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Published on: July 21, 2018
A precision medicine approach to metabolic therapy for breast cancer in mice
Ngozi D Akingbesote1,2, Aaron Norman1,2, Wanling Zhu1,2
1Department of Celullar and Molecular Physiology, Yale University School of Medicine, New Haven, CT, USA.
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.
Insights
Sodium-glucose transport protein 2 (SGLT2) inhibitors like dapagliflozin enhance paclitaxel chemotherapy for breast cancer. This metabolic approach shows promise for patients with specific genetic mutations, improving survival rates.
Area of Science:
- Oncology
- Metabolic pathways
- Pharmacology
Background:
- Metabolic targeting is a promising adjuvant strategy for cancer therapy.
- Sodium-glucose transport protein 2 (SGLT2) inhibitors are a novel class of antihyperglycemic agents.
- The neoadjuvant application of SGLT2 inhibitors in precision cancer medicine remains unexplored.
Purpose of the Study:
- To investigate the efficacy of the SGLT2 inhibitor dapagliflozin as a neoadjuvant therapy for breast cancer, both as monotherapy and in combination with paclitaxel.
- To identify predictive biomarkers for response to SGLT2 inhibitor-based neoadjuvant therapy.
Main Methods:
- Lean breast tumor-bearing mice were treated with dapagliflozin monotherapy and in combination with paclitaxel.
- Tumor glucose uptake, survival rates, and circulating insulin levels were assessed.
- Genetic analysis was performed to identify response signatures.
Main Results:
- Dapagliflozin significantly enhanced the efficacy of paclitaxel chemotherapy, reducing tumor glucose uptake and prolonging survival.
- The therapeutic enhancement correlated with reduced circulating insulin in a subset of tumors.
- Tumors with driver mutations upstream of canonical insulin signaling pathways showed a positive response, unlike those with downstream mutations.
Conclusions:
- Dapagliflozin demonstrates potential as an effective neoadjuvant therapy to enhance chemotherapy response in breast cancer.
- A genetic signature, specifically mutations upstream of insulin signaling, may predict patient response to this combined neoadjuvant approach.
