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Ichiro Nakano

Tumor heterogeneity of adult high-grade glioma (HGG) is recognized in 3 major subtypes based on core gene signatures. However, the molecular signatures and clinical implications of glioma stem cells (GSCs) in individual HGG subtypes remain poorly characterized. Recently genome-wide transcriptional analysis identified two mutually exclusive GSC subtypes with distinct dysregulated signaling and metabolic pathways. Analysis of genetic profiles and phenotypic assays distinguished proneural (PN) from mesenchymal (MES) GSCs and revealed a striking correlation with the corresponding PN or MES HGGs. Similar to HGGs with a MES signature, MES GSCs display more aggressive phenotypes both in vitro and in vivo. Furthermore, MES GSCs are markedly resistant to radiation as compared with PN GSCs, consistent with the relative radiation resistance of MES GBM compared with other subtypes. A systems biology approach has identified a set of transcription factors as the master regulators for the MES signature. Metabolic reprogramming in MES GSCs has also been noticed with the prominent activation of the glycolytic pathway, comprising aldehyde dehydrogenase (ALDH) family genes. This review summarizes recent progress in the characterization of the molecular signature in distinct HGG and GSC subtypes and plasticity between different GSC subtypes as well as between GSCs and non-GSCs in HGG tumors. Clinical implications of the translational GSC research are also discussed.

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Ichiro Nakano, Koichi Iwasaki and Akinori Kondo

✓ An unusual case of a metastatic adenocarcinoma located entirely within the trigeminal nerve is reported. The patient, with a history of breast cancer, presented with a pure trigeminal mononeuropathy. The neurological and neuroradiological findings in this patient were quite similar to those of a patient with trigeminal neurinoma. Surgery revealed that the tumor was located within the trigeminal nerve and its appearance was similar to that of a neurinoma. However, histopathological studies proved the tumor to be an adenocarcinoma that was related to the breast cancer treated earlier. A solitary metastatic tumor arising solely in a trigeminal nerve is quite rare; this is the first report of such a case metastasized from breast cancer.

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Joshua D. Bernstock, James H. Mooney, Adeel Ilyas, Gustavo Chagoya, Dagoberto Estevez-Ordonez, Ahmed Ibrahim and Ichiro Nakano

Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is associated with significant morbidity and mortality despite maximal safe resection followed by chemo- and radiotherapy. GBMs contain self-renewing, tumorigenic glioma stem cells that contribute to tumor initiation, heterogeneity, therapeutic resistance, and recurrence. Intratumoral heterogeneity (ITH) of GBMs is also a major contributing factor to poor clinical outcomes associated with these high-grade glial tumors. Herein, the authors summarize recent discoveries and advances in the molecular and phenotypic characterization of GBMs with particular focus on ITH. In so doing, they attempt to highlight recent advances in molecular signatures/properties and metabolic alterations in an effort to clarify translational implications that may ultimately improve clinical outcomes.

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Ahmed N. Ibrahim, Daisuke Yamashita, Joshua C. Anderson, Moaaz Abdelrashid, Amr Alwakeal, Dagoberto Estevez-Ordonez, Svetlana Komarova, James M. Markert, Violaine Goidts, Christopher D. Willey and Ichiro Nakano

OBJECTIVE

Despite significant recent efforts applied toward the development of efficacious therapies for glioblastoma (GBM) through exploration of GBM’s genome and transcriptome, curative therapeutic strategies remain highly elusive. As such, novel and effective therapeutics are urgently required. In this study, the authors sought to explore the kinomic landscape of GBM from a previously underutilized approach (i.e., spatial heterogeneity), followed by validation of Bruton’s tyrosine kinase (BTK) targeting according to this stepwise kinomic-based novel approach.

METHODS

Twelve GBM tumor samples were obtained and characterized histopathologically from 2 patients with GBM. PamStation peptide-array analysis of these tissues was performed to measure the kinomic activity of each sample. The Ivy GBM database was then utilized to determine the intratumoral spatial localization of BTK activity by investigating the expression of BTK-related transcription factors (TFs) within tumors. Genetic inhibition of BTK family members through lentiviral short hairpin RNA (shRNA) knockdown was performed to determine their function in the core-like and edge-like GBM neurosphere models. Finally, the small-molecule inhibitor of BTK, ONO/GS-4059, which is currently under clinical investigation in nonbrain cancers, was applied for pharmacological inhibition of regionally specified newly established GBM edge and core neurosphere models.

RESULTS

Kinomic investigation identified two major subclusters of GBM tissues from both patients exhibiting distinct profiles of kinase activity. Comparatively, in these spatially defined subgroups, BTK was the centric kinase differentially expressed. According to the Ivy GBM database, BTK-related TFs were highly expressed in the tumor core, but not in edge counterparts. Short hairpin RNA–mediated gene silencing of BTK in previously established edge- and core-like GBM neurospheres demonstrated increased apoptotic activity with predominance of the sub-G1 phase of core-like neurospheres compared to edge-like neurospheres. Lastly, pharmacological inhibition of BTK by ONO/GS-4059 resulted in growth inhibition of regionally derived GBM core cells and, to a lesser extent, their edge counterparts.

CONCLUSIONS

This study identifies significant heterogeneity in kinase activity both within and across distinct GBM tumors. The study findings indicate that BTK activity is elevated in the classically therapy-resistant GBM tumor core. Given these findings, targeting GBM’s resistant core through BTK may potentially provide therapeutic benefit for patients with GBM.

