The role of SHIP in the development and function of myeloid immune suppressor cells

An important role of the immune system is to identify and eliminate tumour cells. When a tumour first forms, the immune system recognizes it as foreign and generates specialized T cells to attack and kill it. However, tumours have evolved a number of mechanisms that prevent the immune system from being able to function properly, resulting in cancer progression. One of the mechanisms by which tumours escape from the immune system is by secreting chemicals that promote the generation of cells that inhibit T cells from carrying out their normal functions. The presence of these suppressive cells is one of the most common reasons current cancer therapies fail. Melisa Hamilton is investigating a specific subset of these suppressive cells, called myeloid immune suppressor cells (MISCs). Previous research has shown that the protein known as SHIP is important in regulating the survival and proliferation of myeloid cells (white blood cells). Hamilton’s research is focused on investigating the specific role SHIP plays in MISC development and function. With a better understanding of how tumours stimulate the development of MISCs and how these cells suppress the immune system, researchers can design targeted therapies to prevent the formation and function of MISCs. These therapies would greatly increase the ability of the immune system to attack and eradicate tumours and would be especially effective in combination with current cancer immunotherapy treatments to improve cancer patient outcomes.

Identification of causal genetic alterations involved in the progression of epithelial cancers

Of the 227,000 newly diagnosed cancer cases in Canada in 2007, approximately 80 per cent were some type of carcinoma. Carcinomas (epithelial cancers) include a vast array of common cancers such as lung, breast, prostate, colorectal, oral, esophageal and cervical cancers. Patients with early stage cancer show the best response to therapies and exhibit the greater survival rate compared to those with the advanced stage disease. However, with current screening techniques, the majority of patients present with advanced stage disease at the time of diagnosis, limiting treatment options. The disruption of genes is responsible for cancer development. However, the accumulation of gene disruptions during cancer progression makes it difficult to distinguish which disruptions are the initiating events in this process. The discovery of these initiating events are crucial for gaining a better biological understanding of how cancer progresses. Conventional methods can only detect large DNA disruptions that may contain many genes, hindering precise identification of the genes responsible for cancer development. MSFHR funded William Lockwood for his early PhD research. He’s now continuing his comparison of DNA profiles of normal cells against cancerous cells. By labelling normal and tumour DNA with different dyes, he will be able to investigate the genetic changes that occur in progressing stages of cancer, in order to retrace the evolving patterns of gene disruption during cancer development. By distinguishing the initiating events, Lockwood’s research will shed light on the pathways driving the progression of cancer cells. This could lead to the identification of biomarkers to predict which early stage cancers are prone to develop into advanced tumours.

Regulatory mechanisms of the anti-apoptotic NAIP gene during cellular stress and malignancy

Apoptosis, or programmed cell death, is a critical physiological process that is turned on and off as appropriate to eliminate abnormal cells. When this switching process goes awry, it can lead to a variety of diseases including cancer. The genetic mechanisms that inhibit activation of the apoptosis protein (IAP) family include molecules that sequester key enzymes necessary for turning on and sustaining the process of programmed cell death. Neuronal apoptosis inhibitory protein (NAIP) is particularly interesting because expression of NAIP is reported to be highly elevated in various leukemias. In addition, NAIP is commonly deleted in the most severe cases of spinal muscular atrophy (SMA) and studies also have shown that a specific copy of this gene is required to suppress replication of the bacterial pathogen that causes Legionnaire’s disease. Researchers have also proposed that expression of NAIP in neurons of patients with Alzheimer’s disease can limit the high levels of cell death. Mark Romanish is studying the expression and regulation of NAIP to better understand its role and function in health and disease. Apoptosis is a highly regulated process receiving many activating and inhibiting signals, but the final outcome relies on which signals tip the scale. Therefore, the question of gene regulation becomes particularly important since those genes capable of rapid activation are more likely to influence the ultimate fate of a cell.

