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.

Novel application of metformin combined with targeted drugs on anticancer treatment

“…Cancer is a disease with a growing mortality worldwide, with an increase to 19.3 million new cancer cases per year predicted in 2025. 63 Targeted therapies have achieved notable success in some cancers; however, significant problems including resistance and high toxicity remain to be solved. To address these limits, combining targeted drugs with known drugs has drawn considerable attention.…”

“…Currently, bevacizumab is widely used to treat various cancers, including advanced nonsquamous NSCLC, metastatic breast cancer, advanced renal cell carcinoma, and advanced epithelial ovarian cancer . A case report showed that bevacizumab combined with metformin in recurrent type I endometrial cancer improved patient performance status: computed tomography scans showed reduced radiologic density of the lung and mediastinal lesions of liver disease, suggesting increased tumor necrosis . Moreover, combining bevacizumab with metformin was also found to be effective in ovarian cancer treatment, Metformin could specifically target cancer stem cells and synergistically inhibits angiogenesis with bevacizumab …”

“…62 A case report showed that bevacizumab combined with metformin in recurrent type I endometrial cancer improved patient performance status: computed tomography scans showed reduced radiologic density of the lung and mediastinal lesions of liver disease, suggesting increased tumor necrosis. 63 Moreover, combining bevacizumab with metformin was also found to be effective in ovarian cancer treatment, Metformin could specifically target cancer stem cells and synergistically inhibits angiogenesis with bevacizumab. 64 A randomized phase II study of metformin plus bevacizumabbased chemotherapy in advanced or metastatic nonsquamous NSCLC patients has been carried out.…”

Efficacy of metformin for advanced-stage endometrial cancer: A case report

“…Despite these limitations, this clinical case suggests that metformin is potentially beneficial in the prevention or treatment of EC. This finding deserves further validation in clinical studies (14)(15)(16). …”

LKB1/AMPK Pathway and Drug Response in Cancer: A Therapeutic Perspective

“…Thus, sequential or simultaneous combination of antiangiogenic drugs and metformin might represent a new treatment opportunity for LKB1-deficient tumors. Although clinical and preclinical data are fragmentary, a case of a terminally ill patient with advanced endometrial cancer, showing radiological response to simultaneous administration of metformin and bevacizumab, was described by our group [75]. Interestingly, the high expression of MCT4—a marker of enhanced glycolysis—and loss of LKB1 expression were detected in the patient's liver metastasis sample.…”