A tale of two multi‐focal therapies for glioblastoma: An antibody targeting ELTD1 and nitrone‐based OKN‐007

Abstract

Glioblastoma (GBM) is the most common primary malignant brain tumour in adults. Despite a multimodal treatment response, survival for GBM patients remains between 12 and 15 months. Anti‐ELTD1 antibody therapy is effective in decreasing tumour volumes and increasing animal survival in an orthotopic GBM xenograft. OKN‐007 is a promising chemotherapeutic agent that is effective in various GBM animal models and is currently in two clinical trials. In this study, we sought to compare anti‐ELTD1 and OKN‐007 therapies, as single agents and combined, against bevacizumab, a commonly used therapeutic agent against GBM, in a human G55 xenograft mouse model. MRI was used to monitor tumour growth, and immunohistochemistry (IHC) was used to assess tumour markers for angiogenesis, cell migration and proliferation in the various treatment groups. OKN and anti‐ELTD1 treatments significantly increased animal survival, reduced tumour volumes and normalized the vasculature. Additionally, anti‐ELTD1 was also shown to significantly affect other pro‐angiogenic factors such as Notch1 and VEGFR2. Unlike bevacizumab, anti‐ELTD1 and OKN treatments did not induce a pro‐migratory phenotype within the tumours. Anti‐ELTD1 treatment was shown to be as effective as OKN therapy. Both OKN and anti‐ELTD1 therapies show promise as potential single‐agent multi‐focal therapies for GBM patients.

Roles of TRPM channels in glioma

“…Early studies found that in more than 20 TRP channels, compared with normal brain tissue, TRPM8 mRNA expression in GBM was upregulated to the highest level, which was closely related to the migration, invasion, and proliferation of glioma. 143 TRPM8 suppression or knockdown has been shown to disrupt the trigger of apoptotic cell death, cell cycle, cloning survival, and impair DNA repair. 144 TRPM8 channels may also regulate cell proliferation by dynamically controlling the level of glioma resting potential, which may be a crucial cell cycle regulator.…”

OKN-007 Alters Protein Expression Profiles in High-Grade Gliomas: Mass Spectral Analysis of Blood Sera

“…During tumor promotion, activated TGF- β led to decreased apoptosis and increased cell proliferation, cell migration, and angiogenesis [ 45 ]. OKN-007 is thought to act via LTBP and downregulates several genes associated with the ECM [ 6 ], and is also a free radical scavenger [ 4 ], resulting in the reversal of the major tumorigenic characteristics, i.e., increases tumor cell apoptosis and decreases cell proliferation, migration and vascular angiogenesis [ 46 ]. Other proteins decreased by OKN-007 include ABCA2, ATP5B, CNTN2, KMT2D, and MYCBP2.…”

Development of Pharmacological Strategies with Therapeutic Potential in Ischemic Stroke

“…In Figure 1, we present some examples of nitrones currently being developed as drug candidates for ischemic stroke or other diseases. NXY-059 has been reported to work as a chemotherapeutic agent against glioblastoma [31,32], with several clinical trials being conducted. TBN (tetramethylpyrazine nitrone), derived from 2,3,5,6-tetramethylpyrazine, an active component of the traditional Chinese herb Ligusticum wallichii, combines a thrombolytic effect with potent radical scavenger properties [33] and a good permeability profile, proving to be neuroprotective in ischemic stroke [34], Alzheimer's disease [35] and amyotrophic lateral sclerosis [36] experimental models.…”