metformin + chloroquine

The combination of metformin and chloroquine has been investigated as a potential treatment for IDH1/2-mutated solid tumors. This drug combination leverages the metabolic vulnerabilities of these cancer types by targeting different aspects of cellular metabolism. ## Pharmacological Properties Metformin is an antidiabetic medication that inhibits complex I of the electron transport chain (ETC), while chloroquine is an antimalarial drug that inhibits autophagy. When combined, these medications are hypothesized to increase metabolic stress in IDH1/2-mutated cancers[2][4]. The maximum tolerated dose (MTD) determined in clinical trials was 1500 mg of metformin twice daily and 200 mg of chloroquine once daily[1][3]. This combination was found to be well-tolerated in patients with no dose-limiting toxicities reported in the Phase Ib clinical trial[1]. ## Clinical Development A Phase Ib clinical trial was conducted in patients with IDH1-mutated chondrosarcoma, glioma, and intrahepatic cholangiocarcinoma. The study enrolled 17 patients who received the combination therapy for a median duration of 43 days[1][3]. Despite the good tolerability profile, the combination did not induce clinical responses in this patient population[1][3]. The trial also investigated biomarkers, finding that a serum D/L-2HG ratio of ≥4.5 predicted the presence of an IDH1 mutation with high sensitivity (90%) and specificity (100%)[1]. ## Mechanism of Action The rationale for this combination is based on the unique metabolic characteristics of IDH1/2-mutated tumors: 1. Metformin targets the electron transport chain, which IDH1-mutated cancer cells are particularly dependent on for energy production[3][4]. 2. Chloroquine inhibits autophagy, which is a crucial energy production mechanism that allows cancer stem cells to survive in hypoxic and nutrient-deprived microenvironments[2][4]. Together, these mechanisms were expected to create synergistic metabolic stress in cancer cells, particularly targeting cancer stem cells[2]. ## Safety Considerations A recent study in mice has raised concerns about the safety of combining metformin with chloroquine or hydroxychloroquine, suggesting an increased risk of death when these medications are used together[5]. This finding highlights the importance of careful monitoring in clinical settings where this combination might be used. A combination therapy consisting of metformin, an antidiabetic drug that inhibits complex I of the electron transport chain, and chloroquine, an antimalarial drug that inhibits autophagy. This combination was developed to target the metabolic vulnerabilities of IDH1/2-mutated solid tumors by increasing metabolic stress in cancer cells, particularly cancer stem cells.

Other names

Metformin and chloroquine combination