Identification of a Prognostic Microenvironment-Related Gene Signature in Glioblastoma Patients Treated with Carmustine Wafers

Abstract

SIMPLE SUMMARY: Carmustine wafer (CW) implantation into the resection cavity of patients operated for glioblastoma (GBM) was approved as an adjuvant treatment before the Stupp Protocol. Although contrasting clinical results limited its use, our retrospective study on 116 GBM treated with CW showed a significant benefit in terms of OS in a subgroup of patients. Since GBM growth, progression, and drug resistance are supported by the surrounding environment, and since the tumor microenvironment (TME) is the source of druggable targets, we hypothesized that the TME of patients who benefited from CW could have different characteristics compared to patients who did not show any advantage. Exploiting a human in vitro model of glioma microenvironment and a transcriptomic approach, we found a different gene signature suggesting the importance of developing in vitro models that mimic the properties of human cancers and that can help to study individual patient characteristics at the cellular and molecular level. ABSTRACT: Despite the state-of-the-art treatment, patients diagnosed with glioblastoma (GBM) have a median overall survival (OS) of 14 months. The insertion of carmustine wafers (CWs) into the resection cavity as adjuvant treatment represents a promising option, although its use has been limited due to contrasting clinical results. Our retrospective evaluation of CW efficacy showed a significant improvement in terms of OS in a subgroup of patients. Given the crucial role of the tumor microenvironment (TME) in GBM progression and response to therapy, we hypothesized that the TME of patients who benefited from CW could have different properties compared to that of patients who did not show any advantage. Using an in vitro model of the glioma microenvironment, represented by glioma-associated-stem cells (GASC), we performed a transcriptomic analysis of GASC isolated from tumors of patients responsive and not responsive to CW to identify differentially expressed genes. We found different transcriptomic profiles, and we identified four genes, specifically down-regulated in GASC isolated from long-term survivors, correlated with clinical data deposited in the TCGA–GBM dataset. Our results highlight that studying the in vitro properties of patient-specific glioma microenvironments can help to identify molecular determinants potentially prognostic for patients treated with CW