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Background TERT promoter mutations are observed in 80% of wild-type IDH glioblastoma (GBM). Moreover, the upstream TERT transcription factor GABPB1 was recently identified as a cancer-specific therapeutic target for tumors harboring a TERT promoter mutation. In that context, noninvasive imaging biomarkers are needed for the detection of TERT modulation. Methods Multiple GBM models were investigated as cells and in vivo tumors and the impact of TERT silencing, either directly or by targeting GABPB1, was determined using 1H and hyperpolarized 13C magnetic resonance spectroscopy (MRS). Changes in associated metabolic enzymes were also investigated. Results 1H-MRS revealed that lactate and glutathione (GSH) were the most significantly altered metabolites when either TERT or GABPB1 was silenced, and lactate and GSH levels were correlated with cellular TERT expression. Consistent with the drop in lactate, 13C-MRS showed that hyperpolarized [1-13C]lactate production from [1-13C]pyruvate was also reduced when TERT was silenced. Mechanistically, the reduction in GSH was associated with a reduction in pentose phosphate pathway flux, reduced activity of glucose-6-phosphate dehydrogenase, and reduced NADPH. The drop in lactate and hyperpolarized lactate were associated with reductions in glycolytic flux, NADH, and expression/activity of GLUT1, monocarboxylate transporters, and lactate dehydrogenase A. Conclusions Our study indicates that MRS-detectable GSH, lactate, and lactate production could serve as metabolic biomarkers of response to emerging TERT-targeted therapies for GBM with activating TERT promoter mutations. Importantly these biomarkers are readily translatable to the clinic, and thus could ultimately improve GBM patient management.

To optimize the development of stem cell (SC)-based therapies for the treatment of glioblastoma (GBM), we compared the pathotropism of 2 SC sources, human mesenchymal stem cells (hMSCs) and fetal neural stem cells (fNSCs), toward 2 orthotopic GBM models, circumscribed U87vIII and highly infiltrative GBM26. High resolution and contrast-enhanced (CE) magnetic resonance imaging (MRI) were performed at 14.1 Tesla to longitudinally monitor the in vivo location of hMSCs and fNSCs labeled with the same amount of micron-size particles of iron oxide (MPIO). To assess pathotropism, SCs were injected in the contralateral hemisphere of U87vIII tumor-bearing mice. Both MPIO-labeled SC types exhibited tropism to tumors, first localizing at the tumor edges, then in the tumor masses. MPIO-labeled hMSCs and fNSCs were also injected intratumorally in mice with U87vIII or GBM26 tumors to assess their biodistribution. Both SC types distributed throughout the tumor in both GBM models. Of interest, in the U87vIII model, areas of hyposignal colocalized first with the enhancing regions (ie, regions of high vascular permeability), consistent with SC tropism to vascular endothelial growth factor. In the GBM26 model, no rim of hyposignal was observed, consistent with the infiltrative nature of this tumor. Quantitative analysis of the index of dispersion confirmed that both MPIO-labeled SC types longitudinally distribute inside the tumor masses after intratumoral injection. Histological studies confirmed the MRI results. In summary, our results indicate that hMSCs and fNSCs exhibit similar properties regarding tumor tropism and intratumoral dissemination, highlighting the potential of these 2 SC sources as adequate candidates for SC-based therapies.

We thank John Gill for writing and editorial support., This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m2 daily during RT and then adjuvantly at 200 mg/m2 daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotininb and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials., This work was supported by Eli Lilly.