Drug screening linked to molecular profiling identifies novel dependencies in patient-derived primary cultures of paediatric high grade glioma and DIPG
Year: 2020
Type: preprint
Abstract: 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-derived in vitro primary 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 included MYCN -amplified cells and ATM/DNA-PK inhibitors, and DIPGs with PPM1D activating truncating mutations and inhibitors of MDM2 or PARP1. Specific mutations in PDGFRA were 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.
Authors: Diana M Carvalho, Sara Temelso, Alan Mackay, Helen N Pemberton, Rebecca Rogers, Ketty Kessler, Elisa Izquierdo, Lynn Bjerke, Janat Fazal Salom, Matthew Clarke, Yura Grabovska, Anna Burford, Nagore Gene Olaciregui, Jessica KR Boult, Valeria Molinari, Mariama Fofana, Paula Proszek, Elisabet F Potente, Kathryn R Taylor, Christopher Chandler, Bassel Zebian, Ranj Bhangoo, Andrew J Martin, Bassam Dabbous, Simon Stapleton, Samantha Hettige, Lynley V Marshall, Fernando Carceller, Henry C Mandeville, Sucheta J Vaidya, Safa Al-Sarraj, Leslie R Bridges, Robert Johnston, Jane Cryan, Michael Farrell, Darach Crimmins, John Caird, Jane Pears, Giulia Pericoli, Evelina Miele, Angela Mastronuzzi, Franco Locatelli, Andrea Carai, Simon P Robinson, Mike Hubank, Michelle Monje, Andrew S Moore, Timothy EG Hassall, Angel Montero Carcaboso, Christopher J Lord, Mara Vinci, Chris Jones
Institutions: Institute of Cancer Research, Breast Cancer Now, Cancer Research UK, Hospital Sant Joan de Déu Barcelona, Royal Marsden NHS Foundation Trust, Royal Marsden Hospital, Stanford Medicine, Stanford University, King's College Hospital, St George's Hospital, St George’s University Hospitals NHS Foundation Trust, Royal Belfast Hospital for Sick Children, Beaumont Hospital, Temple Street Children's University Hospital, Children's Health Ireland at Crumlin, Bambino Gesù Children's Hospital, The University of Queensland, Children's Health Queensland Hospital and Health Service, Queensland University of Technology, Institute for Molecular Bioscience
Language: English
Subfield: Genetics
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W3114676249