Prostate cancer is the second leading cause of cancer death. Comprehensive analysis of genomes has the potential to inform precise prostate cancer treatments. However, a major challenge of prostate cancer genomic analysis is the inaccessibility of metastatic tissue. Circulating tumour cells (CTCs) offer great potential as an alternative source of genetic material, which would enable the identification of the relevant mutations and aberrations that define prostate cancer subtypes.
Despite the tremendous potential of CTC genomics, there has been little progress in genotyping CTCs. This is due to the rarity of CTCs and their genetically heterogeneous population. Current methodologies have overcome this limitation by performing single-cell sequencing. However, existing methods for single-cell isolation require precise manipulations using contaminant-free tools, which are either extremely difficult to perform or are associated with unacceptable cell loss.
Dr. Choi’s research will look to develop a new method to rapidly target and select single CTCs based on their phenotypic profile. This method would enable both in situ immunostaining and single cell sequencing, which would provide important insights when interpreting data from genetic analysis.
The results of this research could be significantly beneficial in the development of personalized therapy, evaluation of anti-cancer drugs, and surveillance for disease recurrence.
Epilepsy is one of the most common brain disorders. The condition is characterized by uncoordinated brain electrical activity and recurrent seizures. Epilepsy patients may die unexpectedly with unknown cause, a phenomenon termed “sudden unexpected death in epilepsy” (SUDEP). SUDEP accounts for about 50% of deaths in individuals suffering from drug-resistant epilepsy in which severe seizures are followed by alterations in respiratory and cardiac functions.
The underlying mechanisms triggering SUDEP remain unknown. Using animal models of human disease and live brain imaging, Dr. Thouta’s research will work to define the specific brain regions that promote brain inactivity during SUDEP-like seizures. This will include testing novel anti-epileptic drugs as a potential preventative SUDEP agent.
The results of this research will provide an understanding of the cause of SUDEP and could have a significant impact on epilepsy drug development efforts, potentially leading to the discovery of novel therapeutics for SUDEP prevention.
The dispersal of tumour cells within malignant tissue relies on a process called chemotaxis, where tumour cells migrate in response to chemical signals in the local microenvironment. There has been longstanding interest in using chemotaxis assays to deduce how invasive a tumour is, and how it might respond to drug therapy. However, current chemotaxis assays are prone to extreme inter-assay variability, due to the inherent instability of the chemical gradient. Additionally, existing assays require a large number of cells, making it impossible to test primary patient tissue, which typically only yields a few hundred tumour cells.
Dr. Park’s research will work towards developing a microfluidic platform to generate highly stable and uniform chemical gradients for the chemotaxis assay of a small number of tumour cells. She will validate the technology by examining the response of cultured tumour cells to chemotherapy. Cells from murine tumour xenograft will further establish the relationship between migration with disease progression and drug-efficacy.
The results of this research could provide a reliable means to evaluate the migratory potential of patient tumour cells both before and in response to therapy, ultimately guiding clinical decisions in practice and within personalized clinical trials.
Diarrheal disease affects 1.7 billion people every year, killing around 760,000 children. A leading cause of this disease are bacteria like enteropathogenic Escherichia coli (EPEC). EPEC’s ability to cause disease relies entirely on creating an environment in which it can thrive. EPEC achieves this by secreting “effector” proteins directly into human host cells, which rewire the human cell, allowing EPEC to take control of cell immune signalling. One way effectors work is by chemically modifying host proteins with phosphate groups (phosphorylation), which may alter how proteins interact with one another.
Dr. McCoy’s research will develop a method for studying the interaction between bacteria like EPEC and their human hosts. His preliminary data has shown that a group of drugs called bumped kinase inhibitors (BKIs) can block this interaction. Expanding on this, he will aim to reveal how EPEC uses phosphorylation to manipulate the human host and establish infection.
Allergic diseases are reaching epidemic proportions, now affecting 1 in 3 Canadians. Allergies are inappropriately high immune responses against innocuous allergens. Understanding why the immune system reacts in this way is crucial to identify new drug targets.
Proteases are enzymes that cut other proteins from allergenic sources, for example dust mites and mould. Proteases are potent triggers of allergic responses. However, an understanding of the proteins they cut and how they fit into the global picture of allergic responses is lacking.
Dr. Machado Hernandez’s research will work to identify the key proteins involved in allergic responses triggered by proteases, or cut by proteases, using an innovative and highly advanced technique known as “degradomics”—a method of uniquely identifying the cut ends of proteins by purifying them from the rest of the protein. As cuts are formed only during active disease, these segments are highly valuable as disease markers to develop new clinical tests and identify new drug targets.
The roles of these proteins and their cut products will be deciphered by biochemical and immunological studies to reveal the damaged proteins and proteases that can be targeted with new drugs to improve health outcomes and ensure sustainable health care costs.
