A novel biguanide (IM1761065) inhibits bioenergetics of glioblastoma tumorspheres.

PURPOSE: Glioblastoma (GBM) is a rapidly growing tumor in the central nervous system with altered metabolism. Depleting the bioenergetics of tumors with biguanides have been suggested as an effective therapeutic approach for treating GBMs. The purpose of this study was to determine the effects of IM1761065, a novel biguanide with improved pharmacokinetics, on GBM-tumorspheres (TSs). METHODS: The biological activities of IM1761065 on GBM-TSs, including their effects on viability, ATP levels, cell cycle, stemness, invasive properties, and transcriptomes were examined. The in vivo efficacy of IM1761065 was tested in a mouse orthotopic xenograft model. RESULTS: IM1761065 decreased the viability and ATP levels of GBM-TSs in a dose-dependent manner, and reduced basal and spare respiratory capacity in patient-derived GBM-TS, as measured by the oxygen consumption rate. Sphere formation, expression of stemness-related proteins, and invasive capacity of GBM-TSs were also significantly suppressed by IM1761065. A gene-ontology comparison of IM1761065-treated groups showed that the expression levels of stemness-related, epithelial mesenchymal transition-related, and mitochondrial complex I genes were also significantly downregulated by IM1761065. An orthotopic xenograft mouse model showed decreased bioluminescence in IM1761065-treated cell-injected mice at 5 weeks. IM1761065-treated group showed longer survival than the control group (P = 0.0289, log-rank test). CONCLUSION: IM1761065 is a potent inhibitor of oxidative phosphorylation. The inhibitory effect of IM1761065 on the bioenergetics of GBM-TS suggests that this novel compound could be used as a new drug for the treatment of GBM.

Tumor treating fields plus temozolomide for newly diagnosed glioblastoma: a sub-group analysis of Korean patients in the EF-14 phase 3 trial.

BACKGROUND: Tumor treating fields (TTFields) are anti-mitotic, non-invasive loco-regional cancer therapy comprising low intensity, intermediate frequency alternating electric fields. TTFields plus Temozolomide (TTFields/TMZ) extended survival versus TMZ alone in newly diagnosed glioblastoma (GBM) patients in the EF-14 trial. We report on Korean newly diagnosed GBM patients who participated in the EF-14 trial. METHODS: Thirty-nine participants of the EF-14 trial were enrolled at 8 sites in South Korea. Patients (24 TTFields/TMZ; 14 TMZ alone) received: TTFields (200 kHz) for > 18 h/day; TMZ at 120-150 mg for 5 days per a 28 day cycle. Safety and efficacy were assessed. RESULTS: Patient baseline characteristics were balanced in the 2 arms and the mean age was 52.1 years, 66.7% were male with a mean KPS of 90. Safety incidence was comparable between the 2 arms. In the TTFields/TMZ arm, 30% suffered from skin irritation versus 52% in the entire study population. No TTFields-related serious adverse events were reported. The median progression-free survival (PFS) in the TTFields/TMZ arm was 6.2 months (95% CI 4.2-12.2) versus 4.2 (95% CI 1.9-11.2) with TMZ alone (p = 0.67). Median overall survival was 27.2 months (95% CI 21-NA) with TTFields/TMZ versus 15.2 months (95% CI 7.5-24.1; HR 0.27, p = 0.01) with TMZ alone. CONCLUSION: Median OS and 1- and 2-year survival rates were higher with TTFields/TMZ and similar to the entire EF-14 population. About 30% of patients reported skin irritation, a lower rate than seen in the entire EF-14 population. These results demonstrate the efficacy and safety of TTFields in Korean newly diagnosed glioblastoma patients. CLINICAL TRIALS: Clinicaltrials.gov Identifier: NCT00916409.

Gamma Knife Radiosurgery for Choroidal Hemangioma: A Single-Institute Series.

