Abstract
Current therapies for high-grade gliomas, particularly glioblastomas (GBM), do not extend patient survival beyond 16–22 months. OKN-007 (OKlahoma Nitrone 007), which is currently in phase II (multi-institutional) clinical trials for GBM patients, and has demonstrated efficacy in several rodent and human xenograft glioma models, shows some promise as an anti-glioma therapeutic, as it affects most aspects of tumorigenesis (tumor cell proliferation, angiogenesis, migration, and apoptosis). Combined with the chemotherapeutic agent temozolomide (TMZ), OKN-007 is even more effective by affecting chemo-resistant tumor cells. In this study, mass spectrometry (MS) methodology ESI-MS, mass peak analysis (Leave One Out Cross Validation (LOOCV) and tandem MS peptide sequence analyses), and bioinformatics analyses (Ingenuity® Pathway Analysis (IPA®)), were used to identify up- or down-regulated proteins in the blood sera of F98 glioma-bearing rats, that were either untreated or treated with OKN-007. Proteins of interest identified by tandem MS-MS that were decreased in sera from tumor-bearing rats that were either OKN-007-treated or untreated included ABCA2, ATP5B, CNTN2, ITGA3, KMT2D, MYCBP2, NOTCH3, and VCAN. Conversely, proteins of interest in tumor-bearing rats that were elevated following OKN-007 treatment included ABCA6, ADAMTS18, VWA8, MACF1, and LAMA5. These findings, in general, support our previous gene analysis, indicating that OKN-007 may be effective against the ECM. These findings also surmise that OKN-007 may be more effective against oligodendrogliomas, other brain tumors such as medulloblastoma, and possibly other types of cancers.
Highlights
Gliomas can either be astrocytomas, oligodendrogliomas, ependymomas, or mixed neuronal-glial tumors, with grades varying from I to IV as established by the World Health Organization (WHO) [1]
We previously established that the TGF-β1 pathway was the master regulator that down-regulated 57 genes associated with the extracellular matrix (ECM) [6]
A “left out” peak above this midpoint is allocated to the higher value classifier, and a “left out” peak below this midpoint is assigned to the lower value classifier
Summary
Gliomas can either be astrocytomas, oligodendrogliomas, ependymomas, or mixed neuronal-glial tumors, with grades varying from I (least malignant) to IV (most malignant) as established by the World Health Organization (WHO) [1]. Our group found that OKN-007 was very effective in significantly reducing tumor volumes and elevating animal survival in various high-grade, orthotopic, glioma models, including rat C6 [2], F98 [3,4], mouse GL261 [5], and human adult U87 [3] and G55 [6], as well as pediatric patient-derived GBM [7] and patient-derived diffuse intrinsic pontine glioma (DIPG) [8] xenografts. In addition to effects on animal survival and tumor volumes, OKN-007 was found to significantly reduce necrosis in F98 rat gliomas [9]. We discovered that OKN-007 is able to augment a decrease in tumor cell growth when co-administered with TMZ in a human G55 xenograft model [6]
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