Oxidative stress (OS) describes the occurrence of reactive oxygen species (ROS), chemicals that cannot be balanced by the body’s antioxidant defenses. OS can occur in every cell of the body and is linked to an increasing number of diseases.
Recently, several reports indicated the influence of OS on transient receptor potential (TRP) channels that are expressed in various cell types and involved in a broad array of functions. More recently, it was discovered that redox reagents can modulate the activity of TRPM3, a nociceptor channel, involved in the detection of pain and heat. TRPM3 is highly expressed in the brain, but no functional role has been established for TRPM3 in this area so far. However, the brain possesses a high oxygen content and diseases like epilepsy have been linked to the occurrence of OS.
Dr. Held’s research will investigate the role of TRPM3 in the brain and in brain-related diseases that induce oxidative stress. The outcome of this project will improve our understanding of TRPM3 function and its role in cell stress-inducing pathological conditions, which could help to develop new treatment options.
The discovery of antibiotics was one of the greatest advances in modern medicine, enabling control of infections. However, bacteria can develop antibiotic resistance over time, and become less sensitive to antibiotics. Without effective treatments, infections by these organisms can lead to prolonged illness, and routine surgeries can become life threatening. The lack of new antibiotics to combat the rapidly growing number of multi-drug resistant (MDR) organisms has become one of the most serious global health concerns. There is an urgent need to develop new therapeutic strategies against MDR organisms.
Dr. Choi’s research will investigate the potential use of a group of natural molecules known as host defence peptides as an alternative therapy to treat chronic infection caused by MDR organisms. The advantage of these peptides is that they do not directly target microorganisms; instead, these molecules promote the body’s immune system to fight against infections. This unique ability prevents microorganisms from developing resistance towards the peptides.
Results from this research will be an exciting example of alternative therapy to treat antibiotic resistant infections.
End of Award Update: October 2022
Most exciting outputs
One of the most exciting outcomes is to have the opportunity to present my results at an international conference—the Gordon Research Conference—and establish networks with scientists across the world.
Impacts so far
The Michael Smith Health Research BC/ Lotte & John Hecht Memorial Foundation Research Trainee award allowed me to focus on my project to develop alternative therapeutic strategies against multi-drug resistant organisms, especially during the COVID pandemic.
Potential future influence
The award gave me opportunities to attend various conferences where I presented my work, met with researchers whom I can learn from to advance my knowledge and skills, and built supporting networks, all of which are invaluable for my career goal as a researcher.
Next steps
We are in the process of writing a manuscript on utilizing lung organoid model for screening antimicrobial and immunomodulatory therapies against Pseudomonas aeruginosa infection.
Useful links
Despite major advances in our understanding of the mechanisms behind the body’s immune response against cancer, several obstacles limit the success of immunotherapy as a cancer treatment. In particular, the physical exclusion of immune cells from tumour beds is associated with poor prognosis and a limited response to immunotherapy.
Dr. Rodriguez’s research will address this issue by investigating the mechanisms underlying the exclusion of immune cells in ovarian cancer. The results will lead to more effective treatments to help the immune system eradicate ovarian and related cancers. The findings of this research will lead directly into first-in-human clinical trials for patients with ovarian cancer and related malignancies.
There are 62,000 strokes in Canada each year–one every nine minutes–and 405,000 Canadians are living with the effects of stroke. Stroke rehabilitation is a large field with a need for further research and treatment development.
Dr. Balbi will investigate brain stimulation and movement-based stroke rehabilitation by studying brain activity and forelimb movement in mice stroke models.
The aim is that this research will yield optimal parameters and inform treatment in humans with regards to intensity and frequency of rehabilitation, specific passive movements and brain stimulation, and ultimately will allow human-translatable stroke treatments to be piloted in a larger sample.
Lung cancer is the leading cause of cancer-related death in Canada. A major reason for the poor prognosis is the lack of effective drugs for treating advanced tumours.
New understanding of the mutations driving lung cancer has led to the development of targeted therapies that selectively inhibit mutated genes, leading to rapid cancer regression in specific subsets of patients. However, while these therapies improve patient survival and quality of life, they are not curative as all patients develop drug resistance.
While some causes behind this resistance have been defined, others remain elusive, and are becoming more prominent with newer generations of drugs. A major example is tumours changing how they look—shifting from one type of lung cancer to another—but what causes this is still not clear.
Dr. Inoue’s research will test whether treatment with targeted therapies creates the environment that allows tumours to “change their skin” and continue to grow in the presence of drugs. The goal is to determine the genes involved in this shift and prove they are responsible for drug resistance. This will lead to new therapeutic strategies that will provide longer-term survival benefits for lung cancer patients.
