Research Pillar: Biomedical

Developing novel cancer diagnostic platforms and advancing treatment options for metastatic cancer

Metastasis, which is the spread of cancer cells from a primary tumor to other areas in the body, remains the main cause of cancer related death. Awareness of the clinical importance of metastasis and our basic scientific understanding of the metastatic process has improved substantially over the past few decades. However, many aspects of metastasis are still not well defined and our ability to identify patients at high risk for cancer spread is limited. In addition, cancer treatments are not metastatic-specific, so despite aggressive treatments many patients still progress to a metastatic disease state. Dr. Williams' research aims to address these issues by identifying aggressive disease early and uncovering key regulators of metastasis for inhibitor development.

Cancer cells are constantly shedding small fragments, which can be readily detected in the blood. This project will develop a test that analyzes these fragments, identifying cancer patients and determining the aggressive nature of their disease. It also aims to uncover how cancer cells move and grow within the body by forming tiny 'feet-like' structures called invadopodia. Understanding their role in cancer progression will shed light on how cancer cells move and grow within the body, validating them as targets for metastatic inhibitor development. Overall, this research program will make powerful strides towards ending metastasis, the most significant cause of cancer mortality.

Platelet signaling in chronic inflammation

Proper function of the immune system is essential for protection against infectious disease and maintaining human health. During the onset of infection, white blood cells and platelets release signaling molecules known as cytokines, which orchestrate a protective inflammatory response. When cytokine release is de-regulated, excessive inflammation causes cell and tissue death and loss of function. This is seen in gum disease (periodontitis), which is characterized by gum inflammation and destruction of tooth-supporting connective tissues and bone. This research will uncover the mechanisms responsible for maintaining the health of periodontal tissues.

Platelets, in addition to regulating blood clotting, are emerging as pivotal components of the inflammatory response. Dr. Kim and team will study how periodontal infection causes cytokine release from platelets, focusing on:

  1. How human platelets respond to periodontal infection and determine how platelet function correlates with clinical gum disease status.
  2. How the cell's structural framework mediates the release of cytokines from platelets.

An improved understanding of platelet function could have important implications for rational treatment of inflammatory diseases, including gum disease.

Neuromodulation research program for youth addiction and mental health

Each year, approximately 1 in 5 Canadians experiences a mental health or addiction problem. Young people aged 15 to 24 are more likely to experience mental illness and substance use than other age groups.

Depression is one of the most common mental illness, but current treatments are either ineffective or lead to side effects in up to 50% of youth. In youth, medications are often borrowed from adult population not accounting for age-related brain differences. New solutions are needed to address major gaps in treatment of youth mental health.

Dr. Farzan is collaborating with physicians, neuroscientists, engineers, and health authorities to develop and apply more precise and innovative methodologies to study the brain and address this gap. She is combining non-invasive brain stimulation and brain monitoring technologies to study what may underlie depression in young age, and how each treatment affects the brain. She is also developing non-invasive brain stimulation technologies for youth that do not respond to medications or behavioral therapy. This research has tremendous potentials for leading to introduction of a new therapy for youth who are failing currently available treatments.

Phosphoinositide kinases: Molecular determinants for their regulation and role in human disease

Lipids are the primary constituent of all cellular membranes, however, they also can play key roles as signaling molecules that controls how a cell responds to its environment.  Almost every aspect of a cell's decision to live and die is impacted by the role of lipid signals called phosphoinositides. These signals are generated in the correct location and at the appropriate time by proteins in our body called phosphoinositide kinases (PI kinases). Misregulation of PI kinases is a key driver of disease, including cancer and immunodeficiencies.

Intriguingly host PI kinases are frequently hijacked by pathogenic viruses to mediate viral replication, and targeted inhibition of parasite PI kinases is a promising therapeutic strategy for treatment of malaria and cryptosporidiosis (a diarrheal disease caused by microscopic parasites). Therefore, understanding the molecular basis for how PI kinases are regulated is of extreme biomedical importance.

Dr. Burke's research is focused on understanding the molecular basis for regulation of PI kinases, and how they are involved in human disease. He and his team have revealed fundamental insight into how these enzymes are involved in cancer and immunodeficiences, and how viruses manipulate them to mediate infection. Overall this work is important in understanding how lipid signals mediate disease, and will be critical in the design of inhibitors as novel therapeutics.

Custom platform for preoperative planning of complex head and neck reconstruction

Advanced head and neck cancers involving facial bone often require aggressive removal of diseased bone. Reconstruction of the bone is typically done by cutting and reshaping patient donor bone. This process involves is complex, since the accuracy of the reconstruction significantly impacts cosmetic and functional outcomes. Doing this during surgery is challenging, time-consuming and can be improved with better planning before surgery. 

One method of pre-operative planning is to use patient imaging data to perform virtual reconstructions and design 3-D printed cutting guides for use during surgery. Currently, the only way to obtain such guides is through a third party and costs between $2000 – $6000 per case. However, this process has a significant turnaround time and surgeons have limited input on how the actual guides are designed. 

