title: Metformin: a modulator of bevacizumab activity in cancer? A case report.
abstract: Recurrent type I endometrial cancer (EC) has poor prognosis and demands novel therapeutic approaches. Bevacizumab, a VEGF-A neutralizing monoclonal antibody, has shown clinical activity in this setting. To our knowledge, however, although some diabetic cancer patients treated with bevacizumab may also take metformin, whether metformin modulates response to anti-VEGF therapy has not yet been investigated. Here, we report the case of a patient with advanced EC treated, among other drugs, with bevacizumab in combination with metformin. The patient affected by relapsed EC G3 type 1, presented in march 2010 with liver, lungs and mediastinic metastases. After six cycles of paclitaxel and cisplatin she underwent partial response. Later on, she had disease progression notwithstanding administration of multiple lines of chemotherapy. In march 2013, due to brain metastases with coma, she began steroid therapy with development of secondary diabetes. At this time, administration of Bevacizumab plus Metformin improved her performance status. CT scans performed in this time window showed reduced radiologic density of the lung and mediastinic lesions and of liver disease, suggestive of increased tumor necrosis. Strong (18)F-FDG uptake by PET imaging along with high levels of monocarboxylate transporter 4 and lack of liver kinase B1 expression in liver metastasis, highlighted metabolic features previously associated with response to anti-VEGF therapy and phenformin in preclinical models. However, clinical benefit was transitory and was followed by rapid and fatal disease progression. These findings--albeit limited to a single case--suggest that tumors lacking LKB1 expression and/or endowed with an highly glycolytic phenotype might develop large necrotic areas following combined treatment with metformin plus bevacizumab. As metformin is widely used among diabetes patients as well as in ongoing clinical trials in cancer patients, these results deserve further clinical investigation.
authors.affiliation: a Immunology and Molecular Oncology Unit ; Istituto Oncologico Veneto-IOV-IRCCS ; Padova , Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Indraccolo
authors.forename: Giovanni
authors.initials: G
authors.lastname: Randon
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Zulato
authors.forename: Margherita
authors.initials: M
authors.lastname: Nardin
authors.forename: Camillo
authors.initials: C
authors.lastname: Aliberti
authors.forename: Fabio
authors.initials: F
authors.lastname: Pomerri
authors.forename: Alessandra
authors.initials: A
authors.lastname: Casarin
authors.forename: Maria Ornella
authors.initials: MO
authors.lastname: Nicoletto
mesh_terms: D020533:Angiogenesis Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D000068258:Bevacizumab / Q000008:administration & dosage / Q000627:therapeutic use; D004357:Drug Synergism; D016889:Endometrial Neoplasms / Q000175:diagnosis / Q000188:drug therapy*; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000556:secondary; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008687:Metformin / Q000008:administration & dosage / Q000627:therapeutic use*; D008875:Middle Aged; D009367:Neoplasm Staging; D049268:Positron-Emission Tomography; D014057:Tomography, X-Ray Computed
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D000068258:Bevacizumab; D008687:Metformin
keywords: AMPK, AMP-activated protein kinase; CT, computed tomography; EC, endometrial cancer; LKB1; LKB1, liver kinase B1; MCT4; MCT4, monocarboxylate transporter 4; OS, overall survival; PFS, progression free survival; TACE, trans-catheter arterial chemoembolization; VEGF; VEGF-A, vascular endothelial growth factor A; antiangiogenic therapy; bevacizumab; endometrial cancer; glycolysis; metformin