Original ArticlesCell surface vimentin-targeted monoclonal antibody 86C increases sensitivity to temozolomide in glioma stem cells
Introduction
Glioblastoma multiforme (GBM) is the most prevalent and aggressive malignant brain tumor and has a median survival duration of approximately 15 months from diagnosis [1]. The current standard of care for GBM patients is surgical resection followed by radiotherapy and chemotherapy. This therapy is not effective in most patients because of factors including drug resistance and poor penetration of the blood-brain barrier. The primary chemotherapeutic agent used to treat GBM is temozolomide (TMZ), a methylating agent that does cross the blood-brain barrier [2,3] but whose efficacy is constrained by frequent development of resistance [[4], [5], [6]]. Median survival duration is increased only 2.5 months by adjuvant combined radiation and TMZ treatment. The efficacy of TMZ is further constrained by toxic effects outside of the central nervous system and by the biologic limits to achieving a sustained tumoricidal concentration in the tissue, as with most other systemic therapies [7]. Intensification of TMZ, in the form of dose-dense adjuvant TMZ, was associated with significantly greater high-grade toxicity without any survival benefit compared with the standard regimen for GBM [8]. There is a great need for more efficacious therapeutic strategies to improve clinical management and survival outcomes in GBM patients.
Glioma stem cells (GSCs) exhibit resistance to radiation and to anticancer drugs such as TMZ [[9], [10], [11], [12]], and elimination of GSCs is considered key to ensuring the long-term survival of GBM patients [13]. Since GSCs are also responsible for tumor initiation and recurrence, they are attractive candidate targets for anticancer therapy. Identifying new drugs that can specifically target and kill GSCs is a critical step in improving GBM patient outcomes.
A potential approach to targeting GSCs is through cell surface vimentin (CSV). Unlike intracellular vimentin, which is found in both cancer cells and normal mesenchymal cells, CSV is tumor-specific. It has been found primarily on cancer cells, including circulating tumor cells, GBM cells, and GSCs [[14], [15], [16]], and can serve as a therapeutic target for such cells. Our previous study showed that the novel monoclonal antibody 86C, which binds CSV on cancer stem cells and is internalized, induces apoptosis of the target cells, suggesting that targeting GSCs using 86C is a promising approach for the treatment of GBM [16]. On the basis of these findings, we hypothesized that targeting CSV with 86C would help overcome TMZ resistance in GSCs, increasing cell killing. Our findings show that 86C efficiently targets GSCs expressing CSV and that this intervention increases GSC sensitivity to TMZ. The addition of 86C reduced the dose of TMZ required to eliminate GSCs, which will ultimately reduce its toxic effects. Treatment with 86C combined with TMZ decreased resistance to chemotherapy and resulted in a striking recovery of GSC sensitivity to TMZ.
Section snippets
Ethics statement
The mice used in this study were maintained under the guidelines of the National Institutes of Health and euthanized according to procedures approved by the Institutional Animal Care and Use Committee of The University of Texas MD Anderson Cancer Center (MD Anderson). Tumor sample collection from patients with GBM at MD Anderson was conducted under protocol #LAB03-0687, which was approved by the institutional review board, after informed consent was obtained from the patients.
Cell lines and cell culture
Twelve GSC cell
GSC sensitivity to TMZ varies widely
To evaluate GSC resistance to TMZ, we first analyzed the individual median inhibitory concentrations (IC50 values) of TMZ for the 12 GSC cell lines. The 12 GSC cell types were treated with TMZ (0–500 μM) for 72 h, and the numbers of viable cells were assessed. The cell growth–inhibitory effects of TMZ on all the GSC lines were dose dependent. Most of the GSC lines showed low sensitivity to TMZ, with IC50 values of >100 μM, well above the peak plasma concentration of TMZ reached in cancer
Discussion
In this study, we demonstrate that the anti-CSV monoclonal antibody 86C efficiently increases GSC sensitivity to TMZ. The combination of TMZ+86C induced greater antitumor effects in most GSC lines tested and prolonged survival in a GBM mouse model compared with TMZ alone. TMZ+86C–sensitive GSCs had higher CSV expression overall and faster CSV resurfacing among CSV− GSCs compared with TMZ+86C–resistant GSCs. The combination of TMZ+86C represents a promising strategy to reverse GSC
Abbreviations
CSV, cell surface vimentin; DMSO, dimethyl sulfoxide; GBM, glioblastoma multiforme; GSC, glioma stem cell; IC50, median inhibitory concentration; PBS, phosphate-buffered saline solution; TMZ, temozolomide.
Conflicts of interest
The authors declare no conflicts of interest.
Funding
This study was supported by National Institutes of Health grants CA120895, CA208113, P50 CA127001, and P30CA016672.
Acknowledgement
We appreciate the Department of Scientific Publications at MD Anderson for helping us edit our manuscript.
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Contributed equally.