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BMC Cancer
Published in: BMC Cancer 1/2015

Open Access 01-12-2015 | Research article

A new anti-glioma therapy, AG119: pre-clinical assessment in a mouse GL261 glioma model

Authors: Rheal A. Towner, Michael Ihnat, Debra Saunders, Anja Bastian, Nataliya Smith, Roheeth Kumar Pavana, Aleem Gangjee

Published in: BMC Cancer | Issue 1/2015

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Abstract

Background

High grade gliomas (HGGs; grades III and IV) are the most common primary brain tumors in adults, and their malignant nature ranks them fourth in incidence of cancer death. Standard treatment for glioblastomas (GBM), involving surgical resection followed by radiation and chemotherapy with temozolomide (TMZ) and the anti-angiogenic therapy bevacizumab, have not substantially improved overall survival. New therapeutic agents are desperately needed for this devastating disease. Here we study the potential therapeutic agent AG119 in a pre-clinical model for gliomas. AG119 possesses both anti-angiogenic (RTK inhibition) and antimicrotubule cytotoxic activity in a single molecule.

Methods

GL261 glioma-bearing mice were either treated with AG119, anti-VEGF (vascular endothelial growth factor) antibody, anti c-Met antibody or TMZ, and compared to untreated tumor-bearing mice. Animal survival was assessed, and tumor volumes and vascular alterations were monitored with morphological magnetic resonance imaging (MRI) and perfusion-weighted imaging, respectively.

Results

Percent survival of GL261 HGG-bearing mice treated with AG119 was significantly higher (p < 0.001) compared to untreated tumors. Tumor volumes (21–31 days following intracerebral implantation of GL261 cells) were found to be significantly lower for AG119 (p < 0.001), anti-VEGF (p < 0.05) and anti-c-Met (p < 0.001) antibody treatments, and TMZ-treated (p < 0.05) mice, compared to untreated controls. Perfusion data indicated that both AG119 and TMZ were able to reduce the effect of decreasing perfusion rates significantly (p < 0.05 for both), when compared to untreated tumors. It was also found that IC50 values for AG119 were much lower than those for TMZ in T98G and U251 cells.

