RESUMEN
BACKGROUND: The cancer stem cell (CSC) hypothesis of tumor genesis suggests that unlike most cancer cells within tumor CSC resist chemotherapy and can regenerate various cell types in tumor thereby causing relapse. Hence drugs that selectively target CSC may offer great promise for cancer therapy especially when combined with chemotherapy. Current treatment options for colorectal cancer (CRC) and other gastrointestinal (GI) tumors rely on combination of surgical resection, cytotoxic and targeted drugs. Recent findings showed that metformin, an ant diabetic drug was associated with a significantly lower risk of CRC (0.63 [0.47 - 0.84]; P = 0.002) in patients with type 2 diabetes. We therefore hypothesize that administration of metformin will reduce CSC. METHODS: Patients with CRC and other GI cancers undergoing resection were enrolled. Metformin was administered at 500 mg orally twice daily for up to 14 days and terminated 24 hours, prior to planned surgery. Both tumor and normal tissue was procured. Adverse events (AEs) were graded according to NCI CTCAE Version 3.0. Primary objective was to establish the safety of administering metformin prior to resection. Secondary objective was to evaluate the effects of metformin on the expression of CSC markers by measuring relative mRNA levels of CD133, OCT4 and NANOG by RT-PCR and immunohistochemistry. RESULTS: A total of 10 patients (4 Male; 6 Female) received metformin. Grade 3 AEs included anemia, hypoalbuminemia, alanine aminotransferase elevation, abdominal pain and nausea but none of these were related to metformin. No hypoglycemia and lactic acidosis were observed. No unexpected post-operative complications were witnessed. Comparison of markers of CCSC results showed that expression of CD133, OCT4 and NANOG expression were decreased following metformin. CONCLUSIONS: Our pilot study showed feasibility of metformin before surgery in GI cancers and indicated impact on CSC. This preliminary data warrants further investigation in a larger randomized placebo-control study to assess these markers and their correlation with survival.
RESUMEN
PURPOSE: Metformin activates AMP-related pathways leading to inactivation of mammalian target of rapamycin (mTOR) and suppression of its downstream effectors, crucial for cancer growth. Epidemiologic studies showed a reduced incidence and improved survival in cancer patients. We conducted a prospective phase I study to assess the safety of metformin in combination with chemotherapy in patients with solid tumors. METHODS: We conducted a delayed-start randomized trial of non-diabetic patients in two stages. In Stage 1, we randomized patients to two arms: concurrent arm (metformin with chemo) vs. delayed arm (chemo alone). In Stage 2, patients in delayed arm were crossed over to receive metformin. Patients received metformin 500 mg twice daily with chemotherapy to define dose-limiting toxicities (DLTs) in both stages. Secondary endpoints assessed adverse events (AEs) and response rates. Translational correlates included effects of metformin on expression and phosphorylation of 5' adenosine monophosphate-activated protein kinase (AMPK) by western blot in PBMCs. RESULTS: A total of 100 patients were enrolled (51 in delayed arm vs. 49 concurrent arm). Rate of DLTs in patients receiving metformin with chemotherapy was 6.1% vs. 7.8% in patients receiving chemotherapy alone. DLTs seen with addition of metformin included those associated with established chemo adverse events. No lactic acidosis or hypoglycemia occurred. Restaging showed stable disease in 46% at cessation of metformin. 28% of patients with measurable tumor markers showed improvement. AMPK phosphorylation showed a four- to sixfold increase in AMPK phosphorylation after metformin. CONCLUSIONS: This is the largest phase I study of metformin combined with chemotherapy, which suggests that metformin can be given safely with chemotherapy, and offers a platform for future studies. Post-metformin increase in AMPK phosphorylation may potentially explain lack of disease progression in nearly half of our patients. FUNDING: UL1 TR001064. CLINICAL TRIAL INFORMATION: NCT01442870.