12 LMP faculty receive CIHR funding to investigate disease and impact health

Ming-Sound Tsao and Kelsie Thu, Princess Margaret Cancer Centre, University Health Network

Lung cancer is the leading cause of all cancer deaths in Canada and worldwide.

During the last decade, new drugs that target specific mutant proteins in lung cancer have significantly improved the overall survival of patients. However, curing lung cancer remains difficult because tumors nearly always develop resistance to these drugs. A major contributor to drug resistance is a small population of tumor cells that can survive the toxic effect of the targeted therapy. These resistant cells are termed drug tolerant persisters or DTPs and usually grow very slowly. When the drug is discontinued, DTPs resume rapid growth and allow the pre-treatment tumor to reform. If drug treatment is maintained, DTPs eventually can acquire further changes that make the cancer cells become resistant to the drug effect. DTPs are the main reason why targeted therapies require lifelong treatment and a major barrier to improving survival of lung cancer patients.

To study DTP biology that mimics what happens in patients treated in the clinic, our group has used patient-derived lung cancer models that respond to the clinically approved drug osimertinib which targets EGFR, a common mutant protein in lung cancer. Treatment of these tumor models with osimertinib resulted in tumor shrinkage and DTP formation. This project aims to characterize biological pathways that are abnormally activated in DTPs to enable drug tolerance and to explore whether inhibitors targeting these pathways can improve the effectiveness of osimertinib.

The results will provide new insights into how to improve the treatment outcome of lung cancer patients.

Valerie Wallace, Department of Ophthalmology & Vision Sciences

Researchers are investigating cell transplantation as a potential remedy for restoring lost neural function in brains that have suffered neuron loss. The eye stands out as a particularly valuable avenue for these investigations due to its unique ability to deliver cells to the precise areas requiring intervention. When light-sensitive cells, known as photoreceptors, die off in the retina, it leads to irreversible vision impairment with no available treatments.

A significant hurdle in the success of cell replacement therapy is that the transplanted photoreceptors often struggle to establish proper connections within the intricate neural network. This connectivity shortfall can severely impact their functionality and impede the process of tissue repair.

To overcome this challenge, our objective is twofold: firstly, we aim to gain insights into the natural process through which photoreceptors form connections, and secondly, we are identifying substances or molecules that could potentially enhance the capability of transplanted photoreceptors to effectively link up with the existing retinal neurons.

This research holds promise for addressing the connectivity issue and thereby improving the overall success of cell transplantation therapy for vision restoration.

Adam Shlien, Hospital for Sick Children

Progress in our understanding of bone and soft tissue cancers, collectively known as sarcoma, has been limited over the last four decades. As such, sarcoma remains one of the most challenging cancers to definitively diagnose and effectively treat. Despite considerable strides, innovation in sarcoma research lags amidst advances in other cancers, especially for aggressive relapse and metastatic disease in cancers such as Ewing sarcoma. Impacting both children and adults, lack of knowledge of the origins of these cancers leaves doctors with the conundrum that aggressive treatments needed to achieve a cure deliver toxicities that may impact the patient for a lifetime. Such medical decisions remain essentially conjecture.

We are working to help change this with our innovative technologies that use advanced techniques in genomic medicine developed over the past decade. Ewing sarcoma is an aggressive childhood cancer with survival rates of 70-80% in some patients but less than 50% and as low as 10% in patients with recurrent metastatic diseases.

Our project investigates these differences at the molecular level as we aim to improve our understanding of how Ewing sarcoma originate, develop, and progress. With this knowledge, we hope to change the trajectory for future patients. Using our expert technologies, we have begun to generate advanced definitions of sarcoma based on their molecular structure (genome) and their molecular behaviour (transcriptome). We will model the activity of these cancers in the lab.

This will give clinicians more information so that they can make more informed diagnoses earlier and more precisely. Clinicians will also be able to make more informed predictions of how each patient's disease may progress and respond to various therapies. Such information will invaluably allow more treatment options, thus finally improving disease trajectories and outcomes for future patients with cancer.

Dana Philpott, Department of Immunology

Recent findings have uncovered a surprising link between patients with the inflammatory bowel disease, Crohn's disease (CD) and an increased risk of type 2 diabetes (T2D). Notably, CD and T2D share certain pathophysiological features in patients, including altered metabolism, accumulation of abdominal fat, an increased "leaky gut" and changes in the microbes that inhabit the gut, yet the relationship between these two diseases is not understood.

We have developed a mouse model of CD featuring intestinal inflammation that promotes features of metabolic disease, similar to what is observed in T2D patients. With this model in hand, we can now study the pathogenesis of this complication of CD, which will help to shed light on mechanisms underlying intestinal health and open up new avenues for treatment.

Wilder Scott, Sunnybrook Research Institute 

The goal of this project is to understand how tendon cells make tendon, so we can improve how it heals. 

