Mantle cell lymphoma (MCL) is an aggressive, incurable non-Hodgkin lymphoma with a median survival of three years. In order to find new, more effective treatments for MCL, researchers are working to better understand how the disease develops and progresses. MCL is characterized by a specific gene translocation, which prompts an unregulated growth signal. However, this translocation is believed to be only the first event in a stream of genetic alterations required to cause the disease. Using a recently-developed test capable of pinpointing previously undetectable genetic alterations, Ronald deLeeuw is compiling a more complete catalog of the secondary genomic alterations associated with MCL. By uncovering the role of secondary genes within the progression of MCL, Ronald hopes to uncover new targets for disrupting these pathways and halting the disease.
Research Location: BC Cancer Agency - Vancouver
Identification of regulatory mutations involved in cancer by gene expression analysis and bioinformatics approaches
Regulatory DNA sequences determine the leveI, location and timing of gene expression. These sequences are important in nearly all biological processes and many disease conditions. In some cases, the onset of cancer is related to changes in these sequences, such as when gene translocation results in the production of a protein that prevents normal cell death. Expanding on his previous MSFHR-funded work, Obi Griffith will make use of public gene expression data and novel computational approaches to identify genes believed to have undergone a change in regulation leading to cancer. Once these genes have been identified, further analysis will investigate the mechanism responsible for the change in regulatory control. Then, Obi will obtain specific tumour samples and validate the predicted changes in the laboratory. Obi hopes to increase understanding of how genes are controlled under normal conditions and how the loss of this control leads to cancer. Such identified genes could make suitable targets for therapeutic intervention as well as having prognostic and diagnostic value.
Protein isoforms generated by alternative splicing: prevalence and relevance to models of cancer progression
Continuing the study that he began in his MSFHR-funded Master’s work, Malachi Griffith is examining the changes in the forms of certain genes due to alternative splicing that may be important in the progression of cancer. Alternative splicing is a phenomenon in which one gene is assembled from its component pieces in many different ways, a process which produces immense diversity and enables genes to fulfill many functions. This diversity in gene structure may also account for the differences in the severity of cancers and response to treatment observed among individuals. Malachi is studying colon and prostate cancer cells – some that are responsive to treatment, and others that are resistant. By studying differences in the structure of expressed genes between these contrasting states, he hopes to gain insight into why treatment initially appears to work well in some patients, yet becomes less effective over time. Such knowledge may lead to improved or novel treatment strategies, resulting in better outcomes for cancer patients.
Risk Assesment for Oral Cancer Prevention in the Community
Even in countries with the best survival rates, 40-50 per cent of patients with cancer of the mouth (oral cancers) do not survive five years beyond diagnosis and treatment. Late diagnosis plays a major role in this high mortality rate because oral lesions at high risk of progressing to cancer are often difficult to differentiate from lesions that are a result of trauma or infection. Denise Laronde is examining two components central to the development of an effective oral cancer screening program. She is identifying and validating tools that can be used by dental professionals to help identify which oral lesions require follow-up. She is also designing and implementing a pilot education program for dental professionals to help train them in the use of these devices. Transferring this new technology to the community may result in earlier identification of high-risk lesions, and increasing the potential for earlier treatment and ultimately, improved long-term survival.
An adaptive intensity modulated radiation therapy (IMRT) technique through complete on-line treatment plan modification
Radiation therapy uses high energy, penetrating radiation to destroy or stop development of cancer cells, a process which also causes damage to surrounding healthy tissue. Conventional radiation treatment is created using a planning software that generates a plan based on the patient’s internal geometry (position of the target cancer cells and surrounding organs), and this plan remains unchanged for the whole treatment process. The ability to more closely and uniformly target the cancer cells, which includes the ability to map and adjust to changes in the internal geometry between and during treatments, would help to minimize impact to surrounding healthy tissue. A new form of radiation therapy known as adaptive radiation therapy (ART) may hold the answer. This modality allows for modifications of the original treatment plan before each treatment fraction, while the patient is in the treatment room. However, due to time constraints, only a selected set of treatment parameters of the original plan can be modified, which limits the full potential of this technique. Ante Mestrovic is exploring the development of a method for rapid, complete treatment plan modification that characterizes the patient’s internal geometry using three-dimensional ray tracing. His goal is to develop a time-efficient way of adapting treatment plans immediately before each treatment session. This would provide for more precise targeting of cancer cells, helping to reduce radiation exposure to healthy tissue and surrounding organs and contributing to a better outcome for patients undergoing radiation therapy.
