Autophagy: Chloroquine combined radiotherapy and temoquine treatment of glioblastoma: Phase IB trial.

Glioblastoma (GBM) is the most common malignant primary brain tumor with an estimated incidence of 4.27/100.000 in Europe.
Although extensive surgery, radiotherapy and TMZ treatment are currently performed on patients, the prognostication is still poor, with a medium total survival period (OS) of approximately 15 months and a five-year OS of 5%-10%.
addition, attempts to improve the prognostics of expected improvements, such as radiation dose escalation, targeted drugs and immunotherapy, did not alter GBM's dismal prognostics.
previous studies have shown that GBM is one of the most heterogeneic tumors in humans, with major intercourse and in-tumor mutations.
molecular biomarkers such as MGMT (O-6-methyl ostrich DNA methyl transferase) initiator methylation, 1p/19q co-missing, and IDH1/2 (ISDP)1/2) mutations can significantly predict patient survival.
addition, the expression of EGFRvIII (the skin growth factor change III) was associated with poor prognosmation, which was observed in tumors with 50 to 60% EGFR gene amplification.
lysosome drug chloroquine (CQ) is a 4-aminoquine commonly used to prevent and treat malaria, rheumatoid arthritis, hepatic amoeba disease, granuloma and lupus erythematosus.
CQ accumulates in lysosomes, which can increase pH in lysosomes and prevent autophagy-lysosome fusion, which is essential for autophagy.
more and more preclinical evidence that hypoxia cells survive on autophagy, and that CQ inhibition of autophagy can enhance radiotherapy and chemotherapy cytotoxicity in GBM.
addition, there is evidence that CQ mediates vascular normalization through NOTCH1 signaling, improving the structure and functional characteristics of blood vessels in tumors, thereby reducing the degree of hypoxia of tumors.
preclinical data available in the united States suggest that glioblastomas expressing EGFRvIII may benefit most from chloroquine due to autophagy dependence.
recently, researchers published the results of a clinical trial in the journal Autophagy, which is the first to explore the safety, pharmacogenetics, and maximum to-to-dosage of chloroquine combined radiotherapy and temoquine in patients with newly diagnosed glioblastoma.
the study was a single-center, open-label, dose-measured Phase I trial.
patients were taken daily oral chloroquine (75 mg/m2/d) from the week before the course of the radiotherapy session until the end of radiotherapy (59.4 Gy/33 minutes).
13 patients were included in the study (n s 6:200 mg, n s 3:300 mg, n s 4:400 mg chloroquine).
the study registered a total of 44 adverse events that may be related to chloroquine, including extended electroeniogram QTc, irreversible blurred vision and nausea/vomiting, resulting in discontinuation of the use of tymoamine or delay of the assisted treatment cycle.
studies have shown that the maximum toned dose of chloroquine is 200 mg.
the total lifetime of the middle is 16 months (range 2-32).
EGFRvIII - The medium survival period was 11.5 months for patients and 20 months for EGFRvIII patients.
, the maximum daily dose of chloroquine for newly diagnosed glioblastoma patients was 200 mg when combined radiotherapy and temocytamine.
to support further clinical studies with beneficial toxicity and promising total lifetimes.
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