Funded Projects

Funded Projects

The Cancer Pathology Translational Research Grants will complement the education and training program available through the Network to increase molecular pathology and research knowledge amongst the pathologist in Ontario. To foster the development of this research community grantees and their trainees will present there work at the Network’s annual meeting, the Ontario Cancer Pathology Research Meeting.

Interested in getting involved with one of our funded projects?

Projects funded by the OMPRN are listed below.

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The Role of the Transcriptional Regulator TBX3 in Early Breast Cancer Progression: a possible regulator of the transition from in situ (DCIS) to invasive mammary carcinoma (IMC)

This study is looking at biomarkers in tissue samples of people with Ductal Carcinoma In Situ (DCIS) to help tell which patients will develop invasive mammary carcinoma (an advanced form of breast cancer).

Ductal Carcinoma In Situ (DCIS) means cells inside some of the ducts of the breast have started to turn into cancer cells. These cells are inside the ducts and have not started to spread into the surrounding breast tissue. Doctors diagnose DCIS by looking at whether or not cells within the ducts of a patient’s tissue sample appear benign (non-cancerous) or malignant (cancerous).  However, only some of these patients will go on to develop invasive breast cancer and it is currently difficult for doctors to tell which of these patients are at risk.

Researchers believe that increased activity of the T-box transcription factor (TBX3) gene is linked to more aggressive breast cancer. In this study researchers will assess which other genes are potentially regulated by TBX3, and will use tissue samples from current breast cancer patients to determine whether increased activity of this gene, and/or specific genes that this gene itself activates (such as Slug and Twist1) might be used as an indicator of the potential to break out of the ducts and invade adjacent breast tissue (i.e to become more aggressive).Researchers hope that one or more of these tests will help doctors predict which patients are at risk of progressing to advanced breast cancer.

All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research. Find out more about pathology or why molecular pathology is important in cancer research here [link].

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A Minimalist Approach to Cancer Tissue-of-Origin Classification by DNA Methylation

Pathologists are responsible for the accurate classification (or categorization) of human diseases, including cancers (e.g. distinguishing breast cancer metastatic to the lung from primary lung cancer). Only when appropriately classified can patients with cancers receive the optimal site-specific treatments. While the examination of tissue samples under the microscope by pathologists is usually sufficient for achieving this end, there often remains a small percentage of cases that are subject to diagnostic discrepancies and/or may be otherwise difficult to classify. For this, DNA-methylation profiling, by providing tumor tissue-of-origin signatures (e.g. breast versus lung), is a potentially useful adjunct. While recent research studies produced very promising results, the profiling technology itself is technically demanding and may be difficult for clinical laboratories to adopt. Accodingly, the goal of this project to simplify methylation-based cancer classification, in part by reducing the number of markers needed. In a preliminary study, using just 28 selected markers (rather than all 27 thousand available markers), we were able to correctly assign ~90% of >1000 cancer cases to their tissues-of-origins. With funding, we will perform additional analyses and test additional samples with the goal of designing a practical and effective methylation-based test that could be validated for routine clinical use in a follow-up study. All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research.

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An integrative DNA sequencing panel to accurately diagnose and appropriately manage patients with ovarian sex cord stromal tumors

In the Canadian health care system, we are often bound by the fiduciary restrictions, and diagnosing rare tumours can be particularly challenging. Research from our group and others have identified that DNA sequencing technology can allow us to accurately diagnose these tumours, allowing the patients to appropriately seek genetic counselling and/or potentially receive new drug that target those mutations. Two barriers prevent such advances: 1) cost of the new tests, and 2) lack of a validating study that confirms the presence of those mutations in a larger group of patients. At the Toronto General Hospital (TGH), we have accrued a large group of cases that would allow us to tackle those two challenges. With a large number of surgeries at TGH, we have enough number of these relatively rare ovarian cancers that would allow us to confirm the presence of those mutations and examine their frequency. Using state-of-the-art DNA sequencing technology available at TGH, we aim to construct a novel sequencing panel that would serve as a one-stop test for a number of these tumours, allowing us to identify these mutations with a single run. We potentially have a solution to the aforementioned barriers that would allow for truly personalized care of these patients. With the TGH. All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research.