Genetic approaches to characterize mammary stem and progenitor cells

A stem cell can both self-renew and divide to form differentiated daughter cells. In adult tissues, stem cells have the ability to generate mature cells of a particular tissue through differentiation, and to do so multiple times. Such cells were recently identified in a mammary gland, and demonstrated their capacity to regenerate their structures in other breast tissues. This was an important discovery, as it is speculated that these stem cells are central to the development of breast cancer. Because stem cells are relatively long-lived compared to other cells, they have a greater opportunity to accumulate mutations leading to cancer. Also, these cells have a pre-existing capacity for self-renewal and unlimited replication. The idea that stem cells are inherent to malignant transformation has wide-stretching implications for therapeutics, particularly with regards to drug resistance. Angela Beckett is studying the growth and differentiation of normal breast stem cells, which will provide knowledge about what drives malignant transformation and how to prevent cancer initiation. By obtaining basic information on stem cell regulation, this research is taking an important step in designing novel therapeutic approaches to their malignant counterparts, cancer stem cells.

Characterization of a new checkpoint in hematopoietic stem cell development

Blood cells are critically important to human health and a significant perturbation of blood production is life-threatening. In addition, the transformation of blood cell precursors leads to fatal leukemias, lymphomas and myeloma that remain difficult to treat and are often fatal within a few years of diagnosis. All blood cells must be produced from a common pool of self-maintaining cells called blood stem cells. Understanding the regulation of these cells and their immediate derivatives is critical because they are thought to be the origin of most blood cancers and it is the transplantation of these cells that is required to rescue the blood-forming system in patients who can benefit from treatment with an otherwise lethal dose of chemotherapy or require replacement of a defective blood-forming system. Although the use of blood stem cell transplants can be life-saving, its application is still limited. A major barrier to more widespread use is the extremely limited number of blood stem cells in the tissues where they are produced, and our inability to grow or expand these cells in tissue culture. Previous research has demonstrated that as they develop from fetal to adult cells, blood stem cells undergo an abrupt change that reduces their capacity to expand. Michael Copley’s research at the Terry Fox Lab focuses on improving our understanding in molecular terms of the mechanism that switches the ability of blood stem cells to expand that occurs shortly after birth. This could lead to the development of ways to block or reverse the switch, so that adult stem cells can be made more effective. It could also lead to an increased understanding of why different types of leukemias and other early onset blood disorders develop in children and adults.

Measurement error issues in studying the effect of gene-environment interactions on disease risks

Complex diseases, such as different types of cancers, are influenced by genetic and environmental factors and their interactions. There is overwhelming evidence that the effects of environmental factors on most cancers are modified by individual genetic characteristics. The accuracy of assessing the effects of gene-environment interactions on disease risks depends on how accurately the exposure to environmental factors can be measured or how accurately genetic makeup can be classified or both. Measurement error or misclassification can seriously distort the true effects of gene-environment interaction and produce biased estimates of the effects. Dr. Shahadut Hossain is developing a flexible modeling approach to adjust for biases when some of the quantitative environmental exposures are measured inaccurately. Hossain is also working to extend this methodology so that it can incorporate both exposure measurement errors and gene misclassification. His research involves studies of non-Hodgkin lymphoma, ovarian cancer and prostate cancer conducted with the Cancer Control Research Program at the BC Cancer Agency. Hossain hopes his work will enable the assessment of gene-environment interactions to be done more precisely, contributing to a better understanding of the effects of these interactions and more effective intervention strategies to prevent these diseases.

Mechanisms for selectivity of vascular-disrupting anti-cancer therapies

Solid cancers rely on blood vessels for delivering the oxygen and nutrients that allow them to grow and metastasize (spread to other parts of the body). Chemotherapy treatment also relies on the vessels for effectively delivering anti-cancer drugs to the tumour cells. When blood vessels have abnormal features, such as in cancerous tumours, the tumours appear to be more resistant to conventional chemotherapies as the result of this abnormal vasculature. A new focus in cancer research attempts to exploit vessel abnormalities that are specific to cancer by using them as cancer therapy targets. A new class of anti-cancer drugs currently under development and in clinical trials targets the blood vessels that supply tumours in two ways: vascular targeting agents (VTAs) damage the existing blood vessels that supply tumours, while anti-angiogenic agents (AAAs) inhibit the growth of new vessels. Although VTAs cause catastrophic damage to blood vessels in the centre of tumours, they leave a rim of viable cells and vessels at the periphery that survive to regrow the tumour; AAAs are also only effective on select populations of vessels within a tumour. Jennifer Baker is studying whether vascular targeting and angiogenic agents will work more effectively in combination with eachother or with other conventional chemotherapies to stifle this subsequent tumour growth. Baker is examining which blood vessels are sensitive or resistant to the drugs, what damage the drugs cause, and how this damage affects tumour growth. The findings could result in more effective combined treatments that are capable of cutting off the blood supply to cancerous tumours, thereby preventing the tumour from growing and metastasizing.

