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BACKGROUND Glioblastoma multiforme (GBM), a high-grade glioma, is characterized by being diffuse, invasive, and highly angiogenic and has a very poor prognosis. Identification of new biomarkers could help in the further diagnosis of GBM. OBJECTIVE To identify ELTD1 (epidermal growth factor, latrophilin, and 7 transmembrane domain-containing protein 1 on chromosome 1) as a putative glioma-associated marker via a bioinformatic method. METHODS We used advanced data mining and a novel bioinformatics method to predict ELTD1 as a potential novel biomarker that is associated with gliomas. Validation was done with immunohistochemistry, which was used to detect levels of ELTD1 in human high-grade gliomas and rat F98 glioma tumors. In vivo levels of ELTD1 in rat F98 gliomas were assessed using molecular magnetic resonance imaging. RESULTS ELTD1 was found to be significantly higher (P = .03) in high-grade gliomas (50 patients) compared with low-grade gliomas (21 patients) and compared well with traditional immunohistochemistry markers including vascular endothelial growth factor, glucose transporter 1, carbonic anhydrase IX, and hypoxia-inducible factor 1α. ELTD1 gene expression indicates an association with grade, survival across grade, and an increase in the mesenchymal subtype. Significantly high (P < .001) in vivo levels of ELTD1 were additionally found in F98 tumors compared with normal brain tissue. CONCLUSION Results of this study strongly suggests that associative analysis was able to accurately identify ELTD1 as a putative glioma-associated biomarker. The detection of ELTD1 was also validated in both rodent and human gliomas and may serve as an additional biomarker for gliomas in preclinical and clinical diagnosis of gliomas.

Gliomas, the most common primary brain tumors in adults, have a poor outcome. PBN (α-phenyl- tert -butylnitrone) and OKN007 (2,4-disulfophenyl-PBN) are nitrones that have demonstrated beneficial effects in many aging diseases. In this study, we evaluated the anti-tumor effects of PBN and OKN007 in several rodent glioma models (C6, RG2, and GL261) by assessing metabolite alterations with magnetic resonance spectroscopy (MRS). PBN or OKN007 was administered in drinking water before or after tumor formation. MR imaging and single-voxel point-resolved spectroscopy were done to assess tumor morphology and metabolites, after therapy. Major metabolite ratios (choline, N -acetylaspartate, and lipid (methylene or methyl), all compared to creatine), as well as quantification of individual metabolite concentrations, were assessed. Nitrones induced tumor metabolism changes that resulted in restoring major metabolite ratios close to their normal levels, in the glioma regression phase. Nitrone treatment decreased the lipid (methylene)-to-creatine ratio, as well as the estimated concentration of lipid (methylene) significantly. Alterations in lipids can be a useful marker for the evaluation of the efficacy associated with treatment and were found in this study to be related to the reduction of necrosis, but not apoptosis. OKN007 was more effective than PBN when administered after tumor formation in the C6 glioma model. In conclusion, 1 H MRS and conventional MRI are useful methods to assess and follow the response of varied glioma models to anti-tumor treatments.

Glioblastoma multiforme (GBM) is characterized by its diffuse, invasive and highly angiogenic nature, and has a very poor prognosis. Early diagnosis of gliomas is an important goal to increase the survival rates of this devastating cancer which has limited treatment options and low survival rates. Identification of new biomarkers could help in the further diagnosis of GBM. Our goal in this study was to determine whether or not ELTD1 could be used as a marker for glioma-related processes, and use immunohistochemistry (IHC) and molecular magnetic resonance imaging (MRI) to validate its presence in human and rodent gliomas, respectively. We used advanced data mining and a novel bioinformatics method to predict ELTD1 as a novel biomarker that is associated with gliomas. A global meta-analysis (GAMMA) of all human genes was conducted to identify gene-gene co-expression patterns that were consistent and specific across heterogeneous microarray experiments. Using the Human Proteome Reference Database (HPRD) and other experimental sources on protein cellular localizations, we screened this list of predicted glioma-associated proteins for those that were extracellular or membrane-bound, because these proteins were thought to be ideal targets for molecular imaging probes and targeting therapies since they are more likely to be accessible to injected antibodies. Validation of this marker was done with IHC which was used to detect levels of ELTD1 in human high-grade gliomas and rat F98 glioma tumors ex vivo. In vivo levels of ELTD1 in rat F98 gliomas were assessed using molecular MRI (mMRI). Dextran-coated NH2 base iron oxide nanoparticles underwent conjugation with an ELTD1-specific Ab. For determination of T2* values of the iron oxide nanoprobes in gliomas, a multiple gradient echo (MGE) method was used. In this study we identified ELTD1 as a putative glioma-associated marker via a bioinformatic method, and experimentally validated its presence in both rodent and human gliomas via IHC and molecular MRI analyses in a rodent glioma model. For IHC, ELTD1 was compared to traditional IHC markers for gliomas including VEGF (vascular endothelial growth factor), GLUT-1 (glucose transporter 1), CAIX (carbonic anhydrase IX), and HIF-1α (hypoxia inducible factor-1α). ELTD1 was found to be significantly higher (P=.03) in high-grade gliomas (50 patients) compared to low-grade gliomas (21 patients), and compared well to traditional IHC markers including VEGF, GLUT-1, CAIX and HIF-1α. Significantly high (P Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2986. doi:1538-7445.AM2012-2986

Gliomas are the most common and lethal primary brain tumors in the adult, with a median survival time of 12 to 15 months for grade IV gliomas, glioblastoma multiforme. PBN and OKN007 are nitrones which have demonstrated beneficial effects in many aging diseases. In this study, we evaluated the anti-tumor effects of PBN or OKN007 in several rodent glioma models (C6, RG2, and GL261) by assessing metabolite alterations with magnetic resonance spectroscopy (MRS). PBN or OKN007 was administered in drinking water prior to or post tumor formation. MRI and short echo time, single-voxel point-resolved spectroscopy (PRESS) were obtained to assess tumor morphology and metabolites, respectively, following therapy. Major metabolite ratios (Choline, N-acetyl aspartate (NAA), Lipid (methylene), and Lipid (methyl), all compared to Creatine) were assessed. Nitrones induced tumor metabolism changes that resulted in restoring major metabolite ratios close to their normal levels, in the glioma regression phase. Nitrones treatment decreased the Lipid (methylene) to Creatine ratio significantly, which can be a useful marker for evaluation of the efficacy of the treatments, and was found to be related with the reduction of necrosis. OKN007 was more effective than PBN when administered post-tumor formation in the C6 glioma model. OKN007 was able to inhibit angiogenic factors (VEGF, bFGF and HGF) and induce apoptosis (indicated by an increase of the apoptotic marker m30) in C6 gliomas, which might be potential mechanisms that are involved in the anti-glioma effects. In conclusion, OKN007 and PBN are effective in inhibiting the growth of several experimental gliomas and may be considered as potential therapeutics for a clinical trial in human gliomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 675. doi:10.1158/1538-7445.AM2011-675