Evidence map›Paper›PMID 37704893›Full record

ArticlePharmaceutical research2023

Constitutively Synergistic Multiagent Drug Formulations Targeting MERTK, FLT3, and BCL-2 for Treatment of AML.

James M Kelvin, Juhi Jain, Aashis Thapa, Min Qui, Lacey A Birnbaum, Samuel G Moore, Henry Zecca, Ryan J Summers, Jeffrey M Switchenko, Emma Costanza and 8 more

Abstract read
PubMed Publisher
In one paragraph

Article in Pharmaceutical research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 1 paper.

0numbers the graph read from it
0cells of the map it votes in
1citing papers in PubMed
0.5field-weighted citation impact, top 30% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

1 citing paper in PubMed, 3 citations in OpenAlex.

  1. Review
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

18 authors at 5 institutions in 1 country.

James M Kelvin *Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30322, USA.
Juhi Jain *Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Aashis ThapaDepartment of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Min QuiDepartment of Pharmacology and Chemical Biology, Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Lacey A BirnbaumCoulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30322, USA.
Samuel G MooreSystems Mass Spectrometry Core Facility, Georgia Institute of Technology, Atlanta, GA, 30332, USA.
Henry ZeccaDepartment of Chemistry, Emory University, Atlanta, GA, 30322, USA.
Ryan J SummersDepartment of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Jeffrey M SwitchenkoDepartment of Biostatistics and Bioinformatics, Rollins School of Public Health, Emory University, Atlanta, GA, 30322, USA.
Emma CostanzaCoulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30322, USA.
Biaggio UricoliCoulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30322, USA.
Xiaodong WangCenter for Integrative Chemical Biology and Drug Discovery, Division of Chemical Biology and Medicinal Chemistry, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA.
Nathan T JuiDepartment of Chemistry, Emory University, Atlanta, GA, 30322, USA.
Haian FuDepartment of Pharmacology and Chemical Biology, Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Yuhong DuDepartment of Pharmacology and Chemical Biology, Emory Chemical Biology Discovery Center, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Deborah DeRyckereDepartment of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA.
Douglas K GrahamDepartment of Pediatrics, Emory University School of Medicine, Atlanta, GA, 30322, USA. Douglas.Graham@choa.org.
Erik C DreadenCoulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, GA, 30322, USA. e.dreaden@emory.edu.
Emory University · USGeorgia Institute of Technology · USAflac (United States) · USThe Wallace H. Coulter Department of Biomedical Engineering · USUniversity of North Carolina at Chapel Hill · US

Funding

T32 Research Training Program in ImmunoEngineeringT32EB021962 · NIBIB · GEORGIA INSTITUTE OF TECHNOLOGY · PI JULIA E BABENSEE · 2017 to 2026
$1.9M
NIH Research Training Program in Immunoengineering T32EB021962
6 · The paper itself

Abstract

purposeAlthough high-dose, multiagent chemotherapy has improved leukemia survival rates, treatment outcomes remain poor in high-risk subsets, including acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) in infants. The development of new, more effective therapies for these patients is therefore an urgent, unmet clinical need.

methodsThe dual MERTK/FLT3 inhibitor MRX-2843 and BCL-2 family protein inhibitors were screened in high-throughput against a panel of AML and MLL-rearranged precursor B-cell ALL (infant ALL) cell lines. A neural network model was built to correlate ratiometric drug synergy and target gene expression. Drugs were loaded into liposomal nanocarriers to assess primary AML cell responses.

resultsMRX-2843 synergized with venetoclax to reduce AML cell density in vitro. A neural network classifier based on drug exposure and target gene expression predicted drug synergy and growth inhibition in AML with high accuracy. Combination monovalent liposomal drug formulations delivered defined drug ratios intracellularly and recapitulated synergistic drug activity. The magnitude and frequency of synergistic responses were both maintained and improved following drug formulation in a genotypically diverse set of primary AML bone marrow specimens.

conclusionsWe developed a nanoscale combination drug formulation that exploits ectopic expression of MERTK tyrosine kinase and dependency on BCL-2 family proteins for leukemia cell survival in pediatric AML and infant ALL cells. We demonstrate ratiometric drug delivery and synergistic cell killing in AML, a result achieved by a systematic, generalizable approach of combination drug screening and nanoscale formulation that may be extended to other drug pairs or diseases in the future.

Indexed as

Leukemia, Myeloid, AcuteProto-Oncogene Proteins c-bcl-2ApoptosisCell Line, TumorChildc-Mer Tyrosine KinaseDrug Compoundingfms-Like Tyrosine Kinase 3HumansInfantProtein Kinase Inhibitorsc-Mer Tyrosine KinaseFLT3 protein, humanfms-Like Tyrosine Kinase 3MERTK protein, humanProtein Kinase InhibitorsProto-Oncogene Proteins c-bcl-2drug combinationsdrug deliveryMERTK tyrosine kinasenanotechnologysynergy

Identifiers

PMID37704893
OpenAlexW4386698137

What Socratic holds

Textmetadata
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.