1. Patient-tailored design for selective co-inhibition of leukemic cell subpopulations
- Author
-
Caroline A. Heckman, Heikki Kuusanmäki, Laura Turunen, Philipp Sergeev, Pirkko Mattila, Komal Kumar Javarappa, Markus Vähä-Koskela, Mika Kontro, Krister Wennerberg, Anil K. Giri, Nora Linnavirta, Kimmo Porkka, Tero Aittokallio, Prson Gautam, Bishwa Ghimire, Aleksandr Ianevski, Jenni Lahtela, Computational Systems Medicine, Institute for Molecular Medicine Finland, Medicum, Department of Medicine, HUS Comprehensive Cancer Center, Biosciences, Krister Wennerberg / Principal Investigator, Helsinki Institute for Information Technology, Tero Aittokallio / Principal Investigator, and Bioinformatics
- Subjects
Drug ,media_common.quotation_subject ,Computational biology ,Disease pathogenesis ,EXTENSIVE DRUG RESISTANCE ,03 medical and health sciences ,0302 clinical medicine ,Medicine ,Research Articles ,Cancer ,030304 developmental biology ,media_common ,0303 health sciences ,Multidisciplinary ,business.industry ,SciAdv r-articles ,Myeloid leukemia ,Cell subpopulations ,113 Computer and information sciences ,3. Good health ,030220 oncology & carcinogenesis ,Computer Science ,Cancer cell ,business ,Ex vivo ,Combinatorial explosion ,Research Article - Abstract
Machine learning and single-cell data inform personalized drug combinations that selectively co-inhibit cancer cell populations., The extensive drug resistance requires rational approaches to design personalized combinatorial treatments that exploit patient-specific therapeutic vulnerabilities to selectively target disease-driving cell subpopulations. To solve the combinatorial explosion challenge, we implemented an effective machine learning approach that prioritizes patient-customized drug combinations with a desired synergy-efficacy-toxicity balance by combining single-cell RNA sequencing with ex vivo single-agent testing in scarce patient-derived primary cells. When applied to two diagnostic and two refractory acute myeloid leukemia (AML) patient cases, each with a different genetic background, we accurately predicted patient-specific combinations that not only resulted in synergistic cancer cell co-inhibition but also were capable of targeting specific AML cell subpopulations that emerge in differing stages of disease pathogenesis or treatment regimens. Our functional precision oncology approach provides an unbiased means for systematic identification of personalized combinatorial regimens that selectively co-inhibit leukemic cells while avoiding inhibition of nonmalignant cells, thereby increasing their likelihood for clinical translation.
- Published
- 2021