TY  - JOUR
A1  - Hagemann, Carsten
A1  - Neuhaus, Nikolas
A1  - Dahlmann, Mathias
A1  - Kessler, Almuth F.
A1  - Kobelt, Dennis
A1  - Herrmann, Pia
A1  - Eyrich, Matthias
A1  - Freitag, Benjamin
A1  - Linsenmann, Thomas
A1  - Monoranu, Camelia M.
A1  - Ernestus, Ralf-Ingo
A1  - Löhr, Mario
A1  - Stein, Ulrike
T1  - Circulating MACC1 transcripts in glioblastoma patients predict prognosis and treatment response
JF  - Cancers
N2  - Glioblastoma multiforme is the most aggressive primary brain tumor of adults, but lacksreliable and liquid biomarkers. We evaluated circulating plasma transcripts of metastasis-associatedin colon cancer-1 (MACC1), a prognostic biomarker for solid cancer entities, for prediction of clinicaloutcome and therapy response in glioblastomas.  MACC1 transcripts were significantly higher inpatients compared to controls.  Low MACC1 levels clustered together with other prognosticallyfavorable markers.  It was associated with patients’ prognosis in conjunction with the isocitratedehydrogenase (IDH) mutation status: IDH1 R132H mutation and low MACC1 was most favorable(median overall survival (OS) not yet reached), IDH1 wildtype and high MACC1 was worst (medianOS 8.1 months), while IDH1 wildtype and low MACC1 was intermediate (median OS 9.1 months).No patients displayed IDH1 R132H mutation and high MACC1. Patients with low MACC1 levelsreceiving standard therapy survived longer (median OS 22.6 months) than patients with high MACC1levels (median OS 8.1 months).   Patients not receiving the standard regimen showed the worstprognosis, independent of MACC1 levels (low: 6.8 months, high: 4.4 months). Addition of circulatingMACC1 transcript levels to the existing prognostic workup may improve the accuracy of outcomeprediction and help define more precise risk categories of glioblastoma patients.
KW  - metastasis-associated in colon cancer 1 (MACC1)
KW  - glioblastoma multiforme
KW  - liquid biopsy
KW  - therapy response
KW  - prognostic marker
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-197327
SN  - 2072-6694
VL  - 11
IS  - 6
ER  - 
TY  - JOUR
A1  - Djuzenova, Cholpon S.
A1  - Fiedler, Vanessa
A1  - Memmel, Simon
A1  - Katzer, Astrid
A1  - Sisario, Dmitri
A1  - Brosch, Philippa K.
A1  - Göhrung, Alexander
A1  - Frister, Svenja
A1  - Zimmermann, Heiko
A1  - Flentje, Michael
A1  - Sukhorukov, Vladimir L.
T1  - Differential effects of the Akt inhibitor MK-2206 on migration and radiation sensitivity of glioblastoma cells
JF  - BMC Cancer
N2  - Background
Most tumor cells show aberrantly activated Akt which leads to increased cell survival and resistance to cancer radiotherapy. Therefore, targeting Akt can be a promising strategy for radiosensitization. Here, we explore the impact of the Akt inhibitor MK-2206 alone and in combination with the dual PI3K and mTOR inhibitor PI-103 on the radiation sensitivity of glioblastoma cells. In addition, we examine migration of drug-treated cells.

Methods
Using single-cell tracking and wound healing migration tests, colony-forming assay, Western blotting, flow cytometry and electrorotation we examined the effects of MK-2206 and PI-103 and/or irradiation on the migration, radiation sensitivity, expression of several marker proteins, DNA damage, cell cycle progression and the plasma membrane properties in two glioblastoma (DK-MG and SNB19) cell lines, previously shown to differ markedly in their migratory behavior and response to PI3K/mTOR inhibition.

Results
We found that MK-2206 strongly reduces the migration of DK-MG but only moderately reduces the migration of SNB19 cells. Surprisingly, MK-2206 did not cause radiosensitization, but even increased colony-forming ability after irradiation. Moreover, MK-2206 did not enhance the radiosensitizing effect of PI-103. The results appear to contradict the strong depletion of p-Akt in MK-2206-treated cells. Possible reasons for the radioresistance of MK-2206-treated cells could be unaltered or in case of SNB19 cells even increased levels of p-mTOR and p-S6, as compared to the reduced expression of these proteins in PI-103-treated samples. We also found that MK-2206 did not enhance IR-induced DNA damage, neither did it cause cell cycle distortion, nor apoptosis nor excessive autophagy.

Conclusions
Our study provides proof that MK-2206 can effectively inhibit the expression of Akt in two glioblastoma cell lines. However, due to an aberrant activation of mTOR in response to Akt inhibition in PTEN mutated cells, the therapeutic window needs to be carefully defined, or a combination of Akt and mTOR inhibitors should be considered.
KW  - DNA damage
KW  - glioblastoma multiforme
KW  - histone H2AX
KW  - irradiation
KW  - migration
KW  - mTOR
KW  - PTEN
KW  - p53
KW  - radiation sensitivity
KW  - wound healing
Y1  - 2019
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-200290
VL  - 19
ER  -