Personalized Medicine research at Lawson is focused on understanding the molecular mechanisms of interindividual variation in drug response. This variation in drug response has long been a hindrance to obtaining effective and safe drug therapy. Differences in a patient’s response to drugs can lead to severe drug toxicity in some or loss of drug efficacy in others. These unexpected responses not only lead to suboptimal patient care but also result in an increased burden to overall health care costs.
Pharmacogenomics seeks to relate genetic variability to variability in drug response. Our laboratory uses a pharmacogenomics approach, combining research on drug metabolism and transport with research on the influence of genetic variation on drug response, to develop personalized drug therapies for cancer, vascular disease, and adverse drug reaction prevention. To date, our research has helped to tailor drug therapies for over 3000 patients.
- To discover new genetic polymorphisms that contribute to patient variation in drug response.
- To elucidate novel roles for drug transporters and determine the full complement of targets they are capable of transporting.
- To investigate new and exciting methods in the fields of pharmacogenomics, pharmacokinetics, and pharmacodynamics.
- To identify drug therapies that would benefit from a personalized medicine approach.
To combine research on drug metabolism and transport with research on the influence of genetic variation on drug response to develop personalized drug therapies that maximize the potential for therapeutic benefit and minimize the risk of adverse side effects for any given medication.
Cardiovascular Disease Research
Direct Oral Anticoagulant Research: Thromboembolic diseases, including heart attack and stroke, are leading causes of death in Western countries. Anticoagulation is often required for prophylaxis and treatment of these diseases. Vitamin K antagonists, such as warfarin have long been the standard of care for patients who needed long-term oral anticoagulation treatment. However, in recent years, several direct-acting oral anticoagulants (DOAC) have been developed to overcome some of the limitations associated with vitamin K antagonists. Though DOAC are a major advance in anticoagulation treatment, there is a large amount of unexplained variation in drug exposure between patients.
Our research goals are to measure drug levels of direct oral anticoagulants (apixaban, rivaroxaban and dabigatran) in patients to determine the interindividual variation in a real-world clinical setting, as well as identify the clinical and/or genetic factors that are predictive of excessive or sub-therapeutic drug exposure. This information will be used to tailor dose selection of these medications for each patient, ensuring optimal anticoagulation treatment.
Statin Research: Clinical use of statin medications surpasses any other drug class in North America for the treatment of high cholesterol. Statins are a class of cholesterol lowering drugs that inhibit the enzyme HMG-CoA reductase, which plays a central role in the production of cholesterol. 10-15% of patients on a statin (atorvastatin (Lipitor™), simvastatin (Zocor™), and rosuvastatin (Crestor™)) complain of muscle aches and weakness which can cause significant discomfort and limit compliance to the medication.
Our current research goals are to identify additional clinical and/or genetic factors that are predictive of excessive or sub-therapeutic statin drug exposure. We are currently researching the effect of food on rosuvastatin exposure. We predict that taking rosuvastatin with food will increase its uptake into the liver (its site of action), thereby reducing the amount of drug available to reach skeletal muscle. This may reduce the muscle related side effects associated with statin use. Additionally, this study will explore a possible bile acid related mechanism for this food effect from which subsequent studies may develop food-independent therapies for enhanced liver uptake of statins.
Cisplatin Induced Ototoxicity: Cisplatin-based chemoradiotherapy remains a standard treatment for head and neck cancers. However, use of cisplatin is complicated by serious side effects, including nephrotoxicity and ototoxicity (hearing loss), resulting in dose delay, reduction and premature discontinuation. Ototoxicity is currently not predictable and may cause permanent hearing loss. Some patients experience severe hearing loss after their first dose of cisplatin while others have a delayed toxicity onset or none at all. We are interested in using sequencing technologies, including Next-generation sequencing (NGS), to identify genetic predictors of ototoxicity.