Tendon injuries are extremely common and affect young and old alike. Tendons can be damaged from intense physical activity or gradually wear out over time. Once tendon is injured, it rarely returns to the preinjury state. Currently in the clinic, we treat the pain and inflammation and hope for scar tissue to restore some of the structural integrity, but tendon is a finely tuned organ with specific biomechanical properties, while a scar is thick disorganized connective tissue which cannot meet the demands put on tendon. This leaves patients in pain and immobilized, which impacts their ability to work and exercise, and deprives them of their independence. A vicious circle ensues, as this state is accompanied by a much higher risk of reinjury. 

True regeneration means restoring the tissue to the preinjury state and is dependent on stem cells to replace the damaged tissue with new tendon tissue. We have found Mesenchymal Progenitor (MP) cells with the potential to make tendon cells in adult mice, however, there are considerable gaps in our understanding of the molecular processes that drive MPs to become tendon cells. Herein, we address this by using a genetic tool, which allows us to identify, isolate and manipulate MPs in mouse injury models. We will perform a systematic analysis of MPs throughout the healing process to find out what genes they need to activate, and in what order, to generate tendon. Then, with the aim to enhance tendon cell formation and reduce scar tissue deposition, we will strategically perform genetic and pharmacological modifications to affect MP behaviour, and evaluate the consequences on tendon healing outcome parameters.

This research will map the path from stem cell to tendon cell and generate leads to uncover targets for therapeutic and tissue engineering strategies that can be used to improve tendon regeneration and mitigate degeneration.

Daniel Winer, Toronto General Hospital, University Health Network

Obesity is a major global health concern. It is associated with poor response to insulin, called insulin resistance (IR), which can lead to high blood sugar and type 2 diabetes (T2D). Interestingly, men are almost twice as likely to develop IR and T2D than women, though obesity rates are similar, suggesting there is an important relationship between sex, weight and diabetes. While sex hormones like estrogens and androgens are thought to play a role, the mechanisms for these sex differences in diabetes predisposition remain unknown. 

We previously showed that inflammation in fat is a major cause of IR in the body. However, the gut also contains immune cells, and evidence suggests that these cells are critical in controlling the inflammatory reaction leading to IR.

In this project, we will leverage the use of a newly generated single cell atlas of how a high fat diet (HFD) changes the composition of the immune cells living in the intestine in both male and female mice to understand sex specific predispositions in IR. Our atlas identifies critical changes in immune cells called innate lymphoid cells (ILC)s and B cells, which make immune mediators, driven by sex and diet. 

This research proposal will investigate how these gut immune cells contribute to the processes cumulating in diabetes, and relate these changes to sex. We will first determine how mice lacking critical identity factors that control ILCs function during HFD feeding. We will then perform experiments to comprehensively characterize potentially inflammatory B cells that seem to emerge only in males during HFD. Finally, we will determine how and why sex is impacting ILCs and B cells in the gut during HFD by examining connections to the microbiota, as well as sex hormones, and the supporting fibroblast cells in the gut that respond to these factors.

The results of this work may explain why sex is a major factor in IR development and may facilitate new therapies better personalized to men or women.

Vinod Chandran, Department of Medicine, with collaborator Igor Jurisica

Psoriasis is a common chronic inflammatory skin disease that affects more than a million Canadians. Many patients with psoriasis also have involvement of the joints and develop a specific form of arthritis called psoriatic arthritis (PsA). Patients with psoriasis and PsA have flaky, red, itchy skin, joint destruction, limitation of function and poor quality of life. 

The disease is heterogeneous with some patients having a mild course with few symptoms while others have a rapid destructive arthritis leading to severe functional limitation and poor quality of life. Identifying molecular pathways that reflect these subsets will help delivering better patient care and personalized treatment. 

Towards these goals, we aim to first identify all previously conducted research on molecular analyses using omics and obtain publicly available data. We will then integrate the data to identify markers and pathways that reflect the patient's disease state. We will then confirm these findings in PsA patients enrolled into our International Psoriasis and Arthritis Team cohort study. Using advanced computational algorithms, we will also identify pathways associated with disease state and treatment response. Future work will confirm these findings in studies conducted by our collaborators and by using animal models and patient tissue-derived disease models. 

The results will be regularly updated as data is generated by researchers worldwide and shared with the research community through a publicly available portal. Thus, the project will leverage data and results from molecular studies done worldwide to provide insights into disease pathways that will promote personalized medicine in psoriatic disease, lead to identification of new drug targets, and serve as a model for similar studies in other immune-mediated diseases.

Christopher McCulloch, Faculty of Dentistry

Many tissues in humans exhibit destruction and loss of function as a result of inflammatory diseases. Some of these diseases, like osteoarthritis, rheumatoid arthritis and a type of gum disease known as periodontitis, are of high prevalence, cause substantial pain and are associated with high treatment costs. These diseases also exhibit long-standing chronic inflammation that is interrupted by brief episodes during which there is rapid tissue destruction.

