Journal article

Defining a therapeutic window for kinase inhibitors in leukemia to avoid neutropenia

Kate McArthur, Akshay A D'Cruz, David Segal, Kurt Lackovic, Andrew F Wilks, Joanne A O'Donnell, Cameron J Nowell, Motti Gerlic, David CS Huang, Christopher J Burns, Ben A Croker

ONCOTARGET | IMPACT JOURNALS LLC | Published : 2017

Abstract

Neutropenia represents one of the major dose-limiting toxicities of many current cancer therapies. To circumvent the off-target effects of cytotoxic chemotherapeutics, kinase inhibitors are increasingly being used as an adjunct therapy to target leukemia. In this study, we conducted a screen of leukemic cell lines in parallel with primary neutrophils to identify kinase inhibitors with the capacity to induce apoptosis of myeloid and lymphoid cell lines whilst sparing primary mouse and human neutrophils. We have utilized a high-throughput live cell imaging platform to demonstrate that cytotoxic drugs have limited effects on neutrophil viability but are toxic to hematopoietic progenitor cells, ..

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Grants

Awarded by NIH


Awarded by Australian National Health and Medical Research Council (NHMRC)


Awarded by Leukemia and Lymphoma Society (SCOR)


Awarded by Israel Science Foundation (ISF)


Awarded by NATIONAL HEART, LUNG, AND BLOOD INSTITUTE


Funding Acknowledgements

We are grateful to Dr Suneet Agarwal for assistance with collection of human peripheral blood, and Rebecca Moss and Timothy Blackmore for assistance with Activity Base and Spotfire analysis. This work was supported by NIH Grant 5RO1HL124209-2, the V Foundation for Cancer Research, Gabrielle's Angel Foundation for Cancer Research, and Alex's Lemonade Stand Foundation (B.A.C.). This work is supported by fellowships and grants from the Australian National Health and Medical Research Council (NHMRC) (Research Fellowships to DCSH; a Dora Lush Scholarship to J.A.O.; an Alan Harris Scholarship to K.M.; Project Grants to DCSH 1057742; Program Grants 1016701; Independent Research Institutes Infrastructure Support Scheme grant 9000220), the Cancer Council Victoria (grant-in-aid to DCSH), the Leukemia and Lymphoma Society (SCOR grants 7001-13), the Australian Cancer Research Foundation, a Victorian State Government Operational Infrastructure Support (OIS) grant, and Dyson Bequest funding (Dunn Fellowship) to CJB.; Israel Science Foundation (ISF) 1416/15 (M.G.) and Varda and Boaz Dotan Research Center Individual Grant (M.G.).