Investigating the effect of SGLT2 inhibitor dapagliflozin on acute lymphoblastic leukemia in obese mice

Patients who are obese at diagnosis of acute lymphoblastic leukemia (ALL) have a 50% higher relapse rate. We showed that diet and exercise can improve ALL treatment outcome in mice and patients, but these interventions can be difficult due to financial and logistical barriers. Alternative interventions that induce weight-loss or metabolic changes could prove more accessible in real-world treatment. The SGLT2 inhibitor dapagliflozin (DAPA) is a diabetes medication that inhibits renal glucose reabsorption, lowers blood glucose, and induces modest weight loss. It has been shown to improve outcomes of heart failure and chronic kidney disease. In mice, SGLT2 inhibitors have been shown to slow tumor growth and synergize with chemotherapy in liver, colon, and breast cancer. However, no studies have tested SGLT2 inhibitors on ALL. We investigated whether SGLT2 inhibition might be an alternative to diet and exercise to improve ALL outcome. Human (BV173, RS4;11) and mouse (8093) ALL cell lines expressed Sglt2 by qPCR (n=4). DAPA showed synergistic effects with chemotherapy vincristine (VCR) in vitro (Table). DAPA treatment (3 mg/kg/day in water, 28 days) in obese male C57Bl/6 mice induced glucose loss in urine (2 g/dL vs. undetectable, n=12) and decreased blood glucose (179±17 vs. 203±14 mg/dL, p=0.008, n=6). As monotherapy, DAPA slowed but did not halt ALL progression in a syngeneic ALL model (median survival: 18 vs. 21 days, p=0.027 log rank, n=6). Surprisingly, combining DAPA with VCR resulted in higher mortality than VCR alone (83 vs. 33% mortality, p=0.047 log rank, n=6). Developing medication-based alternatives to diet/exercise interventions is important to ensure all patients with ALL can benefit from metabolic-interventions. Our study shows that SGLT2 inhibition is effective in vitro, but in vivo data imply it may not be a viable option for improving ALL treatment outcome. Table Cell Line Control (x10 6 ) VCR (2-2.5 nM) DAPA (10 μM) VCR+DAPA P value (VCR vs VCR + DAPA) BV173 1.9 5± 0.45 1.70 ± 0.25 1.73 ±0.38 1.21±0.51 0.037 RS4;11 1.27±0.42 1.15±0.28 1.19±0.33 0.71±0.19 0.035 8093 3.61 ±0.5 8 3. 30± 0.46 2.74 ± 0.48 1.95±0.63 0.048