TY - JOUR
T1 - Phosphorylated Acetyl-CoA Carboxylase Is Associated with Clinical Benefit with Regorafenib in Relapsed Glioblastoma: REGOMA Trial Biomarker Analysis
AU - Indraccolo, Stefano
AU - De Salvo, Gian Luca
AU - Verza, Martina
AU - Caccese, Mario
AU - Esposito, Giovanni
AU - Piga, Ilaria
AU - Del Bianco, Paola
AU - Pizzi, Marco
AU - Gardiman, Marina Paola
AU - Eoli, Marica
AU - Rudà, Roberta
AU - Brandes, Alba Ariela
AU - Ibrahim, Toni
AU - Rizzato, Simona
AU - Lolli, Ivan
AU - Zagonel, Vittorina
AU - Lombardi, Giuseppe
N1 - ©2020 American Association for Cancer Research.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - PURPOSE: Preclinical studies show that antiangiogenic therapy exacerbates tumor glycolysis and activates liver kinase B1/AMP kinase (AMPK), a pathway involved in the regulation of tumor metabolism. We investigated whether certain metabolism-related in situ biomarkers could predict benefit to regorafenib in the phase II randomized REGOMA trial.PATIENTS AND METHODS: IHC and digital pathology analysis were used to investigate the expression in glioblastoma (GBM) sections of monocarboxylate transporter 1 and 4 (MCT1 and MCT4), associated with OXPHOS and glycolysis, respectively, phosphorylated AMPK (pAMPK), and phosphorylated acetyl-CoA carboxylase (pACC), a canonical target of AMPK activity. The status of each biomarker was associated with clinical endpoints, including overall survival (OS) and progression-free survival (PFS) in patients with relapsed GBM treated either with regorafenib or lomustine.RESULTS: Between November 2015 and February 2017, 119 patients were enrolled (n = 59 regorafenib and n = 60 lomustine) and stratified for surgery at recurrence, and baseline characteristics were balanced. Biomarker analysis was performed in 84 patients (71%), including 42 patients of the regorafenib arm and 42 patients of the lomustine arm. Among all markers analyzed, only pACC showed predictive value in terms of OS. In fact, median OS was 9.3 months [95% confidence interval (CI), 5.6-13.2] for regorafenib and 5.5 months (95% CI, 4.2-6.6) for lomustine for pACC-positive patients, HR, 0.37 (95% CI, 0.20-0.70); log rank P = 0.0013; test for interaction = 0.0453. No statistically significant difference was demonstrated for PFS according to pACC status.CONCLUSIONS: We found that AMPK pathway activation is associated with clinical benefit from treatment with regorafenib in relapsed GBM.
AB - PURPOSE: Preclinical studies show that antiangiogenic therapy exacerbates tumor glycolysis and activates liver kinase B1/AMP kinase (AMPK), a pathway involved in the regulation of tumor metabolism. We investigated whether certain metabolism-related in situ biomarkers could predict benefit to regorafenib in the phase II randomized REGOMA trial.PATIENTS AND METHODS: IHC and digital pathology analysis were used to investigate the expression in glioblastoma (GBM) sections of monocarboxylate transporter 1 and 4 (MCT1 and MCT4), associated with OXPHOS and glycolysis, respectively, phosphorylated AMPK (pAMPK), and phosphorylated acetyl-CoA carboxylase (pACC), a canonical target of AMPK activity. The status of each biomarker was associated with clinical endpoints, including overall survival (OS) and progression-free survival (PFS) in patients with relapsed GBM treated either with regorafenib or lomustine.RESULTS: Between November 2015 and February 2017, 119 patients were enrolled (n = 59 regorafenib and n = 60 lomustine) and stratified for surgery at recurrence, and baseline characteristics were balanced. Biomarker analysis was performed in 84 patients (71%), including 42 patients of the regorafenib arm and 42 patients of the lomustine arm. Among all markers analyzed, only pACC showed predictive value in terms of OS. In fact, median OS was 9.3 months [95% confidence interval (CI), 5.6-13.2] for regorafenib and 5.5 months (95% CI, 4.2-6.6) for lomustine for pACC-positive patients, HR, 0.37 (95% CI, 0.20-0.70); log rank P = 0.0013; test for interaction = 0.0453. No statistically significant difference was demonstrated for PFS according to pACC status.CONCLUSIONS: We found that AMPK pathway activation is associated with clinical benefit from treatment with regorafenib in relapsed GBM.
U2 - 10.1158/1078-0432.CCR-19-4055
DO - 10.1158/1078-0432.CCR-19-4055
M3 - Article
VL - 26
SP - 4478
EP - 4484
JO - Clin. Cancer Res.
JF - Clin. Cancer Res.
SN - 1078-0432
IS - 17
ER -