Repurposing Atovaquone as a Therapeutic against Acute Myeloid Leukemia (AML): Combination with Conventional Chemotherapy Is Feasible and Well Tolerated
Survival of pediatric AML remains poor despite maximized myelosuppressive therapy. The <i>pneumocystis jiroveci pneumonia</i> (PJP)-treating medication atovaquone (AQ) suppresses oxidative phosphorylation (OXPHOS) and reduces AML burden in patient-derived xenograft (PDX) mouse models, ma...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2023-02-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/15/4/1344 |
| _version_ | 1797621840759226368 |
|---|---|
| author | Alexandra McLean Stevens Eric S. Schafer Minhua Li Maci Terrell Raushan Rashid Hana Paek Melanie B. Bernhardt Allison Weisnicht Wesley T. Smith Noah J. Keogh Michelle C. Alozie Hailey H. Oviedo Alan K. Gonzalez Tamilini Ilangovan Alicia Mangubat-Medina Haopei Wang Eunji Jo Cara A. Rabik Claire Bocchini Susan Hilsenbeck Zachary T. Ball Todd M. Cooper Michele S. Redell |
| author_facet | Alexandra McLean Stevens Eric S. Schafer Minhua Li Maci Terrell Raushan Rashid Hana Paek Melanie B. Bernhardt Allison Weisnicht Wesley T. Smith Noah J. Keogh Michelle C. Alozie Hailey H. Oviedo Alan K. Gonzalez Tamilini Ilangovan Alicia Mangubat-Medina Haopei Wang Eunji Jo Cara A. Rabik Claire Bocchini Susan Hilsenbeck Zachary T. Ball Todd M. Cooper Michele S. Redell |
| author_sort | Alexandra McLean Stevens |
| collection | DOAJ |
| description | Survival of pediatric AML remains poor despite maximized myelosuppressive therapy. The <i>pneumocystis jiroveci pneumonia</i> (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. |
| first_indexed | 2024-03-11T09:01:42Z |
| format | Article |
| id | doaj.art-2fa86c3a004b4e09b54a5c761db0cfc8 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-11T09:01:42Z |
| publishDate | 2023-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-2fa86c3a004b4e09b54a5c761db0cfc82023-11-16T19:39:41ZengMDPI AGCancers2072-66942023-02-01154134410.3390/cancers15041344Repurposing Atovaquone as a Therapeutic against Acute Myeloid Leukemia (AML): Combination with Conventional Chemotherapy Is Feasible and Well ToleratedAlexandra McLean Stevens0Eric S. Schafer1Minhua Li2Maci Terrell3Raushan Rashid4Hana Paek5Melanie B. Bernhardt6Allison Weisnicht7Wesley T. Smith8Noah J. Keogh9Michelle C. Alozie10Hailey H. Oviedo11Alan K. Gonzalez12Tamilini Ilangovan13Alicia Mangubat-Medina14Haopei Wang15Eunji Jo16Cara A. Rabik17Claire Bocchini18Susan Hilsenbeck19Zachary T. Ball20Todd M. Cooper21Michele S. Redell22Department of Pediatric Hematology/Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatric Hematology/Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX 77030, USADevelopment, Disease Models & Therapeutics Graduate Program, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatric Hematology/Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatric Hematology/Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pharmacy, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatric Hematology/Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatric Hematology/Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatric Hematology/Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatric Hematology/Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatric Hematology/Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatric Hematology/Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX 77030, USADepartment of Pediatric Hematology/Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX 77030, USADepartment of Chemistry, Rice University, Houston, TX 77005, USADepartment of Chemistry, Rice University, Houston, TX 77005, USADuncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USAThe Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21231, USADepartment of Pediatric Infectious Diseases, Baylor College of Medicine, Houston, TX 77030, USADuncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 77030, USADepartment of Chemistry, Rice University, Houston, TX 77005, USACancer and Blood Disorders Center, Seattle Children’s Hospital, Seattle, WA 98105, USADepartment of Pediatric Hematology/Oncology, Texas Children’s Cancer Center, Baylor College of Medicine, Houston, TX 77030, USASurvival of pediatric AML remains poor despite maximized myelosuppressive therapy. The <i>pneumocystis jiroveci pneumonia</i> (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.https://www.mdpi.com/2072-6694/15/4/1344pediatricoxidative phosphorylationmetabolismxenograftpatient-derivedoxygen consumption rate |
| spellingShingle | Alexandra McLean Stevens Eric S. Schafer Minhua Li Maci Terrell Raushan Rashid Hana Paek Melanie B. Bernhardt Allison Weisnicht Wesley T. Smith Noah J. Keogh Michelle C. Alozie Hailey H. Oviedo Alan K. Gonzalez Tamilini Ilangovan Alicia Mangubat-Medina Haopei Wang Eunji Jo Cara A. Rabik Claire Bocchini Susan Hilsenbeck Zachary T. Ball Todd M. Cooper Michele S. Redell Repurposing Atovaquone as a Therapeutic against Acute Myeloid Leukemia (AML): Combination with Conventional Chemotherapy Is Feasible and Well Tolerated Cancers pediatric oxidative phosphorylation metabolism xenograft patient-derived oxygen consumption rate |
| title | Repurposing Atovaquone as a Therapeutic against Acute Myeloid Leukemia (AML): Combination with Conventional Chemotherapy Is Feasible and Well Tolerated |
| title_full | Repurposing Atovaquone as a Therapeutic against Acute Myeloid Leukemia (AML): Combination with Conventional Chemotherapy Is Feasible and Well Tolerated |
| title_fullStr | Repurposing Atovaquone as a Therapeutic against Acute Myeloid Leukemia (AML): Combination with Conventional Chemotherapy Is Feasible and Well Tolerated |
| title_full_unstemmed | Repurposing Atovaquone as a Therapeutic against Acute Myeloid Leukemia (AML): Combination with Conventional Chemotherapy Is Feasible and Well Tolerated |
| title_short | Repurposing Atovaquone as a Therapeutic against Acute Myeloid Leukemia (AML): Combination with Conventional Chemotherapy Is Feasible and Well Tolerated |
| title_sort | repurposing atovaquone as a therapeutic against acute myeloid leukemia aml combination with conventional chemotherapy is feasible and well tolerated |
| topic | pediatric oxidative phosphorylation metabolism xenograft patient-derived oxygen consumption rate |
| url | https://www.mdpi.com/2072-6694/15/4/1344 |
| work_keys_str_mv | AT alexandramcleanstevens repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT ericsschafer repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT minhuali repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT maciterrell repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT raushanrashid repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT hanapaek repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT melaniebbernhardt repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT allisonweisnicht repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT wesleytsmith repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT noahjkeogh repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT michellecalozie repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT haileyhoviedo repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT alankgonzalez repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT tamiliniilangovan repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT aliciamangubatmedina repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT haopeiwang repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT eunjijo repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT caraarabik repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT clairebocchini repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT susanhilsenbeck repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT zacharytball repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT toddmcooper repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated AT michelesredell repurposingatovaquoneasatherapeuticagainstacutemyeloidleukemiaamlcombinationwithconventionalchemotherapyisfeasibleandwelltolerated |