Perivascular tissue models to overcome MGMT-mediated temozolomide resistance in glioblastoma

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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.