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Analyzing Renal Papillary adenomas to elucidate the early tumorigenic events of Papillary Renal Cell Carcinoma and their possible correlation with kidney progenitor cells

We are studying a type of kidney cancer called the papillary type. This type of cancer is particularly common in diseased kidney. Findings from our previous work as well as the work of others led us to believe that these cancers arise from kidney regenerative cells.

These cells are normally hidden in the kidney, but when the kidneys start to shows signs of damage, these regenerative cells are increased in number so as to renew/regenerate the lost cells. Though they should be helpful to the kidney, some disruption in their biology happens at that stage which makes them give rise to cancer. It is important to note that there are small lesions termed papillary adenomas that are also very common to find in the damaged kidneys that look identical to the cancer we study (but smaller) and are though to give rise if left to the full blown cancer. So in essence these lesions are the link between the regenerative cells and the cancer. In this project we will study that proposed connection between these regenerative cells and the cancer by tracking the cells all through from the normal kidney, to the damaged kidney to the small adenoma lesions to the cancer. Through that process we will understand a lot more about the biology of how these cancers form.

That knowledge will help us in the future to prevent these kidney cancers. All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research.

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Assessing the clinical relevance of circulating miRNAs expression signature for early colorectal cancer detection

Colorectal cancer (CRC) is a world-wide health problem especially in wealthier countries and the numbers for CRC are going up. An 80% increase in CRC deaths is projected by 2030 unless there are significant improvements in prevention, early disease detection and treatment. CRC usually develops from polyps that over time change to cancer. Therefore early disease detection improves outcomes. Colonoscopy is the gold standard for detection of CRC, but it is costly and invasive for screening purposes. Fecal-based tests are for useful for screening but they are not very sensitive or specific. Therefore, more accurate, non-invasive tumor biomarkers for the detection of early CRC lesions (ECRCL) are required. There is growing evidence about the role played by microRNAs (miRNAs) human cancer. Tumor-specific circulating miRNAs can be detected in the blood of various cancer patients including CRC. The circulating miRNAs are highly stable and can therefore be useful diagnosing and predicting cancer. The main objectives of this project are to: i) investigate circulating miRNA expression profile in blood from patients with ECRCL and compare them with healthy controls  ii) evaluate miRNA expression profile in ECRCL as well as adjacent mucosa and iii) identify disease specific miRNA signatures that are typical of ECRCL.  This research project will advance knowledge on the role of circulating miRNAs biomarkers in CRC diagnosis and their potential predictive role for disease risk assessment. The findings will help in developing a panel of circulating miRNAs markers usable for accurate early detection of CRC, and improve CRC screening strategy. All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research.

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Assessment of Progestin Response Potential in Grade 2 Endometrial Endometrioid Adenocarcinoma and Interrogation of Biomarkers Associated with Progestin Resistance

Treatment of endometrial (womb) cancers includes surgery (removal of the womb) or hormonal treatment, depending on the degree of severity and spread of disease. There is a growing interest in hormonal treatment for patients wishing to have children or patients that have other medical conditions which prevent them from having surgery.3 Hormonal treatment includes progesterone based therapy, which is currently reserved for precursor lesions and early low grade endometrial cancer (grade 1). However, not all cases respond to hormonal treatment or some tumors recur after treatment. Moreover, some women with cancers of intermediate grade (grade 2) are also interested in hormonal treatment in order to delay surgery and allow time for a successful pregnancy. A current challenge in management of these cases is to identify patients who would respond to hormonal treatment and for whom surgery can be safely delayed. Our aim is to study the molecular profile of intermediate grade cancers and compare them to that of endometrial precancer and low grade cancer that have a known response to progesterone therapy. We believe that a proportion of intermediate grade cancers resemble the low grade responsive cases, which would suggest that select intermediate grade cases can also be safely treated with progesterone. Knowing which patients would benefit from hormonal treatment before starting therapy would allow a better management of cases in clinical practice.

