Autophagy as potential target against glioblastoma

Glioblastoma is a highly aggressive brain tumour against which existing treatments are largely inefficient. Cancer researchers and genomics experts from LIH’s Department of Oncology show that glioblastoma tumour cells activate autophagy to survive in an oxygen-deprived environment and identify the involvement of the autophagy-related protein ATG9A, which could be a promising anti-cancer target.

Glioblastoma rapidly invade brain tissue and subsist well even under hypoxic conditions, when oxygen is rare due to poor vascularisation of the tumour. The activation of autophagy, an intracellular recycling process, is known to be protective for cells when they are exposed to stress conditions such as hypoxia. In this study, the scientists found out that autophagy is activated in glioblastoma to enable tumour cell survival in an unfavourable hypoxic microenvironment. Scientists took advantage of this process and applied autophagy inhibitors together with Avastin, an anti-angiogenic agent which induces hypoxia in vivo. This allowed to lower the effective treatment dose.

When analysing the expression of autophagy-related genes at the transcriptional level, positively and negatively regulated genes where identified under hypoxic conditions. The gene encoding ATGA9, a member of the Autophagy-Related Gene (ATG) family, stood out with its high and consistent induction under hypoxia. ATGA9, known to be important for the formation of autophagosomes, is thus a key molecule for the activation of hypoxia-induced autophagy in glioblastoma.

Currently available drugs that inhibit autophagy are effective only in very toxic doses. We propose that the treatment dose can be lowered in patients by exploiting the vulnerability of tumour cells in hypoxia. We think that novel drugs targeting specific molecules, such as ATG9A, may further bring better results in the clinic’, says Dr Anna Golebiewska, scientist in the NorLux Neuro-Oncology Laboratory and co-responsible of the study.

This study was a collaborative project between the three entities of LIH’s Department of Oncology: the NorLux Neuro-Oncology Laboratory, the Genomics and Proteomics Research Unit and the Laboratory of Experimental Cancer Research. It was supported by the Luxembourg National Research Fund (FNR) and the “Fondation Cancer” in Luxembourg. The results were published in the September 2017 issue in the British Journal of Cancer, a journal of the Nature Publishing Group.

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