Dual blockage of STAT3 and ERK1/2 eliminates radioresistant GBM cells.

Radiotherapy (RT) is the major modality for control of glioblastoma multiforme (GBM), the most aggressive brain tumor in adults with poor prognosis and low patient survival rate. To improve the RT efficacy on GBM, the mechanism causing tumor adaptive radioresistance which leads to the failure of tumor control and lethal progression needs to be further elucidated. Here, we conducted a comparative analysis of RT-treated recurrent tumors versus primary counterparts in GBM patients, RT-treated orthotopic GBM tumors xenografts versus untreated tumors and radioresistant GBM cells versus wild type cells. The results reveal that activation of STAT3, a well-defined redox-sensitive transcriptional factor, is causally linked with GBM adaptive radioresistance. Database analysis also agrees with the worse prognosis in GBM patients due to the STAT3 expression-associated low RT responsiveness. However, although the radioresistant GBM cells can be resensitized by inhibition of STAT3, a fraction of radioresistant cells can still survive the RT combined with STAT3 inhibition or CRISPR/Cas9-mediated STAT3 knockout. A complementally enhanced activation of ERK1/2 by STAT3 inhibition is identified responsible for the survival of the remaining resistant tumor cells. Dual inhibition of ERK1/2 and STAT3 remarkably eliminates resistant GBM cells and inhibits tumor regrowth. These findings demonstrate a previously unknown feature ofSTAT3-mediated ERK1/2 regulation and an effective combination of two targets in resensitizing GBM to RT

Irradiation to Improve the Response to Immunotherapeutic Agents in Glioblastomas.

PurposeGlioblastoma (GBM) remains an incurable disease despite extensive treatment with surgical resection, irradiation, and temozolomide. In line with many other forms of aggressive cancers, GBM is currently under consideration as a target for immunotherapy. However, GBM tends to be nonimmunogenic and exhibits a microenvironment with few or no effector T cells, a relatively low nonsynonymous somatic mutational load, and a low predicted neoantigen burden. GBM also exploits a multitude of immunosuppressive strategies.Methods and materialsA number of immunotherapeutic approaches have been tested with disappointing results. A rationale exists to combine immunotherapy and radiation therapy, which can induce an immunogenic form of cell death with T-cell activation and tumor infiltration.ResultsVarious immunotherapy agents, including immune checkpoint modulators, transforming growth factor beta receptor inhibitors, and indoleamine-2,3-dioxygenase inhibitors, have been evaluated with irradiation in preclinical GBM models, with promising results, and are being further tested in clinical trials.ConclusionsThis review aims to present the basic rationale behind this emerging complementary therapeutic approach in GBM, appraise the current preclinical and clinical data, and discuss the future challenges in improving the antitumor immune response

The Fermi Gamma-ray Burst Monitor: Results from the first two years

In the first two years since the launch of the Fermi Observatory, the Gamma-ray Burst Monitor (GBM) has detected over 500 Gamma-Ray Bursts (GRBs), of which 18 were confidently detected by the Large Area Telescope (LAT) above 100 MeV. Besides GRBs, GBM has triggered on other transient sources, such as Soft Gamma Repeaters (SGRs), Terrestrial Gamma-ray Flashes (TGFs) and solar flares. Here we present the science highlights of the GBM observations.Comment: 4 pages, 1 figure, Proceedings of the 8th Workshop on Science with the New Generation of High Energy Gamma-ray Experiments (SciNeGHE 2010), Nuovo Cimento C, in pres

MicroRNA-129-1 acts as tumour suppressor and induces cell cycle arrest of GBM cancer cells through targeting IGF2BP3 and MAPK1

Background MicroRNA-129-1 (miR-129-1) seems to behave as a tumour suppressor since its decreased expression is associated with different tumours such as glioblastoma multiforme (GBM). GBM is the most common form of brain tumours originating from glial cells. The impact of miR-129-1 downregulation on GBM pathogenesis has yet to be elucidated. Methods MiR-129-1 was overexpressed in GBM cells, and its effect on proliferation was investigated by cell cycle assay. MiR-129-1 predicted targets (CDK6, IGF1, HDAC2, IGF2BP3 and MAPK1) were also evaluated by western blot and luciferase assay. Results Restoration of miR-129-1 reduced cell proliferation and induced G1 accumulation, significantly. Several functional assays confirmed IGF2BP3, MAPK1 and CDK6 as targets of miR-129-1. Despite the fact that IGF1 expression can be suppressed by miR-129-1, through 30-untranslated region complementary sequence, we could not find any association between IGF1 expression and GBM. MiR-129-1 expression inversely correlates with CDK6, IGF2BP3 and MAPK1 in primary clinical samples. Conclusion This is the first study to propose miR129-1 as a negative regulator of IGF2BP3 and MAPK1 and also a cell cycle arrest inducer in GBM cells. Our data suggests miR-129-1 as a potential tumour suppressor and presents a rationale for the use of miR-129-1 as a novel strategy to improve treatment response in GBM