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Deep Learning for Lung Cancer Diagnostics and Biomarker Discovery

Artificial intelligence (AI) research has advanced significantly in recent years, and has given rise to algorithms which are adept at analyzing image data. The application of this technology within pathology is an area of major interest, since these algorithms may be able to help pathologists diagnose cancer with increased accuracy, consistency, and efficiency. Past research has shown that there is considerable variability between the diagnoses of individual pathologists, and the use of diagnostic software promises to bring an added element of objectivity to the diagnostic process. Furthermore, it may become possible to use this software to predict the types of mutations found in a tumour, information which is usually obtained using time-consuming advanced testing techniques. Since many treatments in lung cancer are based on the individual mutations in a patient’s cancer, obtaining this information very rapidly may be allow a patient’s physician to initiate therapies immediately while waiting for definitive test results. Finally, these algorithms may not only be useful for diagnosing known types of cancers, but may help to identify new types of lung cancer which share subtle microscopic features that are not easily visible to the human eye. Since tumours which share microscopic features frequently have similar biological characteristics, identifying new subtypes may help pathologists to classify patients’ tumours, and refine predictions about patients’ expected treatment response and prognosis.

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Development of Pediatric OncoScan Genomic and SNP Array for clinical implementation

This study is looking at biomarkers in tissue samples of children with cancer to help diagnose their cancer and to tell which patients are more likely to respond to different available treatments.

Some pediatric (childhood) cancers develop as a result of changes in the genes’ code and/or the number of copies of the genes (gains or losses of the gene). Researchers believe understanding which changes have occurred in a child’s cancer can help to diagnose the cancer and to identify treatments to which the child is more likely to respond. In this study researchers will use a test normally used to for adult cancers and adapt this for children with cancer. Researchers will use tissue samples from current patients with childhood cancer to develop this test so that doctors can figure out which gene changes are present in an individual's cancer. Researchers hope that this test will help doctors to better match children with cancer to treatments.

All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research. Find out more about pathology or why molecular pathology is important in cancer research here [link].

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Discovery of markers predictive of progestin therapy response in endometrial atypical hyperplasia and low grade endometrioid adenocarcinoma

This study is looking at biomarkers in tissue samples of people with early endometrial (womb) cancer to help tell which patients can avoid having surgery.

Endometrial cancers, which have not grown beyond the womb lining are considered localized, these can often be treated with surgery with or without radiotherapy. However surgery for these patients means partial (removal of the womb) or complete hysterectomy (removal of the womb and ovaries) and can be life-changing for patients wishing to have children or not possible for patients who cannot undergo surgery because of other health conditions.

Researchers believe that womb cancer patients with a change in a type of protein which regulates the hormone progesterone, could put these patients at higher risk of their tumour spreading. Patients with changes to this protein, called progesterone receptor isoforms, PR-A and PR-B, may respond better to a type of hormone therapy called progestin. In this study researchers will develop a test, using tissue samples from current womb cancer patients, which can be used to figure out if this type of protein change is present in an individual's cancer and what impact this has on their tumour spreading.

Researchers will also test whether patients with these protein changes respond better to progestin. Researchers hope that this test will help doctors predict which patients will need surgery and which patients can be given hormone therapy.

All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research. Find out more about pathology or why molecular pathology is important in cancer research here [link].

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Dissecting Papillary Renal Cell Carcinoma on the Molecular Level: Subtype Analysis, Biomarker Discovery and Implications to Therapy

Kidney cancer includes multiple subtypes. Papillary renal cell carcinoma (PRCC), the cancer we are proposing this research for, is the second most common form of kidney cancer. However PRCC itself is divided into two subtypes, the PRCC type 1 and PRCC type 2. That is based upon the way they look under the microscope. Previous researches have noted that type 2 is usually a more aggressive form of cancer than type 1. As such patients with these cancers should be followed differently. Other studies as well as ours have found that the types have a different biology.  Therefore their response to cancer drugs is expected to be different. However to date, they are treated by doctors as one entity.

Part of the dilemma is that nearly half the cases are hard to subtype using the microscope alone. There is a need for a test (biomarker) that can help Pathologist’s (cancer microscope doctors) distinguish between them. Our previous work identified some possible promising markers. We need to confirm these results in another set of cancer patients, which is part of our research proposal. The findings will help doctors divide patients properly in the right group for follow up and treatment.

Yet another confounding factor is that, even though the types are known to have different biology, the exact nature of these changes and how they affect the cancer response to drugs is not properly understood. Our previous research shows that the cancer types should respond differently to certain cancer drugs. We propose studying these differences further and assessing the response of the cancer cells (cancer cells made and grown for research, corresponding to our particular tumor types) to a number of current cancer medications. The results are expected to guide doctors into giving the patients, the right kind of medicine for the right kind of cancer. 

