Major advances have been achieved in the discovery and application of targeted therapy for adult solid tumors. Nevertheless, therapeutic options for pediatric solid tumors have been limited. Current precision medicine programs focus on genomic sequencing to identify discrete mutations that may predict patients’ responses to targeted therapies. Unfortunately, currently 10% or fewer cancer patients harbor actionable mutations and of those that do, only 50% respond to therapy. This underscores a clear need to go beyond genomic sequencing to identify biomarker coupled targeted therapies that improve treatment efficacy and limit the debilitating side effects of standard chemotherapy and/or radiation therapy.
The HMPPM Program was established in September 2017 as a two-year pilot initiative to accelerate cancer precision medicine research and clinical translation, and to address this unmet clinical need. The program focuses on developing and utilizing individual patients’ tumor cells to identify new therapeutic targets and repurpose existing targets using functional genomics technologies. Our program brings together clinicians and researchers across the Monash Health Translational Precinct (MHTP), harnessing the strength of our functional genomics platform to enable innovative research discovery and provide personalized therapeutic options for pediatric cancer patients.
What are the goals of this project?
Whole genome sequencing on germline, tumour tissue and matched cell line-derived DNA will be conducted for patients diagnosed with a high risk solid tumour (sarcomas, brain malignancies, refractory Wilms tumour, neuroblastoma
Transcriptomic analysis will be conducted on tumour tissue and matched cell line for each patient by RNA-sequencing, paired end sequencing 150bp reads at 20 million read depth (Novaseq 6000). Data alignment, trimming and differential gene expression will be conducted by a bioinformatician employed as part of HMPPM Program Stage 2.
For all brain cancer samples (~40% of our patients), data will be entered into the CBTN data analysis pipeline and cross-referenced to over 2000 brain cancers already annotated as part of the CBTN Pediatric Brain Tumor Atlas initiative.
Why the CBTN request is important to this project?
The CBTN and the Gabriella Miller Kids First Data Resource Center (DRC) will supply the required computational and workspace environment for storage and data analysis under the recently launched Kids First Portal and Cavatica platforms (kidsfirstdrc.org/portal) with additional data visualization within pedcbioportal (pedcbioportal.org). The platforms provide data access, harmonization, workflows, cloud‐based computation, and integration across the largest pediatric brain tumor datasets generated to date.
The Children's Brain Tumor Network contributed to this project by providing access to the Pediatric Brain Tumor Atlas and by leading the computational efforts for the brain cancer analysis.
Ron Firestein, Hudson Institute of Medical Research, Australia
- Principal Investigator
Annie Huang, Hospital for Sick Children, Canada
- Perform Assay for Transposase Accessible Chromatic with high-throughput sequencing (ATAC-seq) to chart chromatin accessibility at a genome-wide scale
Roger Daly, Monash University, Australia
- Perform global phospho-proteomic profiling to identify signatures of activated oncogenic pathways and kinases on patient tumour models grown in culture conditions.
Roger Reddel, Children’s Medical Research Institute, Australia
- Large scale proteomic analysis with PROCAN (based at the Children’s Medical Research Institute) to analyse proteins and derive proteomic signatures from both patient tumour tissue and matched models
Adam Resnick, Children’s Hospital of Philadelphia, USA
- Support of large scale data integration and analysis, leading computational efforts with regards to brain cancer analyses.
Holly Beale, University of California Santa Cruz, USA
- Curation of RNA-seq data, as part of the Treehouse Childhood Cancer Initiative, and comparisons of each child’s cancer data as well as cross-referencing with more than 10,000 tumours from previous genomics projects.
Other team members:
- Claire Sun, Hudson Institute of Medical Research, Australia
- Daniel Gough, Hudson Institute of Medical Research, Australia
- Duncan Crombie, Hudson Institute of Medical Research, Australia
Ron Firestein, MD, PhD
Associate Professor Ron Firestein is the Head of the Cancer Centre at the Hudson Institute of Medical Research and Head of Research for the Hudson Monash Paediatric Precision Medicine Program. A/Prof Firestein is a physician scientist double board certified in Pathology (Anatomic and Molecular Ge
Hudson Institute of Medical Research
Jason Cain, PhD
Dr. Jason Cain is Head of the Developmental and Cancer Biology research group in Hudson Institute’s Centre for Cancer Research and a Chief Investigator for the Hudson Monash Paediatric Precision Medicine Program. A developmental and cancer biologist, Dr. Cain is driving cutting-edge research to u
Hudson Institute of Medical Research
Adam Resnick, PhD
Adam Resnick is the Director of Data Driven Discovery in Biomedicine (D3b) at Children’s Hospital of Philadelphia (CHOP) responsible for leading a multidisciplinary team to build and support a scalable, patient-focused healthcare and educational discovery ecosystem on behalf of all children. He i
Children’s Hospital of Philadelphia
Holly Beale, PhD
Holly is an investigator at UC Santa Cruz Treehouse Childhood Cancer Initiative in Santa Cruz, California.
UC Santa Cruz Treehouse Childhood Cancer Initiative