Conclusions

These data support further exploration of the anticancer activity AG119 in HGG, as this compound was able to increase animal survival and decrease tumor volumes in a mouse GL261 glioma model, and that AG119 is also not subject to methyl guanine transferase (MGMT) mediated resistance, as is the case with TMZ, indicating that AG119 may be potentially useful in treating resistant gliomas.
Literature
1.
2.
Ostrom QT, Gitleman H, Liao P, Rouse C, Chen Y, Dowling J et al. CBTRUS statistical report: Primary brain and central nervous system tumors diagnosed in the United States on 2007-2011. Neuro-Oncology 2014;16(Suppl 4):iv1-63.
3.
Dolecek TA, Propp JM, Stroup NE, Kruchko C. CBTRUS (Central Brain Tumor Registry of the United States) statistical report: Primary brain and central nervous system tumors diagnosed in the United States in 2005–2009. Neuro Oncol. 2012;14(suppl 5):v1–49.CrossRefPubMedPubMedCentral
4.
Porter KR, McCarthy BJ, Freels S, Kim Y, Davis FG. Prevalence estimates for primary brain tumors in the United States by age, gender, behavior, and histology. Neuro Oncol. 2010;12(6):520–7.CrossRefPubMedPubMedCentral
5.
6.
Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBACAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for Research on Cancer; 2013. Available from: http://​globocan.​iarc.​fr, accessed on July 15, 2015.
7.
Beal K, Abrey LE, Gutin PH. Antiangiogenic agents in the treatment of recurrent or newly diagnosed glioblastoma: analysis of single-agent and combined modality approaches. Radiat Oncol. 2011;6:2. PMCID:PMC3025871.CrossRefPubMedPubMedCentral
8.
Vredenburgh JJ, Desjardins A, Reardon DA, Peters KB, Herndon JE 2nd, Marcello J, et al. The addition of bevacizumab to standard radiation therapy and temozolomide followed by bevacizumab, temozolomide, and irinotecan for newly diagnosed glioblastoma. Clin Cancer Res. 2011;17(12):4119–24.
9.
Quick A, Patel D, Hadziahmetovic M, Chakravarti A, Mehta M. Current therapeutic paradigms in glioblastoma. Rev Recent Clin Trials. 2010;5(1):14–27.CrossRefPubMed
10.
11.
Niclou SP, Fack F, Rajcevic U. Glioma proteomics: status and perspectives. J Proteomics. 2010;73(10):1823–38.CrossRefPubMed
12.
Vidal S, Kovacs K, Lloyd RV, Meyer FB, Scheithauer BW. Angiogenesis in patients with craniopharyngiomas: correlation with treatment and outcome. Cancer. 2002;94(3):738–45.CrossRefPubMed
13.
Gangjee A, Pavana RK, Ihnat MA, Thorpe JE, Disch BC, Bastian A, et al. Discovery of antitubulin agents with antiangiogenic activity as single entities with multitarget chemotherapy potential. ACS Med Chem Lett. 2014;5(5):480–4.CrossRefPubMedPubMedCentral
14.
Chambers AF. MDA-MB-435 and M14 cell lines: identical but not M14 melanoma? Cancer Res. 2009;69(13):5292–3.CrossRefPubMed
15.
de Lange EC. Potential role of ABC transporters as a detoxification system at the blood-CSF barrier. Adv Drug Deliv Rev. 2004;56(12):1793–809.CrossRefPubMed
16.
Basile JR, Barac A, Zhu T, Guan KL, Gutkind JS. Class IV semaphorins promote angiogenesis by stimulating Rho-initiated pathways through plexin-B. Cancer Res. 2004;64:5212–24.CrossRefPubMed
17.
Towner RA, Gillespie DL, Schwager A, Saunders DG, Smith N, Njoku CE, et al. Regression of glioma growth in F98 and U87 rat glioma models by the nitrone OKN-007. Neuro Oncol. 2013;15:330–40.CrossRefPubMedPubMedCentral
18.
Doblas S, He T, Saunders D, Pearson J, Hoyle J, Smith N, et al. Glioma morphology and tumor-induced vascular alterations revealed in seven rodent glioma models by in vivo magnetic resonance imaging and angiography. J Magn Reson Imaging. 2010;32:267–75.CrossRefPubMedPubMedCentral
19.
Lu R-M, Chang Y-L, Chen M-S, Wu H-C. Single chain anti-c-Met antibody conjugated nanoparticles for in vivo tumor-targeted imaging and drug delivery. Biomaterials. 2011;32:3265–74.CrossRefPubMed
20.
21.
Garteiser P, Doblas S, Watanabe Y, Saunders D, Hoyle J, Lerner M, et al. Multiparametric assessment of the anti-glioma properties of OKN007 by magnetic resonance imaging. J Magn Imaging. 2010;31:796–806.CrossRef
22.
Zhu W, Kato Y, Artemov D. Heterogeneity of tumor vasculature and antiangiogenic intervention: insights from MR angiography and DCE-MRI. PLoS One. 2014;9:e86583.CrossRefPubMedPubMedCentral
23.
Choi EJ, Cho BJ, Lee DJ, Hwang YH, Chun SH, Kim HH, et al. Enhanced cytotoxic effect of radiation and temozolomide in malignant glioma cells: targeting PI3K-AKT-mTOR signaling, HSP90 and histone deacetylases. BMC Cancer. 2014;14:17.CrossRefPubMedPubMedCentral
24.
Kim JT, Kim JS, Ko KW, Kong DS, Kang CM, Kim MH, et al. Metronomic treatment of temozolomide inhibits tumor cell growth through reduction of angiogenesis and augmentation of apoptosis in orthotopic models of gliomas. Oncol Rep. 2006;16:33–9.PubMed
25.
Lefebvre P, Zak P, Laval F. Induction of O6-methylguanine-DNA-methyltransferase and N3-methyladenine-DNA-glycosylase in human cells exposed to DNA-damaging agents. DNA Cell Biol. 1993;12:233–41.CrossRefPubMed
26.
Jacobs VL, Valdes PA, Hickey WF, De Leo JA. Current review of in vivo GBM rodent models: emphasis on the CNS-1 tumor model. ASN Neuro. 2011;3(3):e00063.CrossRefPubMedPubMedCentral
27.
Reis M, Czupalla CJ, Ziegler N, Devraj K, Zinke J, Seidel S, et al. Endothelial Wnt/β-catenin signaling inhibits glioma angiogenesis and normalizes tumor blood vessels by inducing PDGF-B expression. J Exp Med. 2012;209:1611–27.CrossRefPubMedPubMedCentral
28.
Towner RA, Smith N, Saunders D, Coutinho De Souza P, Henry L, Lupu F, et al. Combined molecular MRI and immuno-spin-trapping for in vivo detection of free radicals in orthotopic mouse GL261 gliomas. Biochim Biophys Acta. 2013;1832:2153–61.CrossRefPubMed
29.
Merchant M, Ma X, Maun HR, Zheng Z, Peng J, Romero M, et al. Monovalent antibody design and mechanism of action of onartuzumab, a MET antagonist with anti-tumor activity as a therapeutic agent. Proc Natl Acad Sci USA. 2013;110:E2987–96.CrossRefPubMedPubMedCentral
30.
Heimans JJ, Vermorken JB, Wolbers JG, Eeltink CM, Meijer OW, Taphoom MJ, et al. Paclitaxel (Taxol) concentrations in brain tumor tissue. Ann Oncol. 1994;5(10):951–3.PubMed
31.
32.
Navis AC, Bourgonje A, Wesseling P, Wright A, Hendricks W, Verrijp K, et al. Effects of dual targeting of tumor cells and stroma in human glioblastoma xenografts with a tyrosine kinase inhibitor against c-MET and VEGFR2. PLoS One. 2013;8(3):e58262.CrossRefPubMedPubMedCentral
Metadata
Title
A new anti-glioma therapy, AG119: pre-clinical assessment in a mouse GL261 glioma model
Authors
Rheal A. Towner
Michael Ihnat
Debra Saunders
Anja Bastian
Nataliya Smith
Roheeth Kumar Pavana
Aleem Gangjee
Publication date
01-12-2015
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2015
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-015-1538-9

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