CSIG-10 - Pharmaco-phospho-proteo-genomics of pediatric high-grade gliomas - a pilot study

Friday, November 18, 2022

7:30 PM – 9:30 PM ET

Location: West/Central Hall

Author(s)

IF

Izac J. Findlay

Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
Callaghan, Australia
DS

Dilana Staudt

1 Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
Callaghan, Australia
PK

Padraic S. Kearney

Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
Callaghan, Australia
HM

Holly McEwen

Cancer Signalling Research Group, School of Biomedical Sciences & Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
Callaghan, Australia
RD

Ryan J. Duchatel

Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
Callaghan, Australia
EJ

Evangeline R. Jackson

Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
Callaghan, Australia
TB

Tyrone Beitaki

Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine & Wellbeing, University of Newcastle, Newcastle, NSW, Australia
Newcastle, Australia
NS

Nathan Smith

Analytical and Biomolecular Research Facility Advanced Mass Spectrometry Unit, University of Newcastle, Callaghan, NSW, Australia
Callaghan, Australia
Nicholas A. Vitanza, MD

Ben Towne Center for Childhood Cancer Research, Seattle Children’s Research Institute, Seattle, WA, USA
Seattle, United States
RF

Ron Firestein

Department of Molecular and Translational Science, Monash University, Clayton, VIC, Australia.
Melbourne, Australia
JC

Jason Cain

Hudson Institute of Medical Research, Clayton, VIC, Australia
Clayton, Australia
Sabine Mueller, MD, PhD, MAS (she/her/hers)

UCSF Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco
San Francisco, United States
EP

Eddy Pasquier

Laboratoire d’Oncologie Prédictive, CRCM, Institut Paoli-Calmettes, Aix-Marseille Université, Département d’Oncologie Médicale, Institut Paoli-Calmettes, Marseille, France
Marseille, France
Carl J. Koschmann, MD

Department of Pediatrics, Michigan Medicine, Ann Arbor, MI, USA
Ann Arbor, United States
EH

Esther Hulleman

Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
Utrecht, Netherlands
Javad Nazarian, PhD, MS

Department of Oncology, Children’s Research Center, University Children’s Hospital Zurich, Zurich, Switzerland
Zurich, Switzerland
MH

Mitchell Hansen

Surgical Department, John Hunter Hospital, Newcastle, NSW, Australia
Newcastle, Australia
FA

Frank Alvaro

Precision Medicine Program, Hunter Medical Research Institute, New Lambton Heights, NSW, Australia
New Lambton Heights, Australia
MD

Melissa Davis

Bioinformatics Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, 3052, Australia
Melbourne, Australia
SW

Sebastian Waszak, Ph.D

Oslo University Hospital, University of Oslo
Oslo, United States

Poster Presenter(s)

Matthew D. Dun, Ph.D (he/him/his)

Cancer Signalling Research Group, School of Biomedical Sciences and Pharmacy, College of Health, Medicine and Wellbeing, University of Newcastle, Callaghan, NSW, Australia
Callaghan, Australia

Pediatric high-grade gliomas (pHGG) are the leading cause of cancer-related death in children and young adults. Current treatment strategies are centered on maximal safe resection, followed by radiotherapy, and interrogation of the tumor genome to identify targetable mutations. Unfortunately, we are yet to see an improvement in patient outcomes with a median overall survival remaining 15-months. To improve patient outcomes, we have begun to characterize the genome, proteome, and phosphoproteome of 168 pHGGs to better understand the functional consequences of their somatic alterations as well as their influence of the tumor microenvironment. Employing a novel ‘pharmaco-phospho-proteo-genomics’ pipeline, we have analyzed pHGG cell lines and tumor tissue specimens at diagnosis, relapse (partial resection congenital glioblastoma), and autopsy. Genomic profiling was conducted utilizing the 523-gene TruSight Oncology 500 (TSO500) next-generation sequencing panel. Simultaneously, tumor proteomes and phosphoproteomes were characterized using our high-throughput global phospho-proteomic profiling technique termed pHASED (phospho Heavy-labelled-spiketide FAIMS StEpped-CV DDA). High-fidelity tumor proteomic and phospho-proteomic data were identified and compared to normal control brain samples. Across 40 pHGG samples, we identified 290 unique somatic alterations with a high predicted impact severity and quantified 7,345 unique proteins and 3,327 phosphoproteins. Gene panel sequencing of a critical pediatric glioblastoma patient sample identified 18 somatic alterations, eight of which had a high predicted impact severity, however, none were targetable. Conversely, phosphoproteomic profiling identified enriched MAPK and PRKCB signaling, relative to normal brain tissues, thereby encouraging the use of the TGA/FDA approved therapies trametinib (MAPKs) and enzastaurin (PRKCB). In vitro investigations confirmed the utility of these treatment approaches and in vivo patient derives xenograft mouse models for this sample are under investigation. This pilot study provides critical data to support the benefit of interrogating the genome, proteome, and phospho-proteome of these devastating tumours to aid in the selection/development of effective treatment strategies.