Hydrogel platform to investigate progression of drug-resistant glioblastoma

Acquired drug resistance in glioblastoma (GBM) presents a major clinical challenge and is a key contributor to its poor prognosis, with a median overall survival of less than 15 months. Current treatment strategies offer limited benefits to most patients, despite the use of an aggressive multi-modal treatment approach. The front-line chemotherapeutic agent, temozolomide (TMZ), fails to eradicate residual and highly invasive tumor cells following surgical resection and radiotherapy. While some patients initially respond positively to TMZ, GBM cells often develop resistance, leading to only a modest four-month increase in median overall survival with TMZ included in the treatment regimen. With no effective second-line therapy currently available, there is a pressing need for more clinically relevant in vitro GBM models that can elucidate the complex mechanisms underlying acquired TMZ resistance and inform the development of novel therapeutic interventions to combat this lethal malignancy. Indeed, many existing models for assessing drug response overlook the role of the extracellular matrix (ECM) and the broader tumor microenvironment (TME)—critical elements that contribute to the aggressive nature of GBM. Additionally, those that do consider these key factors often use supraphysiological drug concentrations, which can lead to misleading conclusions. Investigating how the standard-of-care treatment drives phenotypic and mechanistic changes in GBM progression within three-dimensional (3D) ECM models could uncover key insights for identifying novel therapeutic targets. This dissertation describes a bioengineering approach to develop increasingly sophisticated and physiologically relevant in vitro biomaterial models to systematically evaluate drug response in GBM. Herein, we report 3D engineered models of acquired TMZ resistance using two isogenically-matched GBM cell line pairs encapsulated in methacrylamide-functionalized gelatin (GelMA) hydrogels. We benchmark the responses of TMZ-resistant versus TMZ-sensitive cell lines within the GelMA-based ECM platform and further validate drug response at physiologically relevant TMZ concentrations. Our findings demonstrate changes in drug sensitivity, invasive capacity, and matrix-remodeling cytokine production resulting from acquired TMZ resistance. Additionally, this dissertation sheds light on the relationship between TMZ treatment and the go-or-grow plasticity of GBM cells. This platform lays the groundwork for future investigations into how key components of the GBM TME (e.g., vascular, stromal, immune, etc. niches) influence tumor response to therapeutic interventions. Although this platform primarily focuses on TMZ, it also examines other small-molecule therapeutic agents and discusses how the established model systems could be adapted to study alternative therapeutic modalities. By advancing our understanding of GBM progression following chemotherapy, this work proposes novel strategies to mitigate the devastating impact of GBM. Indeed, systematic evaluation of shifts in cellular response to front-line therapies has the potential to guide the development of more effective treatment strategies, and robust bioengineered 3D in vitro assays are uniquely positioned to probe the under-explored GBM TME in a systematic and accessible manner.

Name thesis:degree_name

Ph.D.

Level thesis:degree_level

Dissertation

Discipline thesis:degree_discipline

Chemical Engineering

Grantor

University of Illinois Urbana-Champaign

Year dc:date

2025

Author dc:creator

• Kriuchkovskaia, Victoria Anatolyevna

Contributors dc:contributor

• Harley, Brendan AC
• Hergenrother, Paul J
• Zhao, Huimin
• Riggins, Rebecca B

• Glioblastoma
• Temozolomide
• Drug resistance
• Cancer Model
• Biomaterials
• Hydrogels
• 3D in vitro model
• Drug response
• Migration
• Invasion

Statement dc:rights

• Copyright 2025 Victoria Kriuchkovskaia

Language dc:language

en, eng

Handle dc:identifier

https://hdl.handle.net/2142/129298

OAI record oai:identifier

https://www.ideals.illinois.edu/oai-pmh?verb=GetRecord&metadataPrefix=etdms&identifier=oai%3Awww.ideals.illinois.edu%3A2142%2F129298