Aromatase Inhibitors in Breast Cancer Therapy: Aromatase inhibitors are a class of drugs used in the treatment of breast cancer and ovarian cancer in postmenopausal women. These drugs work by blocking the enzyme aromatase, which turns the hormone androgen into small amounts of estrogen in the body. This means that less estrogen is available to stimulate the growth of estrogen-receptor-positive breast cancer cells. While these drugs are effective for treating breast cancer, they can cause adverse drug reactions in some patients, including musculoskeletal problems such as myalgia and arthralgia. Understanding the pharmacogenetic and pharmacokinetic variability of aromatase inhibitors in patients has the potential to better predict those at risk for adverse drug reactions.
Inflammatory Bowel Disease Research
Inflammatory bowel disease (IBD), made up of Crohn’s disease and ulcerative colitis, is an illness of chronic intestinal inflammation that follows a remitting and relapsing course and is associated with significant morbidity. Canada has among the highest reported prevalence and incidence of IBD in the world. There are over 233,000 Canadians living with IBD, translating to one in every 150 Canadians being affected. Since 2001, the incidence of IBD has been rising, significantly so in children. At this time, IBD is incurable and specialists rely heavily on remission-inducing drugs that target a dysregulated immune system. Patients are often on drugs for extended periods and response rates are variable. Reasons for resistance and loss of response are unknown. Overall, our understanding of drug metabolism in IBD is limited. By leveraging the technologies of liquid chromatography/mass spectrometry, pharmacogenomics, gene expression and animal models, our goal is to gain new insights into IBD-specific modifications of drug metabolism that may allow for improved drug efficacy, reduced drug toxicity as well as expand on possible mechanisms of disease.
Non-Alcoholic Fatty Liver Disease Research
Non-alcoholic fatty liver disease (NAFLD) is one of the causes of fatty liver; occurring when fat is deposited in the liver due to causes other than excessive alcohol use. It is the most common liver disease in the developed world, affecting 30% of the Canadian population. Given the close association with insulin resistance, metabolic syndrome and increased risk of cardiovascular disease, many NAFLD patients are prescribed a variety of medications to manage these comorbidities. The liver is the primary site of drug metabolism and yet, surprisingly, we know little about how NAFLD affects drug response. In collaboration with Dr. Melanie Beaton in the Division of Gastroenterology, we are studying the pharmacokinetics of drugs in patients with NAFLD. Furthermore, we perform studies in animal models and cellular systems to understand the molecular mechanisms involved in altered drug disposition in NAFLD.
Drug Transporter Research
Organic Anion Transporting Polypeptide 2B1 (OATP2B1) and drug disposition: Although oral administration of drugs is the most favorable route, the exact mechanism of intestinal absorption is not well understood. OATP2B1 is a widely expressed drug transporter that facilitates the uptake of solutes into cells. In the intestine and liver, OATP2B1 is considered to play a role in promoting oral drug absorption and hepatic elimination, respectively. We have developed a mouse model whereby the gene encoding Oatp2b1 (Slco2b1) is disrupted, in order to understand the in vivo relevance of this transporter in the pharmacokinetics of drugs. We are also studying how the expression of the Slco2b1 gene is regulated at the molecular level.
Organic anion-transporting polypeptide (OATP) uptake transporters in insulin secretion and pancreatic islet cell function: OATP transport proteins are expressed in various epithelial tissues in the body and have recently been identified in the pancreas. We are currently characterizing OATP transporter expression in the human pancreatic islet as well as their role in statin-induced impairment of beta cell function. Statins are commonly prescribed to lower cholesterol through HMG-CoA reductase inhibition. Though effective and safe for most, recent evidence suggests an increased risk of new-onset diabetes in patients on statin therapy. While the exact molecular mechanisms have not been elucidated, it is known that OATPs mediate the cellular uptake of statins. Their function in the pancreatic islets may play a role in the statin-induced impairment of beta cell function that leads to new-onset diabetes. We are also investigating the role of these uptake transporters in the progression and chemosensitivity of pancreatic cancer, and their potential as a diagnostic marker and therapeutic target.