Development of a novel prognostic model in Follicular Lymphoma

Lymphoid cancers are the fourth most common cancers in Canada. The incidence of follicular lymphoma (FL), a common and incurable subtype of lymphoma, continues to rise and represent an important health care problem. The prognosis for patients with FL can vary widely, from cases that spontaneously go into remission, to aggressive forms of FL where life expectancy is measured in months. Transformation of FL to a more aggressive transformed lymphoma (TLy) occurs in one third of the patients over 10 years and is an important cause of patient morbidity and mortality. With an enhanced ability to distinguish among different FL types and their prognoses, clinicians could safely delay treatment or give minimally toxic therapy to low risk patients, and reserve more aggressive chemotherapy to high risk patients. Dr. Nathalie Johnson is a hematologist working to improve clinical tools for identifying high risk FL patients. She is focusing on novel biomarkers that are associated with disease severity, identifying the most significant genetic factors in the tumour and in the patient that predict overall survival (OS) and transformation to Tly in FL. So far, she and her colleagues have found 85 genes that are highly predictive of survival and 55 genes that are predictive of transformation. Johnson will use this knowledge to develop and test a diagnostic model that can be translated into clinical tests for use by hospital laboratories. Her project seeks to move novel biomarkers into the forefront of outcome prediction, which will lead to individualized patient care and should identify novel targets for future therapies.

The role of notch activation in VEGF-mediated tumour angiogenesis

A major step for cancer cells to form solid tumours and metastasize (spread to other parts of the body) is the development of new blood vessels around the tumour, a process called angiogenesis. Angiogenesis is essential for delivering nutrients that help tumour cells grow and survive. Blocking this process has been shown to inhibit the growth and spread of cancer in animal models, and early angiogenesis-blocking drugs have shown promise in human clinical trials. Still, much work remains to improve these treatments and better target tumour angiogenesis without affecting normal blood vessels. An important piece of this research is to develop a more complete understanding of how cancer cells “hijack” blood vessels to induce this process. Dr. Alexandre Patenaude’s research focuses on the molecular signals that cancer cells produce to recruit the vascular cells required for angiogenesis. He is studying two important factors: the notch protein and vascular endothelial growth factor (VEGF). VEGF is produced by cancer cells to induce the proliferation of the cells that assemble into blood vessels. Notch regulates how the blood vessels form, thereby allowing blood flow to circulate efficiently. Alexandre is also studying the role of these factors in the creation of pericytes, specialized cells that support the endothelial cells and help keep blood vessels open. This research will provide a better understanding of how blood vessels are hijacked by tumour cells. It could also suggest new ways to block this process, such as by inhibiting the generation of pericytes.

Predicting treatment response in Hodgkin Lymphoma by identifying new molecular markers

Hodgkin lymphoma is the most common type of malignant lymphoma in young people in the Western world. Despite modern treatments, about 20 per cent of patients die. Present studies have tried to identify ways to predict which patients are likely to be cured, using characteristics such as age, stage (degree of spread of the lymphoma), blood tests and x-rays or scans. However, these predictions are often inaccurate. Other genetic approaches to testing have proved difficult because malignant cells are present in very low numbers. Dr. Christian Steidl’s research focuses on developing tests to identify patients who will not be cured with current standard therapy, so that they may enrol in clinical trials testing innovative, new treatments. He is using a laser beam to capture individual malignant cells within lymph nodes so they can be studied separately from the surrounding non-malignant cells. This enables him to investigate how the genetic material in the malignant and non-malignant cells is altered and how this affects the behaviour of these cells – leading to the identification of markers that can predict treatment response. With a better understanding of the markers that can predict treatment response, physicians will be able to choose the right therapies for patients with Hodgkin lymphoma. This will help prevent both insufficient treatment and excessive treatment, which can lead to toxic side-effects. Identification of genes that are important for the malignant cells to survive will also help to develop new drugs that specifically target these cells.

