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GAPDH Expression Predicts the Response to R-CHOP, the Tumor Metabolic Status, and the Response of DLBCL Patients to

Johanna Chiche1, Julie Reverso-Meinietti2, Annabelle Mouchotte1

  • 1Université Côte d'Azur, INSERM, C3M, Nice, France.

Cell Metabolism
|March 5, 2019
PubMed

Insights

Low GAPDH levels in diffuse large B cell lymphoma (DLBCL) predict poor response to R-CHOP therapy. Targeting metabolic pathways like OxPhos and glutaminolysis with drugs like metformin and L-asparaginase shows promise for treating these resistant lymphomas.

Area of Science:

  • Oncology
  • Cell Metabolism
  • Immunotherapy

Background:

  • Diffuse large B cell lymphoma (DLBCL) is a heterogeneous cancer.
  • Current standard treatment involves anti-CD20 immuno-chemotherapy (R-CHOP).
  • Patient response to R-CHOP varies significantly, necessitating predictive biomarkers and alternative therapies.

Purpose of the Study:

  • To identify biomarkers predicting R-CHOP response in DLBCL.
  • To investigate the metabolic vulnerabilities of R-CHOP-resistant DLBCL.
  • To evaluate novel metabolic-targeting therapies for DLBCL.

Main Methods:

  • Analysis of GAPDH expression in DLBCL patient samples.
  • Assessment of OxPhos metabolism, mTORC1 signaling, and glutaminolysis in GAPDH-low vs. GAPDH-high DLBCL cells.
  • In vivo studies using phenformin or L-asparaginase in DLBCL mouse models.
  • Clinical trial of a combination metabolic therapy (KTM) in R-CHOP-refractory DLBCL patients.

Main Results:

  • Low GAPDH expression (GAPDHlow) identifies DLBCL patients with poor R-CHOP response.
  • GAPDHlow DLBCL exhibits reliance on OxPhos metabolism, mTORC1 signaling, and glutaminolysis.
  • Metabolic inhibitors (phenformin, L-asparaginase) showed efficacy against GAPDHlow DLBCL in vitro and in vivo.
  • Three of four R-CHOP-refractory DLBCL patients achieved complete response after one cycle of KTM therapy.

Conclusions:

  • GAPDH expression level is a predictive biomarker for R-CHOP treatment response in DLBCL.
  • GAPDHlow DLBCL is metabolically distinct and sensitive to specific metabolic inhibitors.
  • Combination metabolic therapy (KTM) demonstrates significant clinical activity in refractory DLBCL.
Keywords:
DLBCLGAPDHL-asparaginaseOxPhosR-CHOPglycolysismTORpredictive marker

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