胞聚集对 GBM 细胞侵袭和治疗的作用 使用宏观和颗粒水凝胶模型的功效（目标 S2）。本提议的补充将支持 来自生物医学研究领域历来代表性不足的群体的研究生，旨在发展分层 胶质母细胞瘤肿瘤微环境模型。这种颗粒水凝胶方法提供了基础 询问胶质母细胞瘤聚集大小和相对间距对胶质母细胞瘤干细胞活性的作用， GBM 侵袭和对一线疗法的耐药性。我们将展示颗粒水凝胶可以集成到 高通量筛选方法可加速针对目标创建的新型 TMZ 衍生物的评估 弥漫性 GBM 细胞，无论 MGMT 状态如何。