Acute myeloid leukemia (AML) is a devastating disease characterized by poor patient outcome. For example, adult patients (<65 years of age) have a five-year survival rate of less than 10% whereas rates in adolescent and child cases range from 40-60%. Chemotherapy given to AML patients is highly toxic (i.e., many side effects) and associated with high rates of patient relapse - where leukemia cells come back resistant to chemotherapy. The most significant limitation of these drugs is that they fail to target and eliminate leukemia stem cells, the cell responsible for disease onset and patient relapse. Clearly, novel therapies are needed that target and eliminate leukemia and leukemia stem cells.
Our lab is investigating novel drugs that selectively target and eliminate leukemia and leukemia stem cells with a specific interest in exploring the role of nutraceuticals (i.e., food-derived bioactive compounds). By utilizing drug screening technology, we employ a systematic approach of evaluating the anti-cancer activity of these compounds. This enables an unbiased assessment of their potential clinical utility, which brings significant value to the impact of this work particularly given the unrealistic claims that are typically associated with these compounds. Below are two broad principles by which our lab explores these compounds.
Identify Novel Anti-Cancer Nutraceuticals
We evaluate nutraceuticals for their ability to selectively induce death in leukemia cells without effecting normal cells. We have created a unique, in-house nutraceutical library conducive for high-throughput screening (the first in the world!) that enables our utