Overview of Research at the Advanced Center for Detection of Cancer

Our laboratory is focusing on nine areas of research:

1. Kallikrein Biology and Pathophysiology
2. Proteomics
3. Tumor Markers
4. Mechanisms of Carcinogenesis and Metastatic Progression
5. Translational Research
6. Cancer Therapeutics
7. Male Infertility
8. Pathobiology and Biomarkers of Autoimmune Diseases
9. Neurodegeneration

From the point-of-view of human disease research, our major interest is cancer, but other diseases including neurodegeneration, inflammation and skin disorders are also of interest. Our laboratory integrates basic, cell biology and translational research under one roof.

Kallikrein Biology and Pathophysiology

Our laboratory has recently cloned numerous novel genes, in particular those that belong to the kallikrein gene family.
The kallikreins are a group of related serine proteases, clustered in tandem on human chromosome 19q13.4, click here to see the locus map and theoretical 3-dimensional molecular models, or click here to see the annotated genomic sequences.

 
Our research interests related to kallikreins include the following:

1. Kallikrein gene structure and transcriptional regulation.
2. Kallikrein protein function and enzymology.
3. Discovery of physiological pathways involving kallikreins (including enzymatic cascades).
4. Identification of physiological substrates for kallikreins.
5. Kallikrein gene rearrangements in cancer.
6. Kallikreins as diagnostic and therapeutic targets.
7. Kallikreins and Proteinase-Activated Receptors (PARs)

To achieve these goals we develop innovative tools for kallikrein research such as recombinant proteins, monoclonal antibodies, immunological and molecular assays and immunohistochemical procedures. Also, through our collaborators, we use fluorogenic combinatorial libraries and phage-display technology to delineate kallikrein substrates and function. More recently, we are using mass spectrometric techniques to discover novel kallikrein targets and inhibitors.

Proteomics

We are working towards delineating the proteome of biological fluids and cancer cell lines. In particular, we are identifying the secreted proteins (secretome) of breast, ovarian, lung, prostate, colon, pancreatic and other cancer cell lines, in order to discover molecules that may represent novel cancer biomarkers. This research involves extensive use of tissue culture technologies, fractionation and purification with various chromatographic techniques and mass spectrometric analysis of fractionated proteins. Our laboratory operates several state-of-the-art mass spectrometers and has significant bioinformatic expertise. Two expert operators are working in our Proteomics Laboratory at Toronto General Hospital / University Health Network, 3rd Floor Eaton Wing. Our laboratory was the first to delineate the proteomes of amniotic fluid and cervico-vaginal fluid and expanded the proteomes of other fluids such as seminal plasma, nipple aspirate fluid and ascites fluid. The secretomes of over 50 cancer cell lines has also been delineated. In the area of clinical proteomics, we are seeking to identify novel molecules or proteomic signatures that can be used for early detection of cancer. Click on the link below to access the respective PDF of a Review:

Tumor Markers

Our laboratory has developed novel tumor markers for early cancer diagnosis, prognosis and monitoring. Dr. Eleftherios P. Diamandis is the Principal Investigator of the Ontario Cancer Biomarker Network (OCBN), a consortium which aims to discover, use and commercialize novel cancer biomarkers. Please click here to learn more about the Ontario Cancer Biomarker Network at www.ocbn.ca/.

We are interested in discovering and validating novel cancer biomarkers that will aid in the early diagnosis, prognosis and monitoring of various forms of cancer, especially endocrine-related cancers such as breast, ovarian and prostate cancer. Some recent reviews can be accessed here as PDFs:

Mechanisms of Carcinogenesis and Metastatic Progression

We deploy mass spectrometry-based proteomic strategies to investigate pathophysiological pathways involved in carcinogenesis. We are using the in-vitro cell culture model in the context of microenvironment alteration experiments (e.g. stimulation with growth factors, hormones, or other soluble factors, drugs and/or chemical analogs that affect various pathophysiological processes) in combination with the SILAC approach, to identify key mediators that affect cancer-related processes such as tumor cell invasion and metastasis, angiogenesis, proliferation, evasion of apoptosis, resistance to antiproliferative signals/chemotherapy and cell survival.

Our specific research interests are:

1. Investigation of players involved in the metastasic cascade (mediators of epithelial-to-mesenchymal transition, invasion, migration, motility and angiogenesis), by performing differential proteomic analysis between primary and metastatic or between malignant and non-malignant cell lines
2. Investigation of the hormonal dependence in breast and prostate cancers, by stimulating cell lines with androgens or estrogens and performing differential proteomic analysis to identify affected genes and pathways
3. Investigation of tumor-host cell interactions (desmoplasia, angiogenesis, inflammation), by using co-culture systems, including cancer and stromal cells, followed by quantitative proteomic analysis of the conditioned media.

Translational Research

We have access to large biorepositories of biological fluids, tissues and nucleic acids, which are invaluable in our efforts to identify novel cancer biomarkers and new ways for diagnosing and monitoring human disease. An international group of investigators is working closely with us by providing valuable clinical material for translational research.

Some of our translational research interests include:

1. Identification of potential clinical applications of kallikreins (diagnostic markers, therapeutic targets, predictors of prognosis and therapeutic response)
2. Involvement of kallikreins in non-malignant diseases (neurodegeneration, skin diseases, etc.)
3. Identification of non-kallikrein biomarkers that could be used for diagnosis, therapy and monitoring of cancer and other diseases

Cancer Therapeutics

We are using high-throughput technologies to screen candidate drug molecules from large chemical libraries. Recently, we screened libraries such as Spectrum, Prestwick and LOPAC and identified members of the cardiac glycoside family as potential anti-cancer agents. Our efforts to identify therapeutic molecules which could act either alone, or in a synergistic way, against cancer are continuing. To access our review on this area of investigation, please see the following:

Male Infertility

In collaboration with Dr. Keith Jarvi from the Murrray Koffler Urologic Wellness Centre, we are delineating the proteomes of seminal plasma and associated fluids in our efforts to identify biomarkers of infertility and urological diseases such as prostate cancer. In collaboration with Dr. Alex Zlotta, we are studying genomic, proteomic and transcriptomic signatures of prostate cancer.

Pathobiology and Biomarkers of Autoimmune Diseases

In collaboration with Dr. Dafna Galdman and Dr. Vinod Chandran, Professors at the Department of Medicine, Division of Rheumatology, Center for Prognostic Studies in the Rheumatic Diseases, Toronto Western Hospital, University Health Network, we are conducting proteomic studies to identify novel biomarkers of autoimmune and rheumatic diseases including psoriasis, psoriatic arthritics, systemic lupus erythematosus, etc. In such studies, we also collaborate with Drs. Morley Hollenberg, University of Calgary and Dr. Martin Steinhoff, Center for the Neurobiology of Digestive Diseases, University of California, San Francisco, USA

Neurodegeneration

One research interest of the ACDC Laboratory is identification of biomarkers of early diagnosis of neurodegenerative diseases such as Alzheimer's and Parkinson's Disease. Some of our local and international collaborators on this project include Dr. Anthony Lang, Toronto Western Hospital, University Health Network and Dr. Ana-Maria Simundic, University Hospital "Sestre Milosrdnice", Zagreb, Croatia.

Publications

Our laboratory is publishing 20 - 30 research papers per year. To access our complete list of publications and retrieve the relevant PDFs, please click here.

 

 

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