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Glioblastoma multiforme (GBM) is treated by surgical resection followed by radiochemotherapy. Bevacizumab is commonly deployed for anti‐angiogenic therapy of recurrent GBM; however, innate immune cells have been identified as instigators of resistance to bevacizumab treatment. We identified angiopoietin‐2 (Ang‐2) as a potential target in both naive and bevacizumab‐treated glioblastoma. Ang‐2 expression was absent in normal human brain endothelium, while the highest Ang‐2 levels were observed in bevacizumab‐treated GBM. In a murine GBM model, VEGF blockade resulted in endothelial upregulation of Ang‐2, whereas the combined inhibition of VEGF and Ang‐2 leads to extended survival, decreased vascular permeability, depletion of tumor‐associated macrophages, improved pericyte coverage, and increased numbers of intratumoral T lymphocytes. CD206+ (M2‐like) macrophages were identified as potential novel targets following anti‐angiogenic therapy. Our findings imply a novel role for endothelial cells in therapy resistance and identify endothelial cell/myeloid cell crosstalk mediated by Ang‐2 as a potential resistance mechanism. Therefore, combining VEGF blockade with inhibition of Ang‐2 may potentially overcome resistance to bevacizumab therapy.
Purpose: The role of obesity in glioblastoma remains unclear, as previous analyses have reported contradicting results. Here, we evaluate the prognostic impact of obesity in two trial populations; CeTeG/NOA-09 (n = 129) for MGMT methylated glioblastoma patients comparing temozolomide (TMZ) to lomustine/TMZ, and GLARIUS (n = 170) for MGMT unmethylated glioblastoma patients comparing TMZ to bevacizumab/irinotecan, both in addition to surgery and radiotherapy.
Methods: The impact of obesity (BMI ≥ 30 kg/m2) on overall survival (OS) and progression-free survival (PFS) was investigated with Kaplan–Meier analysis and log-rank tests. A multivariable Cox regression analysis was performed including known prognostic factors as covariables.
Results: Overall, 22.6% of patients (67 of 297) were obese. Obesity was associated with shorter survival in patients with MGMT methylated glioblastoma (median OS 22.9 (95% CI 17.7–30.8) vs. 43.2 (32.5–54.4) months for obese and non-obese patients respectively, p = 0.001), but not in MGMT unmethylated glioblastoma (median OS 17.1 (15.8–18.9) vs 17.6 (14.7–20.8) months, p = 0.26). The prognostic impact of obesity in MGMT methylated glioblastoma was confirmed in a multivariable Cox regression (adjusted odds ratio: 2.57 (95% CI 1.53–4.31), p < 0.001) adjusted for age, sex, extent of resection, baseline steroids, Karnofsky performance score, and treatment arm.
Conclusion: Obesity was associated with shorter survival in MGMT methylated, but not in MGMT unmethylated glioblastoma patients.