Prostate cancer is the most commonly diagnosed form of cancer for men in North America. Prostate cancer deaths have been in decline since the mid-1990s after the discovery of Prostate-Specific Antigen (PSA), which, when used for screening, results in a steep increase in the number of early diagnoses. A large percent of these PSA-detected cases do not express clinically, are slow growing, and do not require treatment, and therefore do not contribute significantly to overall mortality. Conversely, some slow growing cancers are very aggressive and result in death.
Treatment for prostate cancer can have significant negative impact on quality of life and healthcare costs, and should only be utilized when the cancer itself is likely to be fatal. Treatment recommendations are based on PSA levels , clinical staging, and Gleason scoring. Active surveillance is a preferred approach when the disease is low-risk and small. Significantly, 5-10% of individuals with low-risk disease treated up-front experience poor outcomes. Additionally, >40% of active surveillance patients may progress and require treatment – and half of those will ultimately fail treatment. The effectiveness of active surveillance is limited without a clinical tool to accurately assess risk of progression.
In small pilot studies, Dr. MacAulay’s lab has demonstrated the ability to predict aggressive behaviour in prostate cancers with >80% accuracy using a specific imaging technology that uses the measurement of GOALS in individual cells along with the cell’s position within the patient’s tissue.
There is a need to improve donor organ preservation strategies to meet donor organ requirements for transplantation. Strategies such as cold flushing and organ preservation solutions are common practices to mitigate organ damage incurred during the transplant procurement, transport and implantation processes, but these solutions can be inadequate for marginal or extended criteria donors (ECD) that are being used in response to increased demand. New organ preservation solutions that are more effective in protecting donor organs, particularly from ECD, are required to fill this gap.
To address this unmet need, Dr. Du’s lab is developing new organ preservation solutions using a novel hyperbranced polyglycerol (HPG). Proof-of-principle studies using cell cultures and rodent transplant models have shown that this HPG organ preservation solution performs better than conventional solutions in the cold preservation of organs and human cells. A patent application for the technology was granted in May 2015.
Dr. Du’s technology has garnered interest from top companies and key opinion leaders in the transplantation field. To sufficiently validate and de-risk the technology, enabling him to attract industrial interest, Dr. Du will compare the efficacy of HPG organ preservation solution with conventional solutions in donor kidney preservation with a non-human primate model. If the HPG solution performs adequately, it will lead to a clinical trial.
The success of this technology could lead to a needed increase in the number of organ transplantations for British Columbians who need them.
Half of all cancer patients receive radiation therapy, impacting about seven million people worldwide each year. Enhancing tumour sensitivity to radiotherapy would have a far reaching and significant impact on patients with many kinds of cancer.
Funded by a $5M grant from the Wellcome Trust, Dr. Minchinton’s lab has developed novel inhibitors of DNA-repair that can dramatically enhance the elimination of cancer cells with radiotherapy. He will improve his previously developed small molecule inhibitors of a DNA repair protein by developing therapeutic regimens to optimize their use for maximum anti-cancer benefit and minimize their effect on normal tissue. The overall aim of the project is to identify optimized inhibitors suitable for clinical candidate evaluation.
After the preclinical work, Dr. Minchinton will seek corporate partners to take the candidate into full clinical evaluation involving Phase I through III clinical trials. DNA damage repair mechanisms as a route to improved therapy could have a significant impact on the effectiveness of radiotherapy for cancer treatment.
Recent advances in targeted therapies have transformed the treatment of several types of cancer. Numerous agents, including small molecule drugs and therapeutic antibodies targeting receptor tyrosine kinases (RTKs) such as EGFR, Her-2 and MET, are currently in clinical trials or have received regulatory approval. These agents are exhibiting impressive clinical responses demonstrating that these RTK pathways are clinically validated drug targets and key drivers of multiple cancers such as breast, lung and colorectal cancers.
Dr. Ong’s lab has discovered that SEMA3C drives prostate cancer growth and treatment resistance through activation of multiple RTKs via Plexin B1. He has developed a plexin B1 receptor, called Fc fusion protein, that not only is able to inhibit SEMA3C induced activation of EGFR, HER-2 and MET but is also able to inhibit activation of these RTK by their cognate ligands, EGF and HGF.
Importantly, Dr. Ong has found that PB1SD-Fc potently inhibited progression of LNCaP xenografts post castration in vivo. Currently, effective therapeutics used for treatment of advanced prostate cancer has been limited to AR pathway inhibitors. This fusion protein represents a new multi-RTK inhibitor drugs that may also show activity in treatment of prostate and other cancers driven by EGFR, HER-2 or MET. Thus, Dr. Ong’s findings may have transformative impact on clinical management of prostate and other cancers.