My group has developed a software that makes the pre-operative process fast, simple and effective. We currently have the capacity to plan mandible (lower jaw) reconstructions with the fibula (lower leg) and are now validating the process through a clinical trial. We hope to extend the software capability to other surgeries and conduct research to generate supporting evidence.

Unraveling disparate roles of Notch-1 and Notch-2 signaling in bladder cancer

Bladder cancer is the fifth most common cancer, yet it remains understudied and we are only now making strides in understanding it’s molecular make-up. Recently we and others have discovered that loss of the cell surface receptor Notch-1 drives growth of some bladder cancers, while increased Notch-2 activity drives growth of other bladder cancers. Here we aim to determine how Notch-1 and Notch-2 can lead to such differing effects on cancer growth even though they share many features. From this we aim to design a new drug to inhibit Notch-2.

We will:

  • Create a mouse model that over-expresses Notch-2 in the bladder. We expect this will cause bladder tumours to form.
  • Use advanced techniques to study the differences between Notch-1 and Notch- 2 signaling that make them have such different effects. We will especially investigate how each Notch protein controls the reading of genes in the cell nucleus.
  • Develop a new a new drug to inhibit Notch-2 using computer-aided drug design.

End of Award Update – April 2024

 

Results

We have identified a candidate Notch-2 inhibitor that requires further testing in pre-clinical models before potential testing in patients with bladder cancer.

 

Impacts

Our work has explained an important pathway that drives growth and progression of bladder cancer in some patients.

 

Potential Influence

This new inhibitor could represent a novel way to treat bladder cancer.

 

Next Steps

We will publish the results on Notch when completed.

Improving outcomes through precision medicine for adults with primary immunodeficiency

Primary immunodeficiencies (PIDs) are a group of conditions in which part of the immune system is either missing or does not function normally. Those affected by PIDs may suffer from recurrent infections, autoimmune disease (where the immune system attacks the body's own tissues), and certain cancers. These conditions are not rare; affecting 1:2,000 to 1:10,000 people, with nearly half of cases diagnosed in adulthood. Too often, adults with PIDs undergo a painful journey that spans decades in search of a diagnosis. Without knowing the cause of their immune deficiency, adults with PIDs may not receive life-changing treatment. 

Our research program will address these challenges using precision medicine: an exciting way of identifying the cause of the disease and finding treatments that specifically target the underlying problem. We will perform next generation sequencing, a method to quickly read genetic material, on adults with PIDs where the underlying cause is undiagnosed. If a new change in a gene (mutation) is identified, we will perform specialized experiments to prove that the mutation is indeed responsible for the patient's symptoms. We will then look for targeted treatments to address the specific cause of that patient's illness. 

By harnessing the power of personalized genetics and precision medicine, our goal is to improve outcomes for adults suffering from PIDs.

Orthogonal multicolour high-affinity tags for RNA imaging and manipulation

RNA plays a very important role in the regulation of gene expression. Yet, the spatial and temporal dynamics of RNA are still poorly understood, mainly due to the scarcity of effective and simple RNA imaging and purification techniques.

The development of technologies that simultaneously allow imaging, purification and manipulation of multiple RNAs in live cells promises to enable the study of RNA in development, metabolism and disease, which is essential for understanding the control of gene expression in diseases such as autism, cancers and type II diabetes.

Dr. Dolgosheina will develop a multicolour RNA-based imaging method that will allow researchers to simultaneously visualize two RNAs in living cells, while concurrently purifying and/or manipulating RNA interactions with other biomolecules. This new technology will build on, and dramatically increase the capabilities of the bright, high affinity RNA Mango system that she developed during her PhD.

The proposed project is working on an outstanding international problem, and since these tools are urgently needed, the research has attracted significant national and international attention.

This research project will 1) result in international level talks and publications, 2) bring together some of the best international researchers in RNA biophysics and 3) result in intellectual property development, industrial research and training and commercialization via a rapidly growing Canadian biotechnology company, Applied Biological Materials (Richmond, BC).

Elucidating the effect of O-GlcNAc modification on protein stability

The glycosylation of proteins with O-GlcNAc is a ubiquitous post-translational modification found throughout the metazoans. Deregulation of O-GlcNAcylation is implicated in several human diseases including type II diabetes, Alzheimer’s disease, and cancer.

 

However, the basic biochemical roles of O-GlcNAcylation remain largely unanswered. Several recent studies have demonstrated a clear link between O-GlcNAc and cellular thermotolerance.

 

It is likely that a basic function of the O-GlcNAc modification prevents the unfolding or aggregation of target proteins. Dr. King will investigate its role in protein stability through series of biochemical and biophysical experiments to probe the effect of O-GlcNAc on protein unfolding, folding, and aggregation. The results of this research will provide important insights into the basic molecular mechanisms governing O-GlcNAc deregulation in human disease.