All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research. Find out more about pathology or why molecular pathology is important in cancer research here [link].

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Enhanced Detection of Prognostic and Predictive Biomarkers Using Whole Genome Methylation Microarrays in Gliomas -Retrospective assessment of methylation array clinical utility as a modifier of glioma histomolecular classification and clinical outcome pre

This study is looking at biomarkers in tissue samples of people with gliomas (a type of brain tumour) to help tell which patients are more likely to respond to different treatments available.

Some gliomas develop as a result of changes in a patient’s genes or a number of different changes in different genes. Understanding which changes have occurred in a patient’s cancer can help to identify treatments which the patient is more likely to respond to.

Methylation is a process in which certain chemicals called ‘methyl groups’ are added to proteins, DNA and other molecules to make them active or inactive. Researchers believe that looking at where methyl groups have been attached can show which genes have been changed. Researchers will use tissue samples from current glioma patients to develop this pattern of methyl groups into a test so that doctors can figure out which gene changes are present in an individual's cancer. Researchers hope that this test will help doctors match patient with gliomas to treatments which target these changes.

All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research. Find out more about pathology or why molecular pathology is important in cancer research here [link].

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Evaluating gene expression in diffuse large B-cell lymphoma using a quantitative nuclease protection assay

Diffuse large B-cell lymphomas are a commonly diagnosed and diverse group of aggressive malignancies that have distinct clinical and molecular features that do not always correlate with their appearance under the microscope. Advances in the genetic and molecular understanding of these cancers has highlighted the importance of having an accurate and reliable method for classifying them into different subtypes as there are significant differences in their genetic and molecular characteristics, differences in patient outcomes, and there are various therapeutic options depending on the risk profile associated with each subtype. Furthermore, the subtype has been proposed to be included in a screening method used by pathologists to test for genetic alterations that would classify the diffuse large B-cell lymphoma as aggressive or 'high-grade.' As the commonly used subtyping algorithm shows suboptimal accuracy and reliability and poor inter-laboratory reproducibility, we aim to study how a new diagnostic testing approach that shows promise as an accurate, reliable, and cost-effective replacement for the standard method currently in practice. This new method may also help with the investigation of new markers that can help predict the outcome in more challenging cases that have been historically categorized as unclassifiable and help screen for mutations that confer a worse patient prognosis.

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Genetic Analysis of Circulating Tumour Cell in Neoadjuvant Breast Cancer Patients

Characteristics of breast cancer tissues can be used to predict outcomes for patients with cancer, and help to choose their appropriate treatment. Some cancer cells can enter the blood stream from the breast and travel to distant sites throughout the body. Breast cancer is the most commonly diagnosed non-skin cancer among women. Blood drawn from many patients contain circulating tumour cells (CTCs). We aim to study features of circulating tumour cells in patients with breast cancer, which we hope will provide a means of guiding treatment.

Previously we studied a group of 17 breast cancer patients and identified several genes that were often changed in these cells. We now need to study CTCs from a bigger group of breast cancer patients to confirm the importance of the changes we have found. We will extract breast cancer cells from the blood of 50 women being treated at Princess Margaret Cancer Centre. We will see if the genetic changes we have found can provide more information to treat breast cancer or predict how the cancer may behave. In terms of impact, studying circulating tumour cells could become a cheaper and minimally-invasive tool to affect treatment of disease, and would lead to more tolerable detection of cancer and financial savings for Canadian healthcare. Not only can this study of circulating tumour cells be used in breast cancer, it can also be extended to other cancer in the future. All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research.

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Genomic profiling of intratumour heterogeneity of MLH1 expression in endometrial carcinoma: significance for hereditary risk and personalized immunotherapy

This study is looking at biomarkers in tissue samples of people with endometrial (womb lining) cancer to determine which patients might respond to targeted therapies.

Endometrial cancers, which have not grown beyond the womb are considered localized. These can often be treated with surgery with or without radiotherapy. Cancers which have advanced beyond the womb are considered advanced and are less likely to respond to treatment.

Researchers believe that some patients with endometrial cancer have a specific genetic defect, in a gene called MLH1, and belong to a special category, called “Mismatch Repair-deficient”.  In this study, researchers will develop a test, using tissue samples from current endometrial cancer patients, which can be used to figure out if this type of gene mutation is present in an individual's cancer and will allow doctors to determine if other family members are at also at increased risk for cancer.

Researchers also believe that patients with this type of gene mutation may respond better to a new and highly promising treatment called immunotherapy; so this test will also help doctors predict which patients might benefit from this treatment.

All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research. Find out more about pathology or why molecular pathology is important in cancer research here [link].

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Identifying predictive biomarkers of outcome in diabetic colorectal cancer patients treated with metformin

Fundamental to how a cancer cell develops and grows is an understanding of the subcellular machinery (gene signaling pathways) that are abnormal (dysregulated). This understanding forms the basis for testing potential anti-cancer treatments to improve patient survival. The overall aim of this project is to improve our understanding of key signaling pathways in colorectal cancer (CRC) cells that are important in tumour growth. We are interested in studying diabetic patients with CRC because these patients, when treated with oral hypoglycemic drug Metformin, have improved survival compared with other CRC groups. Metformin is believed to deplete the energy level of cancer cells and dysregulate the subcellular machinery that impairs cell growth and cancer spread. In this study we will look at the activity (expression) of genes that are associated with these cancer subcellular pathways in tumour samples from 100 diabetic CRC patients (50 Metformin treated versus 50 diet treated) for which we have detailed clinical (including survival) data. We expect that those genes that have abnormal expression in CRC cancer cells in the Metformin treated group when compared to the diet only group will be linked to better clinical outcome and will help identify subcellular pathway(s) associated with the anti-tumour effect of Metformin. This will improve our understanding of potential important components of the tumour subcellular machinery (gene/protein signaling pathways) that should be targeted to help reduce cancer risk and poor outcome. All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research.

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In situ biomarkers of urothelial carcinoma invasion and progression

This study is looking at biomarkers in tissue samples of people with bladder cancer to help tell which patients are at risk of their cancer progressing.

Doctors diagnose bladder cancers by looking at how far cancer tumors have grown into the bladder. Most of these patients are diagnosed with non-muscle invasive bladder cancer (NMIBC). This means the cancer is only in the innermost layer of the bladder lining or has started to grow into the connective tissue beneath the bladder lining. NMIBC can often be treated with surgery.

A small number these patients will progress to advanced bladder cancer. This means the cancer has started to grow beyond the bladder lining and into the surrounding muscle or other parts of the body. Half of these patients with advanced bladder cancer will have incurable disease.

Researchers believe that two gene networks, Sonic HedgeHog (SHH) and Bone Morphogenetic Protein (BMP), are linked to more aggressive bladder cancer when they are turned off. In this study researchers will develop a test, using tissue samples from current bladder cancer patients, which can be used to figure out if these networks are turned off in an individual's cancer. Researchers hope that this test will help doctors predict which patients are at risk of progressing to advanced bladder cancer.

All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research. Find out more about pathology or why molecular pathology is important in cancer research here [link].

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Laying the groundwork for a simple microRNA-based blood test to diagnose and monitor all neuroendocrine tumors

Neuroendocrine tumors (NETs) are clinically diverse neoplasms that affect males and females of all ages and race. Because NETs are hard to diagnose and resource intensive to monitor, better blood tests are needed to guide clinical care. MicroRNAs (miRNAs) are small RNA regulatory molecules that can be excellent biomarkers due to their tissue specificity. While generating an updated atlas of human miRNA expression atlas, my team and I found that miR-375 is abundantly expressed in all NET tissues. The goal of this proposal is to lay the groundwork for a simple miRNA-based blood test to diagnose and monitor all NETs. Our hypothesis is that neuroendocrine cell-specific miR-375 is a circulating marker of NET disease burden. This hypothesis is formulated from extensive, yet incomplete, miRNA expression profiling of NET and control tissues and cell lines in the Renwick lab. We will test our hypothesis through two objectives to: i) consolidate knowledge of miRNA expression in NET and control tissues, and ii) establish and pilot plasma total small RNA profiling for persons with and without NETs. The rationale for our research is to provide doctors with a reliable, accurate, and inexpensive tool for guiding NET clinical care. This proposal represents a new trans-institutional collaboration between Dr. Neil Renwick at Queen’s University and Dr. Simron Singh at Sunnybrook Health Sciences Center and is firmly aligned with the mission of OMPRN to enhance molecular pathology research capacity across Ontario.

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Molecular profiling of Gastric Type Endocervical adenocarcinoma

This study is looking at genetic alterations in tissue samples of people with cancer of the cervix (the neck of the womb) to help tell which patients have a type of cervix cancer called gastric type endocervical adenocarcinomas, this means cervix cancers which contain mucin types similar to gastric (stomach) cancer.

Researchers believe that patients with gastric type endocervical adenocarcinoma are less likely to respond to treatment typically used for cervix cancer. Doctors diagnose cancer of the cervix by looking at whether or not cells within a patient’s tissue sample appear benign (normal) or malignant (cancerous) however it is currently difficult for doctors to tell which of these cervix cancer patients have gastric type endocervical adenocarcinoma.

Changes in a patient’s genes can be associated with different types of cancer. In this study researchers will use tissue samples from current cervix cancer patients to find out which changes in which genes are associated with patients who have gastric type endocervical adenocarcinoma.

Researchers will then develop a test which can be used to figure out if these genes are changed in new patients with cervix cancer. Researchers hope that this test will help to tell which of these cervix cancer patients have gastric type endocervical adenocarcinoma. Also they are hoping their findings might help in new targeted therapies for this type of cancer.

All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research. Find out more about pathology or why molecular pathology is important in cancer research here [link].

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Next generation non-invasive testing for prostate cancer

Currently, testing men to diagnose prostate cancer requires biopsies that often lead to serious complications such as bleeding or infection. We have developed a test that identifies cancer specific chemical modifications to DNA in specific genes. The test is more than 90% accurate when applied to prostate tissue samples. In the proposed work, we will develop procedures for testing urine instead of biopsy tissue. The urine test should more accurately identify men with and without prostate cancer, thereby preventing unnecessary biopsies and saving men from related complications.

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Tumor-First Testing for Hereditary Hematological Malignancies Syndromes

Blood cancers can be acquired (in the tumoral blood tissue only) or inherited (present in any cells). DNA mutations can be identified in the blood of any individuals with blood cancer. 11-37% of patients with acquired blood cancers also bear the same mutations in any cells of their body including their gonads; these mutations can therefore be transmitted to their offspring and predispose them to familial blood cancers. In addition, patients with blood cancers may receive transplants from related family members (e.g. siblings, parents). As familial blood cancers are very frequent in patients with acquired blood cancers, their family related cell donors may be affected with a yet undiagnosed cancer; putting the patient at significant risk of morbidity . The Genome Diagnostics Laboratory at the University Hospital Network (GD-UHN) is funded to test patients with acquired Acute Myeloid Leukemia (AML) in Ontario, but genetic testing for mutations predisposing to inherited blood cancers is not offered in Canada. Currently, there is no way at GD-UHN to tell if a patient has acquired or familial AML. It was shown that patients with familial susceptibility to blood cancers have high levels of disease-causing mutant DNA in their blood tissue; it is then possible to screen for individuals at risk of familial blood cancers by looking at the amount of mutant DNA in specific genes from blood analysis. In this study, we aim to use the levels of mutant DNA4 results from tumor of AML patients to predict their risk of familial blood cancer.

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Using liposarcoma tissue microarrays to characterize the immune environment and identify novel immunotherapy targets for treatment of liposarcoma

Liposarcoma, a malignant cancer arising from fat cells, only responds to chemotherapy 24% of the time and treatment options have not changed in many years. Our long-term goal is to create an immunotherapy treatment that leverages the patient’s own immune system to recognize and destroy the malignant cells. The first vital step in this process is to identify proteins (antigens) for the immune system to target that are unique to the sarcoma cells and not present in the normal cells of the body. A group of proteins that hold great potential for this purpose are called cancer-testis (CT) antigens. For this project, we intend to survey low and high grade liposarcoma for CT antigens by immunohistochemistry (IHC), a process that tags the antigens, if present, with a coloured pigment visible by microscopy. In addition, using IHC as well as cutting edge technology called nanostring that can probe over 700 genes simultaneously from very little material, we will study the immunological status of these liposarcomas to inform the development of the right type of immunotherapy for the right patients. In addition, we will use nanostring results regarding CT antigens to direct further research in cases with low expression of the CT antigens previously tested. Overall, we hope these studies will serve as a springboard for developing new immunotherapies targeted towards liposarcoma.

