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

基本信息

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
项目类别：
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

项目摘要

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，然后用烷基化剂治疗替莫唑胺（TMZ）。切除去除肿瘤的大量，而TMZ为许多患者提供了一些好处。这父癌组织工程协作项目（R01 CA256481）正在开发组织工程加快克服TMZ抗性的新抗癌化合物的评估方法。这个项目正在开发过程，以创建从延伸从肿瘤进入周围的paranchyma，被认为在入侵，复发中起着主导作用 TMZ抗性和生存不良。常规的散装水凝胶，甚至是微型变体，都不提供量身定制或追踪围绕独特细胞亚种群的本地微环境的途径。这种NCI多样性管理补充的目的是支持女性研究助理化学工程系的教授旨在制定一个完全独立的研究计划胶质母细胞瘤肿瘤微环境内神经元 - glioma连通性的分层模型和之后治疗干预。在肿瘤边缘建立的独特微环境是神经元的原因热干预后过度兴奋，肿瘤侵袭和复发。该项目将评估假设神经元输入是肿瘤进展的关键因素。为此，该项目将首先\ Inspect 神经元 - 神经瘤连通性是使用大脑工程水凝胶模型的肿瘤生长的主要驱动力微环境（AIM S1）。随后，我们将确定治疗干预的影响神经脱脂瘤单元（AIM S2）。该提出的补充剂将使初级女研究人员能够开发伊利诺伊大学厄巴纳大学的研究助理教授完全独立的研究计划原野。通过这项独立研究以及主持人部门的互动，校园伊利诺伊州的癌症中心和外部高级导师，我们确定了一个完整但独立的研究轨迹和心理计划，以支持典范初级的全部独立性研究者。