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 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.