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Bone Marrow Derived Proteogenomic Immune-Stromal Cell Signatures Reveal Niche Heterogeneity in Primary Myelofibrosis - Impact on Response to JAK Inhibition

Myeloproliferative neoplasms such as primary myelofibrosis (PMF) are a type of blood cancer where the normal production of red cells, white cells or platelets becomes uncontrolled. In PMF, this abnormal function eventually leads to scarring of the bone marrow and potentially changes the disease from making too many blood cells to making too few. Sometimes, this may even result in a medical emergency called acute leukemia where the bone marrow is scarred but the blood cells that are still being made are all primitive. Aside from bone marrow transplant, there are some drugs that can help slow down the scarring process. Unfortunately, the beneficial effect of these drugs wears out over time in some patients but not others. We do not understand why that is the case but a clue may lie in the kind of scarring that is occurring in the bone marrow. Using special stains, it appears that there are different patterns of scarring in PMF patients, which may explain why some patients do better on therapy. In order to potentially match the right PMF patient to the right therapy, it will be useful to investigate what causes the different kinds of scarring patterns. We plan to use protein, DNA and RNAbased technology to explain how the blood cancer and the non-cancer scar-forming bystander cells interact directly in the marrow itself. Hopefully, by focusing on where the scar formation is actually occurring, we will be able to discover new information for personalized treatment. All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research.

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Brain Tumour Assembloids as Personalized Avatars for Glioblastoma Drug Discovery

Glioblastoma is the most aggressive form of brain cancer, killing the majority of patients within 12-15 months. Unfortunately, despite numerous clinical trials, life expectancy has only marginally increased over the past 50 years. Glioblastoma infiltrates surrounding brain tissue at early stages of disease making surgical management difficult. Traditional laboratory approaches designed to model cancer (ie. growing isolated cancer cells in dishes or mouse brains) are not favorable tools for evaluating response to new therapeutic agents due to their limitations and over simplification of this complex disease. Therefore, there is urgent need to develop more representative model systems to study glioblastoma.

Advances in tissue engineering now allow scientists to transform stem cells into threedimensional, brain-like structures called “cerebral organoids”. Under the microscope, these organoids show human-specific tissue-like architecture providing mini laboratory “avatars” of human brain tissue. In addition to allowing scientists to study how a brain develops, this technology enables researchers to introduce cancer cells into these mini-brains to form structures termed “brain tumour assembloids”. This complex culture system thus provides a more accurate model to simulate how patient glioblastomas grows within these engineered 3D human brain tissue elements. The small size of these structures also allows scientists to simultaneously expand and maintain hundreds of these cerebral organoids, creating a convenient platform for personalized glioblastoma drug screening. Establishment of a brain tumour assembloids screening platform will thus provide patients with a large array of personalized laboratory avatars that, in the future, can help guide individualized selection of empirically effective non-toxic therapies.

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Comprehensive genomic characterization of primary ovarian mucinous carcinoma and the value of genomic profiling in its distinction from metastatic mucinous carcinoma to the ovary

Accurate diagnosis of ovarian mucinous carcinoma (OMC), a rare type of ovarian cancer, is currently challenging. Pathologists, as doctors specialized in laboratory medicine, have traditionally diagnosed OMC based on specific features seen under the microscope.

Nevertheless, this approach is insufficient for accurate distinction between cancers that originate in the ovary (which have an overall good prognosis) from cancers that originate somewhere else and metastasize to the ovary (which have a poor prognosis, they usually arise in the gastrointestinal tract). This distinction is important, not only because the differences in prognosis but also because the ovarian metastasis may be the first sign of disease in a patient with an otherwise occult cancer elsewhere; determining where the metastasis is coming from is vital to direct chemotherapy, radiation and any other treatment. Given the limitations in the tools that the pathologist has for this exercise, diagnosis of a OMC is often inconclusive and further clinical and radiologic investigation is required to find a possible primary tumor, leading to expenditure of time and resources and patient anxiety.