OBJECTIVE: Choroidal hemangioma (CH) is a benign vascular tumor that induces subretinal fluid collection or exudative retinal detachment and consequent visual symptoms. Current standard treatments for CH include cryotherapy, diathermy, photocoagulation, photodynamic therapy, transpupillary thermotherapy, and radiation therapy. Stereotactic radiosurgery has recently been applied to the treatment of CH because of its characteristic stiff dose-fall-off and accuracy. We have adopted gamma knife radiosurgery (GKRS) to treat CH and have retrospectively assessed tumor volume reductions and improvements to visual acuity achieved thereby. METHODS: Fourteen patients with CHs were treated with GKRS from November 2006 to December 2017. Eight patients had circumscribed CH, and 6 exhibited diffuse CHs and were diagnosed with Sturge-Weber syndrome. The mean age of patients was 27.1 years (range: 8-68 years) and the mean duration of clinical or radiological follow-up was 40.2 months (range: 5-105 months). The mean volume of the tumors at the time of GKRS was 533.5 mm3 (range: 124-1150 mm3), and the mean prescribed marginal dose was 11.6 Gy (range: 10-16 Gy) with 50% isodose lines. RESULTS: The tumor volume decreased by the last follow-up in all patients. The visual acuity improved in 9 patients (64%) and decreased in 1 (7%). Six patients (43%) required trans-pars plana vitrectomy before or after GKRS. There were no symptomatic complications from radiation injury during the follow-up periods. CONCLUSIONS: GKRS could be an acceptable alternative treatment for symptomatic CH when standard therapy is not feasible.

Regulation of bioenergetics through dual inhibition of aldehyde dehydrogenase and mitochondrial complex I suppresses glioblastoma tumorspheres.

Background: Targeted approaches for treating glioblastoma (GBM) attempted to date have consistently failed, highlighting the imperative for treatment strategies that operate on different mechanistic principles. Bioenergetics deprivation has emerged as an effective therapeutic approach for various tumors. We have previously found that cancer cells preferentially utilize cytosolic NADH supplied by aldehyde dehydrogenase (ALDH) for ATP production through oxidative phosphorylation (OxPhos). This study is aimed at examining therapeutic responses and underlying mechanisms of dual inhibition of ALDH and OxPhos against GBM. Methods: For inhibition of ALDH and OxPhos, the corresponding inhibitors, gossypol and phenformin were used. Biological functions, including ATP levels, stemness, invasiveness, and viability, were evaluated in GBM tumorspheres (TSs). Gene expression profiles were analyzed using microarray data. In vivo anticancer efficacy was examined in a mouse orthotopic xenograft model. Results: Combined treatment of GBM TSs with gossypol and phenformin significantly reduced ATP levels, stemness, invasiveness, and cell viability. Consistently, this therapy substantially decreased expression of genes associated with stemness, mesenchymal transition, and invasion in GBM TSs. Supplementation of ATP using malate abrogated these effects, whereas knockdown of ALDH1L1 mimicked them, suggesting that disruption of ALDH-mediated ATP production is a key mechanism of this therapeutic combination. In vivo efficacy confirmed remarkable therapeutic responses to combined treatment with gossypol and phenformin. Conclusion: Our findings suggest that dual inhibition of tumor bioenergetics is a novel and effective strategy for the treatment of GBM.

Endoscopic disconnection for hypothalamic hamartoma with intractable seizure. Report of four cases.

Although intractable epilepsy associated with hypothalamic hamartoma (HH) can be controlled by microsurgical resection of the lesion, excision of deep-seated lesions is often associated with morbidity and mortality. Endoscopic disconnection is less invasive and seems to be well suited for this indication. The authors discuss the role of endoscopic-assisted surgery in the management of HH-induced seizures. Four patients with HH-related intractable gelastic seizure underwent endoscopic disconnection surgery. Postoperatively, all patients exhibited improvement. Two patients became seizure free immediately after endoscopic disconnection surgery, one patient with a widespread seizure focus involving the motor strip continued to experience rare complex partial seizures but gelastic seizures ceased, and one experienced a reduced frequency of seizures but persistence of some generalized seizures. Three patients suffered postoperative disconnection-like syndrome, which continued 3 to 7 days and spontaneously disappeared. The authors advocate the endoscopic disconnection surgery as a safe and effective treatment for HH-related epilepsy by blocking the spread of epileptic discharges from the lesion.