DRUG-NEM: Optimizing drug combinations using single-cell perturbation response to account for intratumoral heterogeneity

Proceedings of the National Academy of Sciences of the United States of America
Benedict AnchangSylvia K Plevritis

Abstract

An individual malignant tumor is composed of a heterogeneous collection of single cells with distinct molecular and phenotypic features, a phenomenon termed intratumoral heterogeneity. Intratumoral heterogeneity poses challenges for cancer treatment, motivating the need for combination therapies. Single-cell technologies are now available to guide effective drug combinations by accounting for intratumoral heterogeneity through the analysis of the signaling perturbations of an individual tumor sample screened by a drug panel. In particular, Mass Cytometry Time-of-Flight (CyTOF) is a high-throughput single-cell technology that enables the simultaneous measurements of multiple ([Formula: see text]40) intracellular and surface markers at the level of single cells for hundreds of thousands of cells in a sample. We developed a computational framework, entitled Drug Nested Effects Models (DRUG-NEM), to analyze CyTOF single-drug perturbation data for the purpose of individualizing drug combinations. DRUG-NEM optimizes drug combinations by choosing the minimum number of drugs that produce the maximal desired intracellular effects based on nested effects modeling. We demonstrate the performance of DRUG-NEM using single-cell drug perturba...Continue Reading

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Citations

Jun 23, 2020·NPJ Precision Oncology·George AdamAnna Goldenberg
Sep 15, 2018·International Journal of Molecular Sciences·Joshua M CampbellAdam T Melvin
Sep 28, 2018·Molecular Cancer Research : MCR·Molly R RyanKaren S Anderson
Feb 2, 2021·Biomechanics and Modeling in Mechanobiology·Mohammad Amin HajariXiongbiao Chen
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Nov 3, 2020·Clinical and Translational Medicine·Ting ZhangXianting Ding
Feb 21, 2021·Science Advances·Aleksandr IanevskiTero Aittokallio
Feb 18, 2021·NPJ Precision Oncology·George AdamAnna Goldenberg
Feb 23, 2021·Bioinformatics·Martin Pirkl, Niko Beerenwinkel

Methods Mentioned

BETA
FCS
flow cytometry
Assay

Related Concepts

Antineoplastic Chemotherapy Protocols
In Silico
HeLa Cells
Tumor Markers
Leukemia, Lymphocytic, Acute, L2
Biological Markers
Malignant Neoplasms
Cell Separation
Drug Combinations
Combination Drug Therapy

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