More than 5,000 rare genetic diseases affect over one million Canadians. Most have no treatment and many patients die in childhood. The small number of patients each of these diseases affects makes it difficult to develop treatments. However, about 10% of cases are due to a nonsense mutation that creates a premature termination codon (PTC); the protein produced is consequently cut short at the mutation and cannot function.
A potential therapy for this phenomenon is called ‘PTC readthrough,’ which allows the rest of the protein to form, restoring its function. As PTC readthrough is mutation-specific rather than gene-specific or disease-specific, it has the potential to treat many different rare diseases. However, drugs that induce therapeutic levels of PTC readthrough at safe doses are not yet available.
Dr. Roberge’s research has uncovered that gentamicin B1 (B1) potently induces PTC readthrough in tissue culture cells from patients with different rare diseases, making it a promising drug candidate. His lab will take B1 through the next stage of drug development—efficacy testing in cell and animal models—to see if it induces enough normal protein to correct the defect without toxic side effects. For these proof-of-principle studies he will focus on nonsense mutations causing epidermolysis bullosa (EB), a set of devastating, often fatal, skin fragility diseases.
Dr. Roberge has established collaborations with clinicians and researchers specializing in EB to create a collection of patient cells, from which human skin equivalents can be made, treated with B1, and their full-length protein production measured. A successful outcome would justify the activation of a start-up company in British Columbia to develop B1 towards the clinic, potentially working towards improved patient outcomes for many rare diseases.
Granzyme B (GzmB), an immune-secreted serine protease, is abundant in skin conditions characterized by excessive inflammation (such as burns, blisters, or scarring) at the hair follicle or at or just under the epidermis, and has been identified as a therapeutic target for autoimmune and chronic skin diseases.
Studies have defined a role for GzmB at the interface between the outermost (epidermis) and inner (dermis) layers of skin known as the dermal-epidermal junction (DEJ). In fact, many of the key proteins that anchor these two layers together are proteolytic substrates of GzmB. Given that it is well-documented that GzmB accumulates in the DEJ in many autoimmune conditions associated with separation of these layers (e.g. blistering and skin peeling conditions), it is plausible that GzmB-mediated cleavage of such anchoring proteins would contribute to disruption of the DEJ leading to blistering. In support of this concept, when human GzmB is added to freshly obtained human skin, complete separation of the DEJ ensues.
Dr. Granville has developed a topical first-in-class inhibitor of GzmB and have identified a condition known as Discoid lupus erythematosus (DLE) as our lead indication to enter the clinic. DLE is a rare, autoimmune skin condition that is usually triggered by sunlight. DLE lesions are characterized by DEJ inflammation, scarring, alopecia, and microvascular damage. Importantly, GzmB levels are highly elevated in this form of cutaneous lupus.
The aim is to obtain first approval of our GzmB inhibitor for DLE followed by subsequent approvals for other skin conditions. This project will generate further proof-of-concept data to support the clinical development and commercialization of a topical GzmB therapeutic for inflammatory skin conditions.
Positron emission tomography (PET) is a non-invasive imaging technique used to detect tumours and provide information about a patient’s response to treatment. PET generates a 3D image of the inside of a patient’s body and highlights the location of tumors through detection of a radiotracer administered before generating the image. One of the most common forms of radiotracers are small, drug-like molecules containing a radioisotope that bind to or accumulate in cancer cells, precisely locating tumours.
While many radioisotopes can be used for PET imaging, [18F] is arguably the most desirable due to its high positron output, small atomic size, metabolic stability and worldwide network of production facilities. Despite these advantages, the synthesis of [18F] radiotracers presents many challenges that have limited the scope of radiotracers available for oncological PET imaging. Thus, the majority of oncological PET imaging relies on a single radiotracer: [18F]-FDG, a sugar analogue that preferentially accumulates in cells that have increased metabolism (i.e., cancer cells).
Unfortunately, [18F]-FDG is not cancer-specific and also tends to bind to other tissues such as brain and bladder, and at sites of inflammation, limiting its utility for detecting tumors in those areas. In recent years there has been considerable interest in identifying complementary radiotracers to FDG, and much attention has focused on the synthesis of 18F-labelled amino acids, which also accumulate in rapidly dividing cancer cells. Dr. Britton’s lab has recently discovered a method for incorporating the [18F] radioisotope into complex drug precursors without the need for elaborate precursor synthesis.
Dr. Britton aims to:
- Rapidly expand the number of available amino acid radiotracers using new unique capabilities.
- Evaluate promising lead radiotracers for oncological PET imaging.
- Advance selected radiotracers into preclinical animal studies.
In addition to these research aims, Dr. Britton has filed a provisional patent application and will work with the SFU Innovation Office to identify an industrial partner for this new technology. These new amino acid radiotracers could have a profound impact on the early detection of cancer and positively impact the lives of many British Columbians.
