Phosphorylated Acetyl-CoA Carboxylase Is Associated with Clinical Benefit with Regorafenib in Relapsed Glioblastoma: REGOMA Trial Biomarker Analysis

Stefano Indraccolo, Gian Luca De Salvo, Martina Verza, Mario Caccese, Giovanni Esposito, Ilaria Piga, Paola Del Bianco, Marco Pizzi, Marina Paola Gardiman, Marica Eoli, Roberta Rudà, Alba Ariela Brandes, Toni Ibrahim, Simona Rizzato, Ivan Lolli, Vittorina Zagonel, Giuseppe Lombardi

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)4478-4484
Number of pages7
JournalClin. Cancer Res.
Volume26
Issue number17
DOIs
Publication statusPublished - Sep 1 2020

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