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Nobuhiro Tanaka, Masami Fujii, Hirochika Imoto, Joji Uchiyama, Kimihiko Nakano, Sadahiro Nomura, Hirosuke Fujisawa, Ichiro Kunitsugu, Takashi Saito and Michiyasu Suzuki

Object

The use of focal brain cooling to eliminate epileptic discharges (EDs) has attracted increasing attention in the scientific community. In this study, the inhibitory effect of selective hippocampal cooling on experimental hippocampal seizures was investigated using a newly devised cooling system with a thermoelectric (Peltier) chip.

Methods

A copper needle coated with silicone and attached to the Peltier chip was used for the cooling device. The experiments were performed first in a phantom model with thermography and second in adult male Sprague–Dawley rats in a state of halothane anesthesia. The cooling needle, a thermocouple, and a needle electrode for electroencephalography recording were inserted into the right hippocampus. Kainic acid (KA) was injected into the right hippocampus to provoke the EDs. The animals were divided into hippocampal cooling (10 rats) and noncooling (control, 10 rats) groups.

Results

In the phantom study, the cooling effects (9°C) occurred in the spherical areas around the needle tip. In the rats the temperature of the cooled hippocampus decreased below 20°C within a 1.6-mm radius and below 25°C within a 2.4-mm radius from the cooling center. The temperature at the needle tip decreased below 20°C within 1 minute and was maintained at the same level until the end of the cooling process. The amplitude of the EDs was suppressed to 68.1 ± 4.8% of the precooling value and remained low thereafter. No histological damage due to cooling was observed in the rat hippocampus.

Conclusions

Selective hippocampal cooling effectively suppresses the KA-induced hippocampal EDs. Direct hippocampal cooling with a permanently implantable system is potentially useful as a minimally invasive therapy for temporal lobe epilepsy and therefore could be an alternative to the temporal lobectomy.

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Hirochika Imoto, Masami Fujii, Jouji Uchiyama, Hirosuke Fujisawa, Kimihiko Nakano, Ichiro Kunitsugu, Sadahiro Nomura, Takashi Saito and Michiyasu Suzuki

✓ Local cortical cooling for termination of epileptic discharges (EDs) has recently become a focus of research. The authors report on a newly devised cooling system that uses a thermoelectric (Peltier) chip and examine the system’s performance in experimental neocortical seizures. Experiments were performed in adult male Sprague–Dawley rats after induction of halothane anesthesia. The Peltier chip was attached to a heat sink with a water channel. Two silicon tubes were connected to the heat sink, and water at 37°C was circulated in the channel. The newly designed device was placed on the surface of the cortex. Kainic acid (KA) was injected into the cortex to provoke EDs. In the nonepileptic cortex, the temperature of the cortical surface decreased to 14.8 ± 1.5°C and that 2 mm below the surface to 27.1 ± 3.1°C within 30 seconds after the start of cooling. The temperature of the heated side of the chip was maintained at approximately 36.9°C. Without water circulation, the temperature of the cortical surface decreased to 20°C but soon began to increase, peaking at 30°C. The temperature of the heated side of the chip rose to more than 60°C. The EDs, which appeared within 20 minutes after KA injection, began to decrease in amplitude immediately after cooling began and continued to decrease as the temperature of the cortex was lowered. Sufficient miniaturization and good performance of the cooling device was demonstrated. Further efforts to develop implantable cooling systems and improve existing ones should be continued.

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Ichiro Nakano and E. Antonio Chiocca

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Johan Pallud

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Daisuke Yamashita, Joshua D. Bernstock, Galal Elsayed, Hirokazu Sadahiro, Ahmed Mohyeldin, Gustavo Chagoya, Adeel Ilyas, James Mooney, Dagoberto Estevez-Ordonez, Shinobu Yamaguchi, Victoria L. Flanary, James R. Hackney, Krishna P. Bhat, Harley I. Kornblum, Nicola Zamboni, Sung-Hak Kim, E. Antonio Chiocca and Ichiro Nakano

OBJECTIVE

Despite an aggressive multimodal therapeutic regimen, glioblastoma (GBM) continues to portend a grave prognosis, which is driven in part by tumor heterogeneity at both the molecular and cellular levels. Accordingly, herein the authors sought to identify metabolic differences between GBM tumor core cells and edge cells and, in so doing, elucidate novel actionable therapeutic targets centered on tumor metabolism.

METHODS

Comprehensive metabolic analyses were performed on 20 high-grade glioma (HGG) tissues and 30 glioma-initiating cell (GIC) sphere culture models. The results of the metabolic analyses were combined with the Ivy GBM data set. Differences in tumor metabolism between GBM tumor tissue derived from within the contrast-enhancing region (i.e., tumor core) and that from the peritumoral brain lesions (i.e., tumor edge) were sought and explored. Such changes were ultimately confirmed at the protein level via immunohistochemistry.

RESULTS

Metabolic heterogeneity in both HGG tumor tissues and GBM sphere culture models was identified, and analyses suggested that tyrosine metabolism may serve as a possible therapeutic target in GBM, particularly in the tumor core. Furthermore, activation of the enzyme tyrosine aminotransferase (TAT) within the tyrosine metabolic pathway influenced the noted therapeutic resistance of the GBM core.

CONCLUSIONS

Selective inhibition of the tyrosine metabolism pathway may prove highly beneficial as an adjuvant to multimodal GBM therapies.