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 该申请是根据PA-21-071提交的。胶质母细胞瘤（GBM）是最常见的，并且 脑癌的致命形式。护理标准是手术切除，然后用烷基化治疗 替莫唑胺（TMZ）。切除去除肿瘤的大容量，TMZ为许多人提供了一些好处 患者。父癌组织工程协作项目（R01 CA256481）正在发展组织 工程方法可以加速对克服TMZ的新抗癌化合物的评估 反抗。该项目正在开发过程以创建血管周围壁ches的工程模型 （PVN）从肿瘤延伸到周围的实质，据信它们占主导地位 在入侵，复发，TMZ抗性和存活不良中的作用。传统的散装水凝胶，甚至 微型变体，不提供量身定制或追踪当地微环境的途径 周围独特的细胞亚群。 NCI多样性管理补充的目的是 支持一项新型计划，以创建可以模仿多细胞肿瘤的颗粒状水凝胶组件 微环境却适合于通常用于检查的高通量筛选方法 使用二维培养的药物反应。我们已经建立了创建颗粒状的技术基础 水凝胶研究GBM治疗反应。颗粒水凝胶是产生的宏观结构 微观水凝胶颗粒的堵塞组件。迄今为止，它们主要被用作细胞 水凝胶颗粒具有在颗粒之间的空隙中培养的细胞。作为最近行政的一部分 补充，我们开发了将GBM细胞封装在不同纳米素体积水凝胶中的能力 可以迅速形成的微颗粒，其基质组成为离散的细胞群体量身定制， 并在无毒的降解上。现在，我们寻求扩大使用颗粒水凝胶系统的努力来检查 胶质母细胞瘤细胞的高通量响应数据。为此，该项目将首先衡量治疗 GBM细胞对颗粒水凝胶中脑模拟HA和血管周期分泌组的反应（AIM S1）。 随后，我们将研究多细胞聚集在GBM细胞侵袭和治疗中的作用 使用宏观和颗粒水凝胶模型（AIM S2）的功效。拟议的补充将支持 来自历史上代表性不足的生物医学研究的研究生，以发展等级制度 胶质母细胞瘤肿瘤微环境的模型。这种颗粒状水凝胶方法为 询问胶质母细胞瘤聚集大小和相对间距在胶质母细胞瘤干细胞活性上的作用， GBM入侵和对前线疗法的抵抗力。我们将显示颗粒水凝胶可以集成到 高通量筛选方法，以加快针对目标创建的新型TMZ衍生物的评估 弥漫性GBM细胞不管MGMT状态如何。