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Chien et al. J Cancer Metastasis Treat 2019;5:66 I http://dx.doi.org/10.20517/2394-4722.2019.016 Page 7 of 10
[94]
cytotoxicity . How autophagy was utilized in carmustine-related oxidative stress and anti-oxidant reaction
remains to be elucidated.

AUTOPHAGY INHIBITORS IN CLINICAL TRIAL
Traditionally, CQ is used for malaria treatment. Due to the basic property of CQ, it stays in lysosomes
leading to enhanced lysosomal pH and inhibition of autophagy [95,96] . Hence, CQ has been investigated
in clinical trials for cancer therapy including GBM. An early clinical trial of CQ in a small population of
GBM patients (NCT00224978) showed that the median survival increased in patients receiving CQ in
[97]
combination with standard regimens . Currently, there are 3 ongoing clinical trials involving CQ in GBM
or astrocytoma patients (NCT02378532 (Phase 1), NCT02432417 (Phase 2) and NCT03243461 (Phase 3).
In addition to CQ, more candidate autophagy modulators are expected with or without the standard drugs
to be investigated in clinical trials.

CONCLUSION
The current standard treatments of primary or recurrent GBM can cause autophagy induction and the
enhanced autophagy through DDR, ROS, hypoxia, AKT/mTOR, AMPK and RB pathways may result in cell
resistance, resulting in enhancement of stemness features, increased abilities of metabolism, anti-apoptosis,
and DNA repair. Therefore, in order to reduce the resistance caused by treatments, the usage of standard
treatment plus autophagy inhibitors and signaling inhibitors may be a potential strategy for GBM therapy.

DECLARATIONS
Authors’ contributions
Manuscript writing: Chien CH, Hsueh WT, Chuang JY, Chang KY
Supervised the final version: Chang KY

Availability of data and materials
Not applicable.

Financial support and sponsorship
This work was supported by grants from National Health Research Institutes, Taiwan (CA-107-PP-08) and
the Ministry of Science and Technology, Taiwan (MOST 108-2314-B-400-026).

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.

Copyright
© The Author(s) 2019.

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