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.

Characterization of the function of the nuclear matrix protein Lamin A in the organization of telomeres and chromosomes to determine the role in the pathology of Hutchinson-Gilford Progeria Syndrome

Hutchison-Gilford progeria syndrome (HGPS) is a rare, fatal disease that affects children and causes accelerated aging. Symptoms include dwarfism, loss of body fat and hair, aged-looking skin, stiff joints and hip dislocation. Children with this disease usually die of a heart attack or stroke at an average age of 13. HGPS is caused by a mutation in the LMNA gene which encodes a protein called Lamin A. The mutation causes instability in the cell nucleus, which is believed to lead to the premature aging in HGPS. Michelle Decker is looking for differences in the way normal and mutant versions of the Lamin A protein interact with chromosomes in the cell nucleus. Research has shown that cells from patients with HGPS have shorter than usual chromosome ends (called telomeres) than are usually found in cells of other children. Telomeres normally protect chromosomes from degradation and instability. By improving the understanding of the role that Lamin A and telomeres have in Hutchison-Gilford progeria syndrome, Michelle’s research may contribute to new understandings and therapies for the disease.

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.

SHIP Down-Modulation as a Potential Approach to Protect Hematopoietic Cells During Chemotherapy or Radiotherapy

Chemotherapy and radiotherapy are currently used to treat many types of cancer. However, these treatments are not ideal because they target all dividing cells, including both cancerous and healthy cells. Blood cells, for example, have a finite lifespan and new cells are continuously being generated in the bone marrow. Unfortunately, the high doses of chemotherapy or radiation necessary to destroy malignant cells also kill these bone marrow cells. This reduces the body’s ability to replenish healthy blood cells, leading to life-threatening side effects such as anemia, infections, and uncontrolled bleeding. In such cases, the chemotherapy or radiation dose must be reduced, which, in turn, reduces the likelihood that cancerous cells will be eradicated. Melisa Hamilton is studying ways to protect blood cells during cancer treatment, with a particular interest in understanding how the SHIP protein inhibits blood cell survival. Melisa wants to determine whether reducing the level of this protein can increase cell survival during treatment. This would enable patients to withstand higher doses of chemotherapy or radiation with fewer side effects and increase the likelihood of killing the cancer cells.

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.

Notch signalling in mammary tumorigenesis

Breast cancer is the most common cancer among Canadian women. One in nine women is expected to develop breast cancer in her lifetime, and one in 27 will die of the disease. Metastasis, or the spread of the tumour to another site, is the major cause of death. Notch receptors are cellular proteins required for normal growth and development. However an overproduction of an active component of Notch can cause abnormal cell growth, leading to tumour formation and the spread of cancer to distant sites. Iva Kulic is examining how another protein, called Slug, functions with Notch to promote breast cancer. Both Notch and Slug are found at high levels in some human breast cancers and are a sign of poor outcome. Slug prevents tumour cells from dying and allows them to detach from neighbouring cells and travel to other sites within the body – two key features in tumour development and metastasis. This research will explore whether reducing or eliminating the Slug protein will inhibit breast tumour growth and block the spread of cancer cells. Resolving whether Slug is essential in Notch-induced breast cancer could lead to new ways of preventing and treating the disease.

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.

Gold Nanoparticle-Conjugated Antibodies as Optical Contrast Agents for In Vivo Molecular Imaging of Cancer

Cancer is the leading cause of premature death in Canada, and the number of new cases continues to rise as the population grows and ages. Based on current rates, 38 per cent of Canadian women and 44 per cent of Canadian men will develop cancer in their lifetimes, many when they are 70 or older. Traditionally, physicians assess the severity of cancer tumours by removing tissue samples from a patient and assigning a severity score based on what they see under the microscope. This process can be time-consuming and yields limited information. Recent discoveries have identified a number of molecules produced by cancer cells. Gerald Li is working on an optical imaging system to detect and evaluate the presence of these molecules. In particular, his focus will be on the use of specially designed probes that will flag these molecules, allowing a physician to immediately identify malignant cells. This system will make it possible to image various parts of the body to detect cancer earlier, predict which pre-cancerous lesions will become tumours, and image tumours in the operating room to help determine the boundary between healthy and malignant cells. It will also assist in the selection of treatments targeting cells that create these molecules.

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.

Development and characterization of a new human model of Chronic Myeloid Leukemia

Chronic myeloid leukemia (CML) is a specific type of leukemia in which there is a latent, or dormant, phase for several years before the rapid onset of fatal symptoms. This type of leukemia is difficult to study because the CML cells usually die when they are grown in laboratory conditions. Using human embryonic stem cells for CML research may be a viable option, as this type of cell readily grows in vitro and has the ability to develop into the type of blood cell affected by CML. The cells could be used to mimic some of the genetic changes seen in leukemia to identify important changes that trigger or block the progression of this disease. Melanie Kardel is working to develop techniques for creating leukemic cells from human embryonic stem cells in the laboratory. Because these cells could be grown in the lab for longer periods of time, more extensive studies than are currently possible could be performed, leading to the identification of new targets for therapy. Once targets are identified, this system would also be used to test the potential success of the therapies before they advance to clinical trial.