Antiangiogenesis-induced changes in the tumour microenvironment: a window for therapeutic exploitation in pancreatic cancer

Pancreatic cancer is the deadliest form of cancer, with an average life expectancy of three to six months after diagnosis. Surgical removal of the tumour is the only curative treatment, but the majority of patients have inoperable tumours. A promising treatment strategy for many cancers types is to kill blood vessels in tumours. When blood vessels are disrupted, the tumour becomes starved of nutrients and oxygen. Some success in has already been seen with two different types of drug treatment: drugs that act specifically on blood vessels, and standard anti-cancer drugs delivered at low but continuous doses. While these treatments are promising in the context of pancreatic cancer therapy, their specific effects on pancreatic tumours are unknown. Dr. Jennifer Flexman is studying the effects of both types of drug on tumour growth and blood vessels. Using a variety of imaging techniques and biological methods, she will investigate how the tumour microenvironment (e.g. blood flow, oxygen levels) is changed by antiangiogenic drug therapies. Experimental results could lead to a rational basis for selecting treatments that takes advantage of physiological changes in the tumour. Dr. Flexman hopes her research will ultimately lead to the development of novel and more effective treatments for a deadly and largely untreatable disease, with the end goal of improving the quality of life and prognosis for patients

What happens after conventional treatment? Investigating the feasibility of a complementary and alternative medicine (CAM) modality for breast cancer survivors

It is estimated that there are well over 10.5 million cancer survivors in North America and over 40 percent of the females are breast cancer survivors. Nearly three quarters of the cancer survivors experience some kind of debilitating effect(s) from cancer diagnosis and conventional treatments, including considerable fatigue, psychological distress, impaired quality of life, cognitive dysfunction, cardiac toxicity, loss of appetite, poor mental health and reduced physical and sexual functioning. These effects are particularly prevalent in breast cancer survivors who received multiple treatments over an extended period of time. Increasingly, health care providers and patients are looking to innovative solutions to address adverse effects that are often poorly managed by conventional medicine. Approximately 80 per cent of breast cancer survivors use some form of complementary and alternative medicine (CAM) to help them manage the difficult physiological, emotional and psychological symptoms that often persist. A growing body of randomized controlled research implies that yoga therapy has physiological and psychosocial benefits for the chronically ill – however, controlled trials are lacking for its use within cancer. Dr. Suzanne Slocum_Gori has previously conducted NIH studies within the US investigating yoga therapy for HIV/AIDS. Now, she’s focusing on the feasibility of using yoga therapy as part of the BC Cancer Agency’s (BCCA) health services for breast cancer survivors. Slocum-Gori’s study will consist of two phases. She will examine both the acceptability and sustainability of such a program within BCCA’s mainstream health system for Phase I, including the identification of factors that promote and impede acceptability, sustainability, recruitment and attrition. Phase II of the study will consist of a controlled pilot study to measure the effectiveness of yoga therapy for breast cancer survivors over time.

The development and application of algorithms for interpreting next-generation Solexa sequencing data: creation of a genome-wide breast cancer mutation map

Breast cancer is the most common malignancy in North American women, with more than 20,000 new cases diagnosed each year in Canada. Promising new treatments like Herceptin take advantage of genetic changes that occur in breast cancer cells, which can be detected by assessing specific tumour biomarkers. This approach is possible thanks to the successful sequencing of the human genome and the development of faster, cheaper sequencing technologies. One such technology is the Illumina 1G, a sequencing platform that can sequence a full genome for medical purposes in a matter of weeks. However, this new technology requires the development of new methods for the analysis and interpretation of the output. Anthony Fejes is demonstrating the utility of these new sequencing technologies by applying them to the study of breast cancer. By fully sequencing the genome of breast cancer-derived cell lines, he will create a genetic “map” that identifies the location and nature of the changes underlying the transformation of healthy cells into cancer cells. He will then validate the maps by identifying specific genetic errors that contribute to the development of cancer, and attempt to identify currently available drugs that can be re-purposed to target these broken cellular elements. This combination of sequencing, computational analysis, and drug candidate testing provides a single “”genome-to-therapeutic”” work flow, demonstrating a method that can be applied to the development of personalized medicines. Fejes’ research will also allow researchers to find new approaches to the treatment of cancers, through development of a technique that can be applied to other genetic disorders.

Bioinformatic approaches for the interpretation of cancer genomes

The rapidly developing field of genomics is providing increasingly powerful tools to investigate our genetic make-up and provide a fundamental understanding into how cells and organisms function. Previously funded by an MSFHR Scholar award, Dr. Steven Jones’ ongoing research focus is to apply genomic and bioinformatic technologies to cancer research. Next-generation DNA sequencing machines at Canada’s Michael Smith Genome Sciences Centre provide the underlying technology platform for Jones to conduct a number of studies that will expand our knowledge about the fundamental mechanisms underlying health and disease. Jones will develop a number of studies around three key themes: • Understanding the genetic changes present in human cancer cells, as compared to the normal human genome, to improve drug screening and testing methods. • Investigating the changes that occur in cells in response to drug treatments to identify ways to improve the efficacy of these drugs. • Using the mouse liver as a model, identifying active regions of the genome in order to further understand the functional elements within our genetic material and how, in concert, they are able to coordinate and maintain the activity of a tissue or organ.

