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

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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.