Mechanism of androgen regulated expression of SESN1, a potential tumor suppressor

Male sex hormones (androgens) regulate tumour growth in prostate cancer. The only effective treatment for advanced prostate cancer is the removal of androgens using medication, or the surgical removal of the testes — treatments that cause impotence and a decreased sex drive. The results are usually temporary since some tumour cells survive, become independent of androgens, and continue to grow. Prostate cancer cells depend primarily on the androgen receptor, which encodes genetic information, for growth and survival. Gang Wang is studying how the androgen receptor decreases the expression of the SESN1 gene — a gene that may inhibit the growth of prostate tumour cells. Wang believes the SESN1 gene is no longer repressed when patients receive hormone therapy. This would explain the initial suppression of prostate cancer cells seen in these patients and the subsequent reappearance of cancer cells which later follows. Wang will confirm if the androgen receptor begins lowering the gene following therapy, allowing the cancer cells to grow. If so, the SESN1 gene could be a promising therapeutic target for treating prostate cancer.

Molecular Imaging of Cancer with Positron Emission Tomography

Recent developments in imaging devices provide researchers with powerful tools to detect cancers and explore the impact of therapy on tumour cells. This research program plans to leverage the strengths of positron emission tomography combined to computed tomography (PET/CT) to characterize and rapidly assess response to therapy in 3 common cancers (breast, prostate, and lymphoma) and combine this information with other predictors of aggressiveness and treatment failure. PET/CT imaging is a powerful technique that combines the strenghts of a PET scanner (which can measure tumor receptors and metabolic activity) with those of a CT scanner (which provides detailed images of a patient’s anatomy). The combination of both approaches could rapidly identify patients that are likely to fail conventional therapy and offer them alternatives that are better suited to the nature of their cancer. The research program is designed around 3 core themes. The first research them focuses on the development of methods to predict the outcome of patients with breast cancer who are treated with chemotherapy or hormone therapy. We will pursue ongoing work to develop animal models of breast cancer and imaging methods to monitor response of these tumors to chemotherapy and hormone therapy. We will also conduct clincial studies to correlate the results of imaging studies performed with PET/CT with outcome and response to therapy. The second theme focuses on the development of new probes that target specific proteins that are overexpressed at the surface of breast and prostate tumors. These probes might eventually be translated into clinical studies as breast and prostate cancer diagnostic agents for use with PET/CT, or even for therapy by tagging them with radioisotopes that can destroy tumor cells by proximity. The last theme proposes practical research studies of immediate clinical interest. We will assess the accuracy of PET/CT imaging in staging prostate cancer (with 2 radiopharmaceuticals designed to assess tumor lipid synthesis and bone turnover). We will also extend to the Vancouver site an ongoing study that assesses PET/CT imaging to predict the early response to chemotherapy in large cell lymphoma.

Molecular Epidemiology of Gastric and Esophageal Cancer Survival

Cancers of stomach and esophagus (the tube from the mouth to the stomach) are a major cause of illness and death. Worldwide, the incidence of tumours at the stomach-esophagus border is increasing more rapidly than any other type of cancer. Historically, gastric and esophageal cancers have been studied separately; however, recent evidence suggests these cancers have a lot in common. As a result, studying these cancers together may result in information about the origin or effective treatment of one cancer having similar implications for the other. Morteza Bashash is investigating whether certain genes are associated with the disease progression of these cancers. Specifically, he is testing whether these patients have alteration of two groups of genes that are associated with cancer progression, Matrix Metalloproteinase (MMP) and Tissue Inhibitors of Metalloproteinase (TIMP). He is monitoring newly-diagnosed patients to determine whether the progression of the disease depends on these genes or other possible determinants such as family history, and/or the patients’ ethnicity. He is also assessing whether the effects are different in geographic areas where the cancers are becoming more common (BC), and areas where the cancers are already common. The results from this research could help identify high risk patients and provide them with more effective treatment.