T Cell Therapy of Breast Cancer; Challenges and Opportunities

T cell therapy is a promising approach in cancer treatment that aims to use the body’s own immune system to rid itself of cancer. The therapy involves isolating T cells that react to the tumour from a patient’s blood, expanding their numbers in culture and infusing them back into the patient, with the expectation that the T cells will recognize and destroy cancer cells throughout the body. This approach has yet to be applied clinically to breast cancer. MSFHR funded Michele Martin’s early PhD work using an innovative mouse mammary tumour model to study this approach for future use in human breast cancer. By infusing tumour-reactive T cells, she has been able to induce complete tumour regression of about 37 per cent of tumours, an unprecedented result compared to other forms of immunotherapy. However, the remaining tumours show partial regression or no regression at all. Martin now seeks to understand why some tumours are resistant to this treatment. Intriguingly, while all regressing tumours demonstrate heavy infiltration with T cells after treatment, many non-regressing tumours show no infiltration at all. Martin’s hypothesis is that many resistant tumours are able to physically exclude T cells. Her research will determine the molecular factors behind the physical mechanisms contributing to a tumour’s exclusion of these T cells, and test whether she can disrupt the tumour environment to facilitate the effective infiltration of T cells. The information gathered from Martin’s genetic analysis of infiltrated and uninfiltrated/resistant tumours will provide valuable data for defining the molecular barriers to T cell infiltration, and could point to ways to overcome these barriers.

Use of a recombinant fusion protein to expand hematopoietic stem cells in vitro and to elucidate mechanisms that determine the expansion and self-renewal potential of mouse fetal liver and adult stem …

Bone marrow is the tissue that fills most bone cavities and is the source of red blood cells and many white blood cells. Disorders that require bone marrow transplantation include aplastic anemia (inadequate blood cell formation by bone marrow), immune disorders, and many types of blood cancers. Current bone marrow transplantation therapies are limited by the number of blood-forming hematopoietic stem cells (HSC) that can be isolated from the patient or donor and transplanted to the patient. Typically, bone marrow or peripheral blood, as closely matched as possible to the patient, is transplanted into the patient. As this match is rarely perfect, patients will often develop a condition of varying severity known as graft-versus-host disease, which causes the patient’s immune system to destroy donor cells. Michelle Miller aims to generate in the laboratory a non-viral method of expanding HSC in the aim of avoiding certain complications that can arise from gene therapy or allogenic bone marrow transplantation.. Michelle (or Ms. Miller) is in the process of testing a fusion protein, which in viral form, has proven to lead to significant HSC expansion and generation of functional mature cells without leading to malignancy. She is also investigating whether there are pathways in common between the self-renewal capacity of mouse fetal liver HSC and those found in the adult as these cells perform better in transplantation tests when compared to HSC from adults. Ms. Miller (or Michelle – see above)hopes her research will lead to increased knowledge about hematopoietic stem cells, and to safer, more effective stem cell therapies.

Identification of microRNAs, their targets and roles in human embryonic stem cells

Stem cells are a special variety of cells that can self-renew indefinitely and can become a multitude of cell types. Embryonic stem cells are the most versatile variety of stem cells and can potentially develop into any adult cell type. Many cancer researchers believe that in most (if not all) types of cancers, there is a population of cancer stem cells that actively sustain the production of cancer cells. A better understanding of stem cells is crucial in advancing knowledge of all cell types, including cancer cells. Before manipulation of embryonic stem cells can be explored as a method of treating disease, and before anti-cancer drugs that target cancer stem cells can be designed, there is a need to understand the genetic structure and the signaling pathways that maintain these cells. Ryan Morin’s research is directed at understanding how the regulation of gene expression differs between embryonic stem cells during their differentiation into other cell types. His particular focus applies new sequencing technologies to unravel the cellular complexity of the regulatory molecules known as microRNAs and their involvement in embryonic stem cell gene regulation.