PMID- 36831684
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20230227
IS  - 2072-6694 (Print)
IS  - 2072-6694 (Electronic)
IS  - 2072-6694 (Linking)
VI  - 15
IP  - 4
DP  - 2023 Feb 20
TI  - Repurposing Atovaquone as a Therapeutic against Acute Myeloid Leukemia (AML): 
      Combination with Conventional Chemotherapy Is Feasible and Well Tolerated.
LID - 10.3390/cancers15041344 [doi]
LID - 1344
AB  - 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 microM) by day 11 and at the end of Induction, 
      respectively. Seven (29%) patients achieved adequate concentrations for PJP 
      prophylaxis (>40 microM). 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.
FAU - Stevens, Alexandra McLean
AU  - Stevens AM
AD  - Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, 
      Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Schafer, Eric S
AU  - Schafer ES
AD  - Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, 
      Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Li, Minhua
AU  - Li M
AD  - Development, Disease Models & Therapeutics Graduate Program, Baylor College of 
      Medicine, Houston, TX 77030, USA.
FAU - Terrell, Maci
AU  - Terrell M
AD  - Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, 
      Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Rashid, Raushan
AU  - Rashid R
AD  - Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, 
      Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Paek, Hana
AU  - Paek H
AD  - Department of Pharmacy, Texas Children's Hospital, Baylor College of Medicine, 
      Houston, TX 77030, USA.
FAU - Bernhardt, Melanie B
AU  - Bernhardt MB
AUID- ORCID: 0000-0002-9612-3624
AD  - Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, 
      Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Weisnicht, Allison
AU  - Weisnicht A
AD  - Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Smith, Wesley T
AU  - Smith WT
AD  - Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, 
      Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Keogh, Noah J
AU  - Keogh NJ
AD  - Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, 
      Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Alozie, Michelle C
AU  - Alozie MC
AD  - Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, 
      Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Oviedo, Hailey H
AU  - Oviedo HH
AD  - Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, 
      Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Gonzalez, Alan K
AU  - Gonzalez AK
AD  - Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, 
      Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Ilangovan, Tamilini
AU  - Ilangovan T
AD  - Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, 
      Baylor College of Medicine, Houston, TX 77030, USA.
FAU - Mangubat-Medina, Alicia
AU  - Mangubat-Medina A
AD  - Department of Chemistry, Rice University, Houston, TX 77005, USA.
FAU - Wang, Haopei
AU  - Wang H
AD  - Department of Chemistry, Rice University, Houston, TX 77005, USA.
FAU - Jo, Eunji
AU  - Jo E
AD  - Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 
      77030, USA.
FAU - Rabik, Cara A
AU  - Rabik CA
AD  - The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of 
      Medicine, Baltimore, MD 21231, USA.
FAU - Bocchini, Claire
AU  - Bocchini C
AD  - Department of Pediatric Infectious Diseases, Baylor College of Medicine, Houston, 
      TX 77030, USA.
FAU - Hilsenbeck, Susan
AU  - Hilsenbeck S
AD  - Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX 
      77030, USA.
FAU - Ball, Zachary T
AU  - Ball ZT
AUID- ORCID: 0000-0002-8681-0789
AD  - Department of Chemistry, Rice University, Houston, TX 77005, USA.
FAU - Cooper, Todd M
AU  - Cooper TM
AD  - Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, WA 
      98105, USA.
FAU - Redell, Michele S
AU  - Redell MS
AD  - Department of Pediatric Hematology/Oncology, Texas Children's Cancer Center, 
      Baylor College of Medicine, Houston, TX 77030, USA.
LA  - eng
GR  - no grant numbers/Cure Childhood Cancer, Turn it Gold, Robert A. Welch Foundation 
      Research Grant C-1680/
PT  - Journal Article
DEP - 20230220
PL  - Switzerland
TA  - Cancers (Basel)
JT  - Cancers
JID - 101526829
PMC - PMC9954468
OTO - NOTNLM
OT  - metabolism
OT  - oxidative phosphorylation
OT  - oxygen consumption rate
OT  - patient-derived
OT  - pediatric
OT  - pneumocystis jiroveci pneumonia
OT  - xenograft
COIS- The authors declare no conflict of interest.
EDAT- 2023/02/26 06:00
MHDA- 2023/02/26 06:01
PMCR- 2023/02/20
CRDT- 2023/02/25 01:42
PHST- 2023/01/19 00:00 [received]
PHST- 2023/02/15 00:00 [revised]
PHST- 2023/02/15 00:00 [accepted]
PHST- 2023/02/25 01:42 [entrez]
PHST- 2023/02/26 06:00 [pubmed]
PHST- 2023/02/26 06:01 [medline]
PHST- 2023/02/20 00:00 [pmc-release]
AID - cancers15041344 [pii]
AID - cancers-15-01344 [pii]
AID - 10.3390/cancers15041344 [doi]
PST - epublish
SO  - Cancers (Basel). 2023 Feb 20;15(4):1344. doi: 10.3390/cancers15041344.