Double autophagy modulators reduce 2-deoxyglucose uptake in sarcoma patients

Area of Science:

• Oncology
• Cancer Metabolism
• Fibroblast Biology

Background:

• Cancer cells can co-opt stromal fibroblasts to support their metabolic needs through autophagy and aerobic glycolysis.
• The metabolic symbiosis model highlights nutrient recycling between cancer cells and fibroblasts.

Purpose of the Study:

• To evaluate the efficacy of combined hydroxychloroquine (HCQ) and sirolimus (Rapa) in reducing glucose utilization in sarcoma patients.
• To investigate the role of autophagy modulation in sarcoma metabolic activity.

Main Methods:

• Ten sarcoma patients received a two-week course of Rapa (1 mg) and HCQ (200 mg) twice daily.
• Changes in standardized uptake values (SUVmax) from [18F]-fluorodeoxyglucose positron emission tomography (FDG PET) scans were analyzed pre- and post-treatment.

Main Results:

• Six patients showed a partial response, and three had stable disease based on FDG PET criteria.
• A mean SUVmax reduction of -19.6% was observed, but tumor volume increased by a mean of +16.4%.
• Grade 1 toxicities were the only adverse events reported; elevated lactate dehydrogenase was noted in metabolic responders.

Conclusions:

• Reduced SUVmax without tumor shrinkage suggests glycolysis primarily occurs in cancer-associated fibroblasts.
• The combination of Rapa and HCQ effectively decreased glycolytic activity, indicating a potential therapeutic strategy targeting tumor-stroma interactions.