Epigenetic Regulation of Natural Killer Cell Receptor Genes
The innate immune system, unlike the adaptive immune system, does not first require exposure to a foreign substance before immunity can be developed. Natural killer (NK) cells—a subset of white blood cells—make up a major part of the innate immune system. NK cells are considered a first line of defence in the body as they can recognize and destroy cells that have been altered, such as in the case of virus-infected or tumour cells and also foreign cells. This recognition is through the interaction of receptors on the surface of NK cells, with the receptor molecules called MHC class-1, expressed on the surface of target cells. The absence or alteration of numbers of MHC class-1 on abnormal target cells results in their destruction by NK cells. In both humans and mice, there is great variability in the number and combination of receptors on individual NK cells. Furthermore, it has recently become evident that the receptor repertoire of NK cells can change in response to various stimuli. Building on her previous MSFHR-funded work, Arefeh Rouhi is studying the mechanisms that control these variations among NK cells. Understanding how NK receptors are controlled is critical to the interpretation of how the repertoire is modified in response to infection and tumour cells, and the response of NK cells to mismatched bone-marrow grafts. Ultimately, this knowledge may lead to the development of methods to use the body’s own immune system to protect against infections and malignancy.
Computational methods for array CGH analysis for improved diagnosis of human cancers
Chromosomal instability is a hallmark of tumour cells in human cancer. Regions of chromosomal instability can have various forms including single point mutations, rearrangements, whole chromosome loss or duplication, or chromosomal segments containing DNA copy number change. The alterations change the expression of cellular constituents and eventually result in cells that do not function normally. Finding regions of chromosomal instability provides important locations in the human genome that are both symptomatic and diagnostic markers of various cancers. Recently developed techniques called array comparative genomic hybridization (aCGH) have allowed scientists an unprecedented high degree of resolution to detect regions of chromosomal instability in cancer patients. The experiments produce both a high volume of data and noisy signals that are not cleanly interpretable. Therefore, robust computational techniques must be developed that can automatically identify regions of chromosomal instability. Sohrab Shah is developing computational methods and statistical models that, given aCGH data for one or more patients, can accurately and reliably detect chromosomal aberrations. His research will first evaluate this method on standard data sets where the location of the aberrations are known, and then apply the method to three large scale genomic studies to discover chromosomal locations affected in lung, brain and lymphoma tumours. He will also assess the diagnostic utility of chromosomal alterations that are recurrent across patients and develop prototype diagnostic tests that may ultimately be put into clinical practice.
Mining the genome and transcriptome of lung cancer for clinically relevant molecular signatures
Lung cancer is responsible for the greatest number of cancer deaths in Canada. Current chemotherapy treatments are largely palliative, and only a small percentage of patients show a favourable response. Like other cancers, the progression of lung tumours is driven by a series of genetic alterations that can vary significantly between patients. The specific set of changes that occur in any individual tumour influences not only its aggressiveness and outcome, but also the effectiveness of cancer treatment. Scott Zuyderduyn will determine the genetic changes in several hundred lung tumour samples for which treatment and outcome is known. He will then employ computational and statistical approaches to determine which changes can accurately predict how a tumour will respond to different treatments. This research has important implications for determining, at diagnosis, the best choice of cancer-fighting treatment.
Genome-scale variation in health and disease
The sophisticated approaches of genomics are increasingly being used to analyze the majority of the genetic material contained within cells. The tools of genomics have catalyzed remarkable developments in health and disease research. These tools continue to evolve at a rapid pace, making possible additional health research opportunities that are increasingly comprehensive. Dr. Marco Marra is Director of the British Columbia Cancer Agency Genome Sciences Centre. Dr. Marra was funded as an MSFHR Scholar in 2001, with a specific focus of using genomics to comprehensively search for genes that play roles in cancer. In 2003, Dr. Marra also distinguished himself as leading the team that cracked the genetic code for SARS. In addition to his continuing work in cancer genomics, Dr. Marra is also working to identify and analyze DNA mutations correlated with, or causing, mental retardation. A consistent theme in Dr. Marra’s research is the identification and analysis of new genes and new gene products to determine their potential for use as new therapies or vaccines to combat cancer, infectious diseases, and other disorders.
Identification of predictive drug response signatures by whole genome profiling of lung tumors
Non-small cell lung cancer (NSCLC) accounts for an estimated 80% of known lung cancer cases. In many instances, these tumors are inoperable by the time of diagnosis, leaving chemotherapy as the main option for treatment. Unfortunately, tumor response to chemotherapy can vary and the presence of even a few drug-resistant cells within a tumor may result in disease recurrence as these cells expand to form a new tumor mass. Using archived NSCLC tumour samples, Timon Buys is working to identify genomic “signatures” that might predict how well or poorly a drug will act to destroy tumour tissues. First, he is using a technology called array comparative genomic hybridization, which allows researchers to assess changes in gene copy number throughout the whole human genome. Second, isolated patient cancer tissue will be grown and treated in mice to preview how a specific case will behave after treatment with chemotherapy drugs. Information from these studies could point to ways to effectively eliminate tumor recurrence due to drug resistance, helping to improve the prospects of patient survival.