Recently, it has been shown that genetic analysis of mutations in ovarian cancer may help better diagnose disease subtypes and predict their biological behavior. However, due to the rarity of the disease, OMC is underrepresented in such studies, thus its status within the classification system of the disease has not been elucidated. This study aims to characterize the global genetic makeup of OMC using a technology known as “next-generation” sequencing. In this manner, researchers hope to identify a set of genetic alterations unique to OMC to build individual molecular profiles that will help doctors make better decisions to care for their patients. Additionally, analyzing the genetic differences between primary and metastatic cancer may demonstrate the value of a customized molecular panel in diagnosis, determination of prognosis and treatment decision-making for patients with this disease. Lastly, this study may also help identify new targeted therapeutic treatment options for women with OMC. All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research.

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Ezrin as a novel biomarker for response to chemotherapy in breast cancer

This study is looking at biomarkers in tissue samples of people with breast cancer to help tell which patients will respond to chemotherapy.

Researchers believe that activity of a protein called ezrin can increase a patient’s risk of developing advanced breast cancer, which does not respond to chemotherapy. In this study researchers will develop a test, using tissue samples from current breast cancer patients, which can be used to figure out the level of activity of this protein in an individual's tissue sample and what impact this has on whether their cancer will respond to chemotherapy.

Researchers also believe that patients with a decreased level of ezrin protein activity may be more sensitive to two drugs called doxorubicin and paclitaxel. Researchers hope that this test will help doctors predict which patients will benefit from these treatments or a combination of these treatments.

All studies funded by the OMPRN also have an educational objective for trainee pathologists or early career pathologists. Ensuring new researchers have experience in conducting or leading studies helps the OMPRN to develop the next generation of molecular pathology leaders in cancer research. Find out more about pathology or why molecular pathology is important in cancer research here [link].

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Methylome biomarker discovery and circulating tumor cell-derived xenografts by liquid biopsy in small cell lung cancer

Lung cancer is the most common cancer killer worldwide. Small cell lung cancer (SCLC) is an extremely aggressive type of lung cancer that represents about 1 in 7 of all lung cancer cases. SCLC patients live on average about 8-12 months and only 7 in 100 patients survive to 5 years. Two chemotherapy drugs are given to essentially all patients and are called cisplatin and etoposide. They have been proven to extend life for patients because the cancer is initially very sensitive and shrinks when treated by these two drugs. But for the vast majority of SCLC patients, the cancer eventually grows again and is no longer responsive to additional treatments with cisplatin and etoposide. In addition, some patients with SCLC are resistant to chemotherapy upfront. However, a path way forward has been our increasing understanding of how cancer also corrupts changes on top of our genetic code (i.e. epigenetics) without directly altering the genetic code. One of the greatest challenges in examining SCLC epigenetics is lack of adequate tumor samples as they are difficult to obtain. We will address this limitation by maximizing use of patient blood samples to address our research goals. This project is designed to understand the epigenetics of SCLC and to develop a molecular biomarker to predict treatment response from the plasma (i.e. “cell-free”) portion of patient blood samples. In addition, we will generate renewable cancer models from circulating tumor cells extracted from patient blood samples for correlation with our cell-free epigenetic molecular biomarker.

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Mutation analysis as a prognostic and predictive marker of cardiac disease in patients with myelodysplasia

Myelodysplastic syndromes (MDS) are cancers that can cause infection or bleeding because they prevent the formation of blood components, such as red blood cells, white blood cells, and platelets. MDS can also cause leukemia which can lead to a patient’s death. MDS can be caused by changes (or mutations) to a patient’s DNA. There have not been any studies to see if these mutations cause an increased risk of heart disease in MDS patients, although it is known that MDS patients do have an increased risk of heart disease compared to healthy adults. We will look at these mutations and see if they are linked to an increased risk of heart disease. We will also use “CT imaging” to see if MDS patients have artery disease that isn’t causing symptoms but may lead to heart disease in the future and if that is related to the mutations that they have. We also think that the mutations seen in MDS patients lead to inflammation which leads to heart disease, so we will try to link mutations in MDS patients to markers of inflammation to see if there is a pattern between them as well as the amount of artery disease we see on CT imaging. We are lo