Double autophagy modulators reduce 2-deoxyglucose uptake in sarcoma patients
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Mau-Shin Chi1,3, Cheng-Yen Lee1, Su-Chen Huang1, Kai-Lin Yang1, Hui-Ling Ko1, Yen-Kung Chen2, Chen-Han Chung3, Kuang-Wen Liao3, Kwan-Hwa Chi1,4
1Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
2Department of Nuclear Medicine and PET Center, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
3Institue of Molecular Medicine and Bioengineering, National Chiao-Tung University, Hsinchu, Taiwan
4School of Medicine and Institute of Biomedical Imaging and Radiological Sciences, National Yang-Ming University, Taipei, Taiwan
Kwan-Hwa Chi, e-mail: M006565@ms.skh.org.tw
Keywords: hydroxychloroquine, sirolimus, soft tissue sarcoma
Received: April 21, 2015 Accepted: August 26, 2015 Published: September 07, 2015
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.
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