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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：
10520022
负责人：
Brendan A. Harley
金额：
$ 49.05万
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：
2020
资助国家：
美国
起止时间：
2020-12-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10520022
关键词：
Acceleration Address Alkylating Agents Animal Model Animals Automobile Driving Behavior Benchmarking Biocompatible Materials Biological Assay Biophysics Blood Vessels Brain Brain Neoplasms Cancer Model Cell Line Cells Clinic Clinical DNA DNA Modification Process DNA Repair Diffuse Dimensions Disparate Drug resistance Engineering Evaluation Excision Failure Gelatin Generations Glioblastoma Glioma Goals Human Hyaluronic Acid Hydrogels Imaging Device Invaded Libraries Link Malignant Neoplasms Malignant neoplasm of brain Mediating Meta-Analysis Metabolic Methyltransferase Microfluidics Modeling Molecular Weight Operative Surgical Procedures Outcome Patients Pattern Pericytes Physiological Play Process Proliferating Proteins Recurrence Resistance Resources Role Signal Transduction Specimen Surgical margins Survival Rate Technology Tissue Engineering Tissue Model Variant Work Xenograft procedure anti-cancer bioinformatics tool detection limit drug candidate in vivo insight migration mimetics miniaturize mortality neurovascular novel novel therapeutics pressure programs repaired response standard of care stem temozolomide therapeutic evaluation therapy resistant tumor

项目摘要

ABSTRACT 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). However, two major challenges make GBM currently untreatable: 1) its diffuse invasion beyond the surgical margin; and 2) TMZ resistance that is tightly linked to expression of the DNA damage repair protein MGMT. While perivascular niches (PVNs) extending from the tumor into the surrounding parenchyma are believed to regulate invasion, recurrence, and poor survival, the majority of animal glioma models are sensitive to TMZ and most do not express MGMT, making it difficult to assess novel therapeutics in animal models that don’t display TMZ resistance. This Cancer Tissue Engineering Collaborative project will develop and thoroughly characterize a multidimensional engineered PVN biomaterial, study pathophysiological processes driving GBM invasion and TMZ resistance, and accelerate the evaluation of novel TMZ derivatives created to target diffuse GBM cells regardless of MGMT status. We will use advanced microfluidics to create libraries of miniaturized gelatin hydrogels containing margin-mimetic hyaluronic acid (HA) and an embedded perivascular network. We also use a novel synthetic pipeline to create TMZ derivatives that generate alternate DNA modifications that cannot be removed by MGMT that we hypothesize work in an MGMT- independent fashion. Merging these technologies, we will benchmark an engineered PVN platform formed using primary brain neurovascular cells for rapid evaluation of GBM invasion, MGMT expression, and TMZ resistance amenable to analysis of cell lines and patient-derived GBM specimens with disparate MGMT profiles. To do this, we will first construct and thoroughly characterize an engineered perivascular niche (Aim 1). We will use this novel biomaterial to benchmark patterns of invasion and MGMT expression in GBM cell lines (Aim 2). Finally, we will establish predictive efficacy of TMZ variants in an engineered perivascular niche (Aim 3). Together, we will develop, characterize, and benchmark a tissue engineered PVN to examine the role of microenvironmental selection pressures in the tumor margin on behaviors related to invasion, MGMT-mediated TMZ resistance, recurrence, and poor survival. Consistent with score-driving criteria of the CTEC program, we will develop and thoroughly characterize an engineered PVN biomaterial, show it fits within the continuum of existing cancer models, use it to examine phenomena underlying the failure to achieve durable survival, and gain actionable insight regarding novel TMZ derivatives with potential to effectively target GBM cells in the margins independent of MGMT status.

摘要