Double autophagy modulators reduce 2-deoxyglucose uptake in sarcoma patients

Mau-Shin Chi, Cheng-Yen Lee, Su-Chen Huang, Kai-Lin Yang, Hui-Ling Ko, Yen-Kung Chen, Chen-Han Chung, Kuang-Wen Liao, Kwan-Hwa Chi, Mau-Shin Chi, Cheng-Yen Lee, Su-Chen Huang, Kai-Lin Yang, Hui-Ling Ko, Yen-Kung Chen, Chen-Han Chung, Kuang-Wen Liao, Kwan-Hwa Chi

Abstract

Rationale: According to the metabolic symbiosis model, cancer stromal fibroblasts could be hijacked by surrounding cancer cells into a state of autophagy with aerobic glycolysis to help provide recycled nutrients. The purpose of this study was to investigate whether combined treatment with the autophagy inhibitor: hydroxychloroquine (HCQ) and the autophagy inducer: sirolimus (rapamycin, Rapa) would reduce glucose utilization in sarcoma patients.

Methods: Ten sarcoma patients who failed first-line treatment were enrolled in this study. They were treated with 1 mg of Rapa and 200 mg of HCQ twice daily for two weeks. The standardized uptake values (SUV) from pretreatment and posttreatment [18F]-fluorodeoxyglucose positron emission tomography (FDG PET) scans were reviewed, and changes from the baseline SUVmax were evaluated.

Results: Based on FDG PET response criteria, six patients had a partial response; three had stable disease, and one had progressive disease. Nevertheless, none of them showed a reduction in tumor volume. The mean SUVmax reduction in the 34 lesions evaluated was - 19.6% (95% CI = -30.1% to -9.1%), while the mean volume change was +16.4% (95% CI = +5.8% to + 27%). Only grade 1 toxicities were observed. Elevated serum levels of lactate dehydrogenase were detected after treatment in most metabolic responders.

Conclusions: The results of reduced SUVmax without tumor volume reduction after two weeks of Rapa and HCQ treatment may indicate that non-proliferative glycolysis occurred mainly in the cancer associated fibroblast compartment, and decreased glycolytic activity was evident from Rapa + HCQ double autophagy modulator treatment.

Trial registration: ClinicalTrials.gov NCT01842594.

Keywords: hydroxychloroquine; sirolimus; soft tissue sarcoma.

Figures

Figure 1. A waterfall plot of posttreatment…
Figure 1. A waterfall plot of posttreatment changes in SUVmax from baseline for thirty-four evaluable lesions
Figure 2. Maximum post treatment SUVmax versus…
Figure 2. Maximum post treatment SUVmax versus tumor volume changes from baseline for each enrolled patient
(■ indicates SUVmax change, □ indicates tumor volume change).
Figure 3. Calibration plots of fasting plasma…
Figure 3. Calibration plots of fasting plasma glucose A. lactate dehydrogenase B. total cholesterol C. and triglyceride D. levels before and after two weeks of hydroxychloroquine and sirolimus treatment
Figure 4. Correlation between SUVmax and lactate…
Figure 4. Correlation between SUVmax and lactate dehydrogenase level changes after two weeks of hydroxychloroquine and sirolimus treatment
Figure 5. Synergistic effect of Rapa and…
Figure 5. Synergistic effect of Rapa and HCQ combination
CAF cells are glycolytic-dependent cells. The combined use of Rapa and HCQ has synergistic effect on reducing glucose consumption rate.
Figure 6. Model of uncoupling energy transfer…
Figure 6. Model of uncoupling energy transfer within sarcoma tumor
Rapa and HCQ combination will inhibit the aerobic glycolysis and reduce the energy transfer from CAFs to OXPHOS sarcoma cells and glycolytic sarcoma cells. The decreased lactate supply has little effect on OXPHOS sarcoma cells due to their independent energy sources, their mitochondria.

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Source: PubMed

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