 

End of Award Update: July 2022

 

Most exciting outputs

The modification of proteins by O-linked N-acetylglucosamine (O-GlcNAc) is a widespread post-translational modification (PTM) that is dysregulated in several human diseases including type II diabetes, Alzheimer’s disease and cancer. However, research progress in this area is hampered by the fact that it is challenging to detect O-GlcNAc on proteins. Further, the basic biochemical roles of O-GlcNAcylation remain largely unanswered.

 

Therefore, we developed a mass spectrometry based method to precisely map sites of O-GlcNAc on proteins. This method employs a UV laser to produce a diversity of O-GlcNAc retained fragment ions, enabling mapping protein modification sites with unprecedented precision.

 

We then explored the role of O-GlcNAc as a biochemical regulator of protein stability. We developed a new high-throughput approach to profile the effect of O-GlcNAc on the thermostability of the proteome. Using this method, we identify several proteins that are regulated by O-GlcNAc. Interestingly, the majority of these proteins display an O-GlcNAc dependent decrease in stability, challenging the prevailing view of O-GlcNAc as being a predominantly stabilizing modification. Thus, we show that O-GlcNAc is a bi-directional regulator of protein stability. We deliver a powerful approach that provides a blueprint for determining the impact of, in principle, any PTM on the thermostability of thousands of proteins in parallel.

 

Impacts so far
This work delivers powerful tools for exploring the role of O-GlcNAc and other labile PTMs as regulators of protein biochemistry.

 

Potential future influence
Decreased levels of protein O-GlcNAcylation is associated with Alzheimer’s disease. However, the basic biochemical mechanisms underlying this association remain unknown. Here we show that O-GlcNAc regulates the stability of several proteins within human cells, a phenomenon that may impact cellular protein levels in Alzheimer’s disease. This fundamental research is important for understanding the impact O-GlcNAc has on protein structure and stability, particularly in the context of its dysregulation in neurodegenerative disorders.

 

Next steps
We plan to continue exploring the influence O-GlcNAc has on protein structure and function. In doing so, we hope to improve our understanding of the fundamental mechanisms underlying neurodegeneration. This research may ultimately provide knowledge that contributes toward the development of new therapeutic strategies.

 

Useful links

Development of improved substrates for live cell imaging to aid in discovering new glucocerebrosidase therapeutic agents

Parkinson’s disease (PD) is a neurodegenerative disorder that affects millions of people worldwide, with no standard treatment currently available. Therefore, there is a major need for new therapeutic agents to treat or prevent the progression of PD. One promising solution involves targeting the protein glucocerebrosidase (GCase) encoded by the gene GBA1. Studies have shown small molecules that increase GCase activity could help prevent the progression of PD.

Dr. Ashmus will use a combination of organic chemistry, chemical biology, and cell biology to discover new therapeutic agents that increase GCase activity. Fluorescently-quenched substrates will be chemically synthesized and used in enzymatic assays to monitor GCase activity in vitro and in neuroblastoma cells. The assay will then be adapted and optimized for use in a high-throughput screen of compounds from the Canadian Glycomics Network and from a natural products collaborator, Roger Linington, at SFU.

The results of this research could produce new lead compounds that increase GCase activity. In addition, the compound screen could aid in identifying new therapeutic targets for PD, which would drive preclinical translation research in this area.

End of Award Update – March 2022

Most exciting outputs

An exciting and successful specific output as part of the project was that we were able to develop a newly designed probe that performs better than the original probe the Vocadlo Lab published and patented back in 2015. The new probe is also capable of being used in a high-throughput screening in live cells. Moreover, the new design led to the development of probes that could for the first-time target other disease-related enzymes of interest in live cells and led to a high-impact publication in Nature Chemical Biology.

Impacts so far

While the main purpose of the research project failed to discover any lead compounds that could be developed as a potential therapeutic agent for Gaucher/Parkinson’s disease, the steps (develop a better probe and optimize use for screening) required to reach the point of running the screen were successful. The data collected (unpublished) has helped secure funding for the Vocadlo Lab and led to collaborations with biotech companies interested in targeting the same enzyme.

Potential future influence

I think some of the work described briefly will start to gain more attention in the next few years. Over the past year or so, I have noticed an increased interest from research institutes and biotech companies in studying enzymes found within the lysosome. This is in part because more of these lysosomal enzymes are being linked to neurological diseases so having biochemical tools that can study them in live cells will be desired. I think some of the probes we have developed over the past couple of years will be of interest to a broader scientific community.

Next steps

The work searching for potential therapeutic agents for Gaucher/Parkinson’s disease is currently ongoing. The majority of my research efforts have shifted to developing and evaluating novel probes targeting other disease-related enzymes. One notable example is a new project collaborating with an expert clinician in Fabry’s Disease. Using one of our recently developed probes, we aim to advance current diagnostic methods and improve dosing and timing of current therapeutics for Fabry Disease patients. I am excited to see some of my work being used in a clinical setting and hope this can lead to something more fruitful in time. Dissemination of the work will be continued through publications, presentations at conferences and through social media platforms.

Useful links