Increased epithelial membrane protein 2 expression in glioblastoma after treatment with bevacizumab

Abstract

Introduction Anti-angiogenic therapy with bevacizumab has failed to provide substantial gains in overall survival. Epithelial membrane protein 2 (EMP2) is a cell surface protein that has been previously shown to be expressed in glioblastoma, correlate with poor survival, and regulate neoangiogenesis in cell lines. Thus, the relationship of bevacizumab and EMP2 was investigated. Methods Tumor samples were obtained from 12 patients with newly diagnosed glioblastoma at two time points: 1) during the initial surgery and 2) during a subsequent surgery following disease recurrence post bevacizumab treatment. Clinical characteristics and survival data from these patients were collected, and tumor samples were stained for EMP2 expression. The IVY glioblastoma atlas project database was used to evaluate EMP2 expression levels in 270 samples by differing histological areas of tumor. Results Patients with high EMP2 staining at initial diagnosis had decreased progression free and overall survival after bevacizumab [median progression free survival 4.6 months vs. 5.9 months; Log-Rank P = 0.076 & overall survival 7.7 months vs. 14.4 months; Log-Rank P = 0.011]. There was increased EMP2 staining in samples obtained after bevacizumab treatment in both unpaired [Mean H-score 2.31 vs 1.76; P=0.006] and paired analyses [Mean difference 0.571; P=0.019]. This expression increase correlated with length of bevacizumab therapy [R2=0.449; Pearson P=0.024]. Conclusions Bevacizumab treatment increased EMP2 protein expression. This increase in EMP2 correlated with reduced mean survival time post bevacizumab therapy. We hypothesize a role of EMP2 in clinical bevacizumab resistance and as a potential anti-angiogenic therapeutic target in glioblastoma.

Systematic Review of Molecular Targeted Therapies for Adult-Type Diffuse Glioma: An Analysis of Clinical and Laboratory Studies

“…HER2 expression tends to be low in GBM, and though one clinical trial examining a HER2 inhibitor has yet to show therapeutic gain, laboratory studies have promising evidence for efficacy [ 140 , 352 ]. EMP2 has been implicated in bevacizumab resistance and thus shows promise as a molecular target for preventing resistance in conjunction with this common therapeutic [ 117 , 353 ]. STAT3 plays a role in astrocyte development and has tumor suppressive roles in glial malignancies; this target shows promise in laboratory research using tetrandrine as an inhibitor [ 108 ].…”

Exploring the Past, Present, and Future of Anti-Angiogenic Therapy in Glioblastoma

“…More recently, Patel et al investigated the potential impact of bevacizumab treatment on EMP2 levels in a cohort of 12 glioblastoma patients. In paired analysis, EMP2 histological scores were significantly higher following bevacizumab treatment, and this increase was proportional to the length of treatment [32]. More importantly, patients with higher levels of EMP2 had significantly shorter time to repeat surgery, progression-free survival, and overall survival [32].…”

“…In response, there is a decrease in the growth of microvasculature and blood supply to the tumor, and down-regulation of angiogenesis [12,30]. Given the highly vascularized nature of glioblastoma, bevacizumab is theoretically a suitable agent for these tumors, and it remains the most commonly used anti-angiogenic agent in the treatment of recurrent glioblastoma [31,32], despite no significant improve in overall survival [33] due to its role in reducing brain edema [34]. The most common adverse events associated with bevacizumab are gastrointestinal perforations, hemorrhage, and arterial thromboembolism [31].…”

“…The constantly evolving genetic composition of glioblastoma leads to high rates of intratumor heterogeneity, which subsequently facilitates anti-angiogenic therapy resistance [68,69]. Knowing this, it is evident that targeting the VEGF pathway in glioblastoma via monotherapy is insufficient, and therefore there is an urgent need to discover novel targets that can be used in concert to improve patient survival [32].…”

“…Under physiologic conditions, EMP2 appears to stabilize select integrins and modulates their adhesion onto various extracellular matrices [84]. Its expression has been investigated in a number of neoplasms including endometrial carcinoma, breast cancer, and primary brain tumors [32,85,86].…”