Repurposing Atovaquone as a Therapeutic against Acute Myeloid Leukemia (AML): Combination with Conventional Chemotherapy Is Feasible and Well Tolerated

Abstract

Survival of pediatric AML remains poor despite maximized myelosuppressive therapy. The pneumocystis jiroveci pneumonia (PJP)-treating medication atovaquone (AQ) suppresses oxidative phosphorylation (OXPHOS) and reduces AML burden in patient-derived xenograft (PDX) mouse models, making it an ideal concomitant AML therapy. Poor palatability and limited product formulations have historically limited routine use of AQ in pediatric AML patients. Patients with de novo AML were enrolled at two hospitals. Daily AQ at established PJP dosing was combined with standard AML therapy, based on the Medical Research Council backbone. AQ compliance, adverse events (AEs), ease of administration score (scale: 1 (very difficult)-5 (very easy)) and blood/marrow pharmacokinetics (PK) were collected during Induction 1. Correlative studies assessed AQ-induced apoptosis and effects on OXPHOS. PDX models were treated with AQ. A total of 26 patients enrolled (ages 7.2 months–19.7 years, median 12 years); 24 were evaluable. A total of 14 (58%) and 19 (79%) evaluable patients achieved plasma concentrations above the known anti-leukemia concentration (>10 µM) by day 11 and at the end of Induction, respectively. Seven (29%) patients achieved adequate concentrations for PJP prophylaxis (>40 µM). Mean ease of administration score was 3.8. Correlative studies with AQ in patient samples demonstrated robust apoptosis, OXPHOS suppression, and prolonged survival in PDX models. Combining AQ with chemotherapy for AML appears feasible and safe in pediatric patients during Induction 1 and shows single-agent anti-leukemic effects in PDX models. AQ appears to be an ideal concomitant AML therapeutic but may require intra-patient dose adjustment to achieve concentrations sufficient for PJP prophylaxis.

DPEP Inhibits Cancer Cell Glucose Uptake, Glycolysis and Survival by Upregulating Tumor Suppressor TXNIP

“…Because Dpep suppresses glucose uptake and glycolysis, we reasoned that it might combine effectively in a complementary fashion with drugs described to interfere with oxidative phosphorylation. We therefore tested its suppression of cancer cell growth/survival in combination with metformin and atovaquone, two clinically employed drugs with favorable safety profiles that have been shown to interfere with oxidative metabolism in multiple cancers and to suppress tumor growth both in vivo and in vitro [ 45 , 46 , 47 , 48 , 49 , 50 , 51 ]. To do so, we employed fixed concentrations of Dpep (10 and 20 µM) and various concentrations of metformin or atovaquone.…”

Oncogenic STAT Transcription Factors as Targets for Cancer Therapy: Innovative Strategies and Clinical Translation

“…From the pharmacokinetic data available, it is clear that levels of atovaquone sufficient to suppress STAT3 phosphorylation were readily and safely achieved in patients [206,225]. In fact, serum from patients taking atovaquone can be shown to have anti-leukemic effects compared to serum from patients taking other drugs for prophylaxis of Pneumocystis pneumonia [226]. Retrospective data also provided evidence that after allogeneic hematopoietic stem cell transplantation for AML, patients receiving more atovaquone were less likely to experience disease relapse.…”

DPEP Inhibits Cancer Cell Glucose Uptake, Glycolysis and Survival by Upregulating Tumor Suppressor TXNIP

“…Because Dpep suppresses glucose uptake and glycolysis, we reasoned that it might combine effectively in a complementary fashion with drugs described to interfere with oxidative phosphorylation. We therefore tested its suppression of cancer cell growth/survival in combination with metformin and atovaquone, two clinicallyemployed drugs with favorable safety profiles that have been shown to interfere with oxidative metabolism in multiple cancers and to suppress tumor growth both in vivo and in vitro [45][46][47][48][49][50][51]. To do so, we employed fixed concentrations of Dpep (10 and 20 µM) and various concentrations of metformin or atovaquone.…”