Editors' ChoiceCancer

B cell lymphoma R-CHOPped by metabolic inhibitors

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Science Translational Medicine  27 Mar 2019:
Vol. 11, Issue 485, eaax3456
DOI: 10.1126/scitranslmed.aax3456

Abstract

Some patients with diffuse large B cell lymphoma are resistant to conventional combination therapy but respond to metabolic inhibitors.

Diffuse large B cell lymphoma (DLBCL) is an aggressive and heterogeneous disease affecting B cells in the lymphatic system. Combination chemotherapy involving cyclophosphamide, doxorubicin, vincristine, and prednisone plus anti-CD20 immunotherapy (called R-CHOP) is a conventional treatment for DLBCL. Yet, ~40% of the patients respond poorly to the regimen. A recent study reports that tumors from DLBCL patients refractory to R-CHOP have distinct metabolic features targetable by metabolic inhibitors.

To identify a potential biomarker in this subset of patients, Chiche et al. analyzed gene microarray data from DLBCL patients receiving R-CHOP. Low expression of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was associated with poor survival outcomes in patients. GAPDH is an enzyme involved in glucose metabolism, and the investigators reported that low GAPDH–expressing (GAPDHlow) tumors were less reliant on glycolysis but had increased mitochondrial metabolism. The authors also observed that GAPDHlow tumors exhibited active mTOR signaling, whereas suppressing mTOR signaling decreased mitochondrial respiration. Interestingly, metabolomic analysis demonstrated that GAPDHlow tumors increased glutamine metabolism (which is also regulated by mTOR signaling) to compensate for impaired glycolysis. In GAPDHlow lymphoma–bearing mice, inhibiting mitochondrial respiration, mTOR signaling, or glutamine availability prolonged the animals’ survival.

Based on the preclinical studies, inhibiting metabolism could provide an alternative therapeutic approach to improve the outcomes of DLBCL patients refractory to R-CHOP. This was tested in a clinical trial via combination therapy involving Kidrolase (an l -asparaginase), the mitochondrial respiration inhibitor metformin, and temsirolimus, referred to as KMT. In the trial, fourpatients were selected for KMT on the basis of biopsies showing GAPDHlow tumors and having exhausted all other treatment options. Tumor regression was reported in three out of four patients during the first two weeks of KMT treatment, whereas one patient experienced side effects in which treatment had to be discontinued. All of the patients relapsed after longer treatment, with a median response duration of six months.

Future work should improve on the safety profile of this combination therapy and expand to studies with larger cohorts or with earlier diagnosed disease. This study suggests that GAPDH may be a biomarker for DLBCL and could help inform treatment options for patients, especially for those who respond poorly to conventional chemotherapy. Combinations of metabolic inhibitors may also offer a treatment strategy for other highly metabolically active cancers.

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