Inherited mismatch repair (MMR) deficiency (also known as Lynch Syndrome, LS) affects at least 1 in 300 Canadians. It is a feature of families with heightened risk of colon, brain and gynaecological cancer. Despite a tenfold increased risk, the majority of LS patients are not well identified by the Canadian health system, which takes a piecemeal and overly complex approach to testing, including an excessive use of often-limited tumour tissues. As a result, the length of time to diagnosis is currently 1-3 years in Ontario and up to 6 years in other provinces. While they wait, many Canadians are developing advanced cancers. There is an urgent need for a more efficient, comprehensive MMR screening protocol to identify and treat high-risk patients earlier.

MMR tumours all display a biological feature (microsatellite instability, MSI) that leads to the accumulation of 10,000s of DNA mutations. The project aims to commercialize a MultiMMR tumour test previously developed by the researchers involved. In a single cost-efficient test, this comprehensive DNA sequencing method queries the MMR genes for germline and somatic mutations, MSI status and promoter methylation. MultiMMR conserves tissue, eliminates the need for serial molecular testing and helps differentiate LS from other hereditary cancers.

In partnership with the health solutions company Dynacare, the team will test and clinically validate the MultiMMR panel through a pilot study with various clinics nationally, and validate a new application of MultiMMR to blood cell-free DNA for proactive cancer screening in LS and constitutional mismatch repair deficiency (CMMRD) carriers. Within 3-5 years of completion, the project will reduce LS/CMMRD diagnosis time from 1-6 years to 4 months, saving 50-75% of patients from lifelong cancer screening. It will also reduce healthcare spending on molecular testing by more than 10%, and ultimately improve patient experiences and outcomes.

Cancer is responsible for more than 1 in 4 deaths in Canada, with more than 600 new cases diagnosed daily. Sarcomas – tumours of the bone and soft tissue – are the most challenging cancers to diagnose. The many sarcoma types all have intrinsically different molecular pathogenesis (the process by which a disease develops). Patients with sarcomas, which are proportionately more common in children, face delays of weeks to months until they can be referred to a specialist centre and there are few clinical trials. Current histomorphology and immunohistochemistry approaches to diagnosis are also extremely subjective, requiring clinicians to order 10-20 tests per patient. These challenges lead to ultimately higher health system costs and lower patient survival rates.

Pathologists need a comprehensive approach with better tools to diagnose sarcoma. Project researchers have recently developed a platform to accurately diagnose (with 85-95% accuracy) any sarcoma using its ribonucleic acid (RNA). The highly scalable RNA-Seq-based tumour classification system has been trained on >13,000 tumours and normal samples, and improves with every sample analyzed. This project will validate and implement the platform at two major Toronto hospitals, which together treat around 1,000 patients with tumours of soft tissue and bone each year. The team will implement the initial web platform and will work with two commercial partners: DNAstack to expand the platform to the cloud; and Illumina to expand access to this platform outside of Ontario. It will also compare the platform to World Health Organization classifications to support future global adoption of the platform. In 3-5 years, the platform will be expanded to other types of cancer and altogether better streamline the diagnosis of sarcomas of cancer patients.

Fungi have been the source of some of the most effective medicines in history, such as penicillin. However, producing the active medicinal ingredients at scale for R&D has been a key challenge to further fungal drug discovery. This project aims to create a flexible, scalable and cost-efficient synthetic biology platform that supports the synthesis of diverse fungal molecules and produces sufficient compound. It will leverage Kapoose Creek Bio’s (KCB’s) proprietary AI-enabled drug discovery platform (unEarth Rx), which mines nature for new therapeutic drug leads. The platform will use genomics and metabolomics solutions to develop a biosynthetic expression system for genetically-encoded fungal compounds.

The implementation of an in-house synthetic biology platform at KCB will provide a significant competitive advantage, both to accelerate the drug discovery program and enable future clinical-stage partnerships. The project is anticipated to catalyze KCB’s growth and position the company to bring new therapies to market with the potential to counteract cognitive impairment, a major health burden for Canadians, particularly as they age.

Clinical trials are a crucial element of the modern health system. Cancer patients in Canada, however, face substantial barriers to accessing state-of-the-art precision therapies. This is because matching patients to trials is an increasingly resource-intensive and time-consuming task. The disjointed nature of the digital infrastructure means that already overworked clinicians have to spend time parsing through complex eligibility criteria and clinical diagnostic data.

The result is fewer patients are enrolled in trials for which they are eligible. This project will develop PMATCH, an innovative open-source software platform using powerful machine learning techniques to search through complex clinical and genomic eligibility criteria along with the data generated by each patient during their cancer journey, e.g., blood tests, surgery, family history.

Clinicians will be able to match their patients with the best clinical trials for each individual in near-real-time. PMATCH will also standardize the clinical and sequencing data and ensure their FAIRness (findability, accessibility, interoperability and reusability).

Expected benefits of the PMATCH pilot include a 50 per cent increase in patients matched to precision medicine trials across Ontario, acceleration of the identification of actionable biomarkers, increased pharmaceutical support for academic clinical trials, and improved patient experience in trials.

An estimated 1 in 15 children is born with a rare genetic disease. Since 75 per cent of the 4,000 diseases manifest in childhood, children affected by them occupy 25 per cent of pediatric hospital beds in Canada, with diagnostic assessments often exceeding $10,000 per child. Despite advances in genome sequencing, most people with rare disorders remain undiagnosed, resulting in a significant socioeconomic burden related to the so-called “diagnostic odyssey”, impacting treatment, reproductive planning and access to specialized care services. In addition to genetics, a significant cause of birth and neurodevelopmental defects involves prenatal exposures to teratogenic toxins including lifestyle choices, drugs and pathogens.

Toxic exposures are challenging to resolve due to the lack of genetic biomarkers that can be detected with standard molecular tests. In partnership with Canadian biotech start-up EpiSign Inc., London Health Sciences Centre’s Dr. Bekim Sadikovic has developed the first technology, called EpiSign, that uses a patient’s epigenome to diagnose both genetic and teratogenic disorders.

EpiSign’s proprietary and continuously evolving AI-based algorithms compare Illumina microarray-generated epigenetic DNA methylation profiles in a patient’s blood to the EpiSign Knowledge Database, the largest, rare disorder DNA methylation database.

This project will expand clinical adoption of EpiSign as a Tier I test, using new Illumina technology. The project will advance molecular diagnostics of rare disorders and enhance Canada’s leadership in clinical epigenomics. Improved and earlier diagnosis will give patients better access to care options and support networks, while improving health equity and socioeconomic impacts on healthcare systems in Canada and internationally.