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Phosphorylated Acetyl-CoA Carboxylase Is Associated with Clinical Benefit with Regorafenib in Relapsed Glioblastoma: REGOMA Trial Biomarker Analysis.
Indraccolo, Stefano; De Salvo, Gian Luca; Verza, Martina; Caccese, Mario; Esposito, Giovanni; Piga, Ilaria; Del Bianco, Paola; Pizzi, Marco; Gardiman, Marina Paola; Eoli, Marica; Rudà, Roberta; Brandes, Alba Ariela; Ibrahim, Toni; Rizzato, Simona; Lolli, Ivan; Zagonel, Vittorina; Lombardi, Giuseppe.
Afiliación
  • Indraccolo S; Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy. stefano.indraccolo@unipd.it.
  • De Salvo GL; Clinical Research Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
  • Verza M; Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
  • Caccese M; Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
  • Esposito G; Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
  • Piga I; Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
  • Del Bianco P; Clinical Research Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
  • Pizzi M; Surgical Pathology and Cytopathology Unit, Department of Medicine-DIMED, University of Padova, Padova, Italy.
  • Gardiman MP; Surgical Pathology and Cytopathology Unit, University Hospital of Padua, Padua, Italy.
  • Eoli M; Molecular Neuro-Oncology Unit, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy.
  • Rudà R; Department of Neuro-Oncology, University of Turin and City of Health and Science Hospital, Turin, Italy.
  • Brandes AA; Department of Medical Oncology, AUSL-IRCCS Scienze Neurologiche, Bologna, Italy.
  • Ibrahim T; Osteoncology and Rare Tumors Center- Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.
  • Rizzato S; Department of Oncology, Azienda Sanitaria Universitaria Friuli Centrale, Udine, Italy.
  • Lolli I; Medical Oncology Unit-IRCCS Saverio de Bellis, Castellana Grotte, Bari, Italy.
  • Zagonel V; Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
  • Lombardi G; Medical Oncology 1, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
Clin Cancer Res ; 26(17): 4478-4484, 2020 09 01.
Article en En | MEDLINE | ID: mdl-32518098
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.
Asunto(s)

Texto completo: 1 Colección: 01-internacional Asunto principal: Compuestos de Fenilurea / Acetil-CoA Carboxilasa / Piridinas / Neoplasias Encefálicas / Biomarcadores de Tumor / Glioblastoma / Recurrencia Local de Neoplasia Tipo de estudio: Clinical_trials / Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Female / Humans / Male / Middle aged Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2020 Tipo del documento: Article País de afiliación: Italia

Texto completo: 1 Colección: 01-internacional Asunto principal: Compuestos de Fenilurea / Acetil-CoA Carboxilasa / Piridinas / Neoplasias Encefálicas / Biomarcadores de Tumor / Glioblastoma / Recurrencia Local de Neoplasia Tipo de estudio: Clinical_trials / Etiology_studies / Prognostic_studies / Risk_factors_studies Límite: Female / Humans / Male / Middle aged Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2020 Tipo del documento: Article País de afiliación: Italia