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Drug screening linked to molecular profiling identifies novel dependencies in patient-derived primary cultures of paediatric high grade glioma and DIPG

Authors :
Michael Farrell
Ketty Kessler
Jessica K.R. Boult
Safa Al-Sarraj
Fernando Carceller
Evelina Miele
Alan Mackay
Mariama Fofana
Leslie R. Bridges
Ranj Bhangoo
Rebecca Rogers
Paula Proszek
Lynley V. Marshall
Matthew Clarke
Janat Fazal Salom
Bassam Dabbous
Franco Locatelli
Christopher J. Lord
Chris Jones
Sucheta Vaidya
John Caird
Michelle Monje
Elisa Izquierdo
Angel M. Carcaboso
Andrea Carai
Samantha Hettige
Sara Temelso
Yura Grabovska
Christopher Chandler
Darach Crimmins
Lynn Bjerke
Simon R. Stapleton
Mara Vinci
Jane Pears
Angela Mastronuzzi
Giulia Pericoli
Kathryn R. Taylor
Elisabet F Potente
Simon P. Robinson
Anna Burford
Andrew J. Martin
Mike Hubank
Timothy E.G. Hassall
Bassel Zebian
Henry Mandeville
Jane Cryan
Helen N. Pemberton
Andrew S. Moore
Robert Johnston
Nagore G. Olaciregui
Valeria Molinari
Diana Carvalho
Publication Year :
2020
Publisher :
Cold Spring Harbor Laboratory, 2020.

Abstract

Paediatric high grade glioma and diffuse midline glioma (including DIPG) are comprised of multiple biological and clinical subgroups, the majority of which urgently require novel therapies. Patient-derivedin vitroprimary cell cultures represent potentially useful tools for mechanistic and preclinical investigation based upon their retention of key features of tumour subgroups under experimental conditions amenable to high-throughput approaches. We present 17 novel primary cultures derived from patients in London, Dublin and Belfast, and together with cultures established or shared from Barcelona, Brisbane, Rome and Stanford, assembled a panel of 52 models under 2D (laminin matrix) and/or 3D (neurospheres) conditions, fully credentialed by phenotypic and molecular comparison to the original tumour sample (methylation BeadArray, panel/exome sequencing, RNAseq). In screening a subset of these against a panel of ~400 approved chemotherapeutics and small molecules, we identified specific dependencies associated with tumour subgroups and/or specific molecular markers. These includedMYCN-amplified cells and ATM/DNA-PK inhibitors, and DIPGs withPPM1Dactivating truncating mutations and inhibitors of MDM2 or PARP1. Specific mutations inPDGFRAwere found to confer sensitivity to a range of RTK inhibitors, though not all such mutations conferred sensitivity to targeted agents. Notably, dual PDGFRA/FGFR and downstream pathway MEK inhibitors showed profound effects against both PDGFRA-sensitising mutant and FGFR1-dependent non-brainstem pHGG and DIPG. In total, 85% cells were found to have at least one drug screening hit in short term assays linked to the underlying biology of the patient’s tumour, providing a rational approach for individualised clinical translation.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........0c89e3a42fb668fa43263a196c0ca138