|
BACKGROUND
Brain tumours are currently the leading cause of childhood cancer death. The last decade has seen a massive growth in our understanding of brain tumour genetics including the discovery of diagnostic, prognostic, and therapeutic markers. Currently, molecular characterization of these tumours requires a biopsy, which is invasive and risky, particularly in the brain. We can remove this risk to patients by using “liquid biopsies”, taking advantage of the discovery that fluids like blood and cerebral spinal fluid carry small amounts of tumour DNA (ctDNA) (Figure 1). While this technology has been developed for many adult cancers, no such tests exist for children. A lack of clinical translation and developed tests for paediatric cancers has meant the increasing demand for innovative minimally invasive diagnostics has remained largely unmet.
DESCRIPTION OF THE INVENTION
The Hawkins group at SickKids has designed and validated a list of novel biomarkers as a liquid biopsy platform that can detect paediatric gliomas in minimally invasively acquired CSF samples. The protocol sequences 89 kb spanning through intronic and exonic regions of interest. There are 21 genes analysed in the assay which utilizes the Illumina platform to detect single nucleotide variants (SNVs), fusions, and copy number alterations (CNAs) with low pass whole genome sequencing. With 10 ng of ctDNA, the assay can detect a variant allele frequency (VAF) of 0.5% with a sensitivity of 83% and specificity of 100%. As the input DNA increases to 30 ng the sensitivity increases to 100% (Figure 2).
COMMERCIAL APPLICATIONS & ADVANTAGES
Current limitations in the development of paediatric liquid biopsy diagnostics include:
• high cost
• lack of expertise
• a smaller market
Liquid biopsies utilizing mainly plasma ctDNA are currently in use in adult oncology with multiple FDA approved assays, but there are no diagnostics approved for paediatric brain cancers. SickKids is well positioned to develop the first of its kind laboratory developed test (LDT) as a complementary diagnostic.
Our strategy includes developing and validating a liquid biopsy platform that will offer informative actionable details of the tumor genetics at all stages of care. Beginning with diagnosis and tumor sub-typing, to monitoring tumor response to therapeutics, and finally minimal residual disease monitoring, this diagnostic could provide unparalleled insight into the patients’ therapeutic course. Additionally, this panel could be adopted by an industry partner and tailored for their diagnostic systems for commercial development either as a companion diagnostic or screening tool.
DEVELOPMENT STAGE
Panel and protocol design has been completed and the test has been validated against 45 patient samples. Validation continues with additional patent samples from SickKids and centers from across Canada. The priority is to register the panel with the Ministry of Health as a Laboratory Designed Test (LDT) and offer it to provincial (Ontario), national (Canada), and international (USA) patients, either directly from SickKids or through a network of diagnostic company partnerships.
A longer-term goal of the project is to validate this panel in additional cancers and age groups. For example, the Hawkins group is interested in exploring the applicability of this test in all paediatric brain tumors (not just glioma), and as a tool for minimal residual disease monitoring. The group has recently made progress evaluating the panel for brain cancers in the adolescent and young adult population (AYA) and is establishing partnerships with many groups in Canada to access samples in the often-overlooked patient population.
|
