Double autophagy modulators reduce 2-deoxyglucose uptake in sarcoma patients

Abstract

RationaleAccording 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.MethodsTen 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.ResultsBased 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.ConclusionsThe 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.

Cancer-associated fibroblasts enhance tumor 18F-FDG uptake and contribute to the intratumor heterogeneity of PET-CT

“…Furthermore, Zhang et al found that 18 F-FDG accumulated predominantly in noncancerous stroma in a tumor model under fed status 26 . Moreover, Chi's group found that double autophagy modulator (rapamycin + hydroxychloroquine) treatment only reduced the SUVmax without affecting tumor growth 46 . As CAFs are the major component of the tumor stroma, these findings suggest that non-proliferative glycolytic CAFs increase the local accumulation of 18 F-FDG in tumors, and the SUVmax may be a perfect marker for anti-CAF therapy.…”

Sirolimus and Autophagy Inhibition in Lymphangioleiomyomatosis

“…Multiple clinical trials have evaluated the effectiveness of autophagy inhibition in solid malignancies. [30][31][32][33][34][35][36][37][38] This is the first report, to our knowledge, of autophagy inhibition in lung disease. Our findings could have important application to other lung diseases such as COPD and idiopathic pulmonary fibrosis in which autophagy has been shown to be altered, and modulating autophagy could have therapeutic benefits.…”

Measuring biological aging in humans: A quest

“…Whether rapamycin or rapamycin analogs have potential for improving healthspan and lifespan in humans is unclear, and their potential side effects are of significant concern. Rapamycin analogs that selectively target TORC1, which should have less side effects, have been proposed for treatment of diseases of aging (Arriola Apelo & Lamming, 2016;Bjedov et al, 2010;Chi et al, 2015;El-Chemaly et al, 2017;Miller et al, 2010).…”