In this application we examine one important mechanism by which a protein released from cells in chronic inflammation causes tissue destruction during brief episodes and we examine how this destructive mechanism can be inhibited to conserve tissue structure and function.

Claudia Dos Santos, Department of Medicine, with collaborators Gilbert Walker and Joao de Rezende

Sepsis is an exaggerated, systemic, immune response to an infection that often leads to multiple organ failure. It is the most common cause of death in critically ill patients, and over 2 billion dollars is spent every year in Canada on sepsis care. The current standard of care is supportive - antibiotics or antivirals are given to deal with the source of infection, then supportive care is used such as mechanical ventilation and fluid management, which requires (at least) days of bedside care and frequent assessment. 

There are no treatments for the underlying genetic dysregulation of sepsis, and we aim to change this. The proposed solution's innovation is a therapeutic formulation to supplement beneficial and reduce detrimental microRNAs, which regulate protein synthesis and influence multiple biochemical pathways. The microRNAs will be encapsulated in a lipid nanoparticle to ensure the therapy's efficacy. The in vivo data show that leading microRNAs are anti-inflammatory, anti-microbial and protect organs from injury. In a mouse model for bacterial induced cardiomyopathy, after treatment with microRNAs the infected mice have significantly improved survival - from ~25% to ~80% after 7 days, which is highly promising. 

Previous work in profiling the genomic response of the host to sepsis enabled the selection of the therapeutic microRNA type to use. This microRNA-nanoparticle technology is currently at TRL4 having shown the efficacy of the therapeutic in vivo. By using materials prepared under good manufacturing practice, including a larger animal model, then further studying the therapeutic characteristics and efficacy at multiple time points post-infection, we will bring the project to TRL5 and TRL6, respectively. 

Our research will be supported by the Innovations & Partnerships offices of the institutions. NorthMiRs, a strategic partner that will work to develop further the market potential of the proposed therapeutic, is a spin-off from the University of Toronto.

Gregory German, St. Joseph's Hospital, Unity Health Toronto, with collaborator Duminda Wijeysundera

Fix recurrent Bladder infections which affect 1 in 4 of all women and the whole health system benefits economically and with less antibiotic resistance. By 2050, more people are anticipated to die from infections that fail traditional antibiotics than will die from cancer and we need immediate action. A traditional antibiotic costs 2 billion dollars and takes 10 years to develop and then only one DNA change can make the antibiotic ineffective. 

For over 100 years a non-traditional antibiotic, a good virus, has been used to destroy infection-causing bacteria. This type of virus does not attack humans and is called a bacteriophage (bacteria eater) or phage for short. Like all viruses, they reprogram their target to make more of itself at the target. 

Phage therapy can be found rapidly for the patient's specific UTI-causing bacteria and provides personalized medicine. We propose a randomized controlled trial targeting the E. coli germ which causes 3 out of 4 of all urinary tract infection organisms. First, we find patients who have failed routine therapy and even specialized intravenous therapy with a strong antibiotic called ertapenem. Second, we send the E. coli bacteria to be tested in a laboratory to find the single or group of phages that can shut down the E. coli in a test tube. Next, when the patient is well and without active infection, purified phages or mock preparations are placed in the bladder once, provided by mouth, and given topically over the vagina. A brief course of ertapenem is given to all patients to improve the phage when given. We then monitor microbiology interactions and the patient to see if they have an infection with the same bacteria within 1 to 6 months. 

We anticipate that the success with phage will be up to 50% effective vs 10% effective with no phage provided at the one-month mark. We calculate that 50 women are required for recruitment and those that initially receive a placebo will receive phage if they still require care.

Mario Ostrowski, Department of Medicine 

The COVID-19 coronavirus pandemic due to SARS-CoV-2 continues with accumulated 769 million cases, and 6.9 million deaths globally, and although rates have dropped, increased SARS-CoV-2 infections in the fall of 2024 are predicted. 

Within the pandemic, community groups had identified 'long COVID', as a major personal and economic problem. Long COVID is characterized by fatigue, shortness of breath, brain dysfunction and other symptoms, impacts everyday functioning, and has been reported in at least 10% of individuals recovering from SARS-CoV-2 infection. Despite vaccination, and new variants, the number of long COVID cases continues to increase. 

The cause of long COVID is still unclear. Recent studies have suggested the that the immune system in long COVID individuals is not working properly and that another virus, EBV (Epstein -Barr Virus), a virus known to be associated with chronic fatigue might be contributing to long COVID. 

Our research team will try to understand whether long COVID is due to abnormal immune responses to both of these viruses, SARSCoV-2 and EBV. In addition, we will search for possible new bio-markers in the blood that may help explain this condition. By further understanding the nature of the immune dysfunction and uncovering new biomarkers, we may be better able to offer good therapies.