Multiplex Screening for Interacting Compounds in Paediatric Acute Myeloid Leukaemia.

Lauren V Cairns,Ken I Mills,Alexander Mutch,Katrina M Lappin,Kyle B Matchett,Ahlam Ali

doi:10.3390/ijms221810163

Abstract

Paediatric acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the malignant transformation of myeloid precursor cells with impaired differentiation. Standard therapy for paediatric AML has remained largely unchanged for over four decades and, combined with inadequate understanding of the biology of paediatric AML, has limited the progress of targeted therapies in this cohort. In recent years, the search for novel targets for the treatment of paediatric AML has accelerated in parallel with advanced genomic technologies which explore the mutational and transcriptional landscape of this disease. Exploiting the large combinatorial space of existing drugs provides an untapped resource for the identification of potential combination therapies for the treatment of paediatric AML. We have previously designed a multiplex screening strategy known as Multiplex Screening for Interacting Compounds in AML (MuSICAL); using an algorithm designed in-house, we screened all pairings of 384 FDA-approved compounds in less than 4000 wells by pooling drugs into 10 compounds per well. This approach maximised the probability of identifying new compound combinations with therapeutic potential while minimising cost, replication and redundancy. This screening strategy identified the triple combination of glimepiride, a sulfonylurea; pancuronium dibromide, a neuromuscular blocking agent; and vinblastine sulfate, a vinca alkaloid, as a potential therapy for paediatric AML. We envision that this approach can be used for a variety of disease-relevant screens allowing the efficient repurposing of drugs that can be rapidly moved into the clinic.

Highlights

Acute myeloid leukaemia (AML) is a heterogeneous disease characterised by the malignant transformation of myeloid precursor cells with impaired differentiation [1,2].AML is often considered as a disease of the elderly with incidence rising markedly with age; the median age at diagnosis is approximately 70 years old [3]
We demonstrate the utility of a novel multiplex screening approach [8] to identify potential repurposed combination therapies for the treatment of paediatric AML
We identified the combination of glimepiride, a sulfonylurea used in the management of type 2 diabetes mellitus [25]; pancuronium dibromide, a neuromuscular blocking agent [26]; and vinblastine sulfate, a vinca-alkaloid anticancer agent [27], as a potential therapy for paediatric AML

Summary

Introduction

AML is often considered as a disease of the elderly with incidence rising markedly with age; the median age at diagnosis is approximately 70 years old [3]. Rates for paediatric AML range between 60 and 70%, which is a significant improvement from the 40% 5-year survival rates observed in the early 1980s. This can be attributed to more intense chemotherapeutic regimens and improved supportive care [5,6]. Despite these significant improvements, relapse and refractory AML remains a leading cause of mortality in children [7]

Objectives

Methods

Results

Conclusion