A precision medicine approach to metabolic therapy for breast cancer in mice

Abstract

Increasing evidence highlights approaches targeting metabolism as potential adjuvants to cancer therapy. Sodium-glucose transport protein 2 (SGLT2) inhibitors are the newest class of antihyperglycemic drugs. To our knowledge, SGLT2 inhibitors have not been applied in the neoadjuvant setting as a precision medicine approach for this devastating disease. Here, we treat lean breast tumor-bearing mice with the SGLT2 inhibitor dapagliflozin as monotherapy and in combination with paclitaxel chemotherapy. We show that dapagliflozin enhances the efficacy of paclitaxel, reducing tumor glucose uptake and prolonging survival. Further, the ability of dapagliflozin to enhance the efficacy of chemotherapy correlates with its effect to reduce circulating insulin in some but not all breast tumors. Our data suggest a genetic signature for breast tumors more likely to respond to dapagliflozin in combination with paclitaxel. In the current study, tumors driven by mutations upstream of canonical insulin signaling pathways responded to this combined treatment, whereas tumors driven by mutations downstream of canonical insulin signaling did not. These data demonstrate that dapagliflozin enhances the response to chemotherapy in mice with breast cancer and suggest that patients with driver mutations upstream of canonical insulin signaling may be most likely to benefit from this neoadjuvant approach.

Potential Therapies Targeting the Metabolic Reprogramming of Diabetes-Associated Breast Cancer

“…Dapagliflozin is also an effective agent in ameliorating hyperinsulinemia, which causes BC progression in DM patients [ 39 ]. However, the inhibitors’ effect is limited to BC with a specific mutation, namely Pten-driven EMT6 tumors and HRAS-driven Ac711 tumors [ 40 ]. Several clinical trials are ongoing to determine the safety and efficacy of SGLT2 inhibitors when used in combination with other BC chemotherapy ( Table 1 ).…”

Immunometabolism at the crossroads of obesity and cancer—a Keystone Symposia report

“…Dapagliflozin blocks glucose uptake in the renal tubules, allowing it to be excreted in the urine. She showed that in a mouse model of triple‐negative breast cancer, dapagliflozin enhanced the efficacy of chemotherapy specifically in tumors driven by mutations upstream of insulin signaling 92 . Perry's group is designing a clinical trial in obese women with TNBC to see if similar effects are seen in humans.…”

Understanding the Role of Adipocytes and Fibroblasts in Cancer

“…The utilization of antidiabetic treatment presents a potentially valuable approach for the treatment of melanoma, as well as various other types of cancers. [36][37][38][39][40][41][42][43][44][45][46][47]…”

“…The use of antiadipogenic drugs such as metformin and thiazolidinediones (TZD)—peroxisome proliferator–activated receptor γ (PPARγ) agonists—has shown promise in slowing down the spread of a degree of cancers such as melanoma. The utilization of antidiabetic treatment presents a potentially valuable approach for the treatment of melanoma, as well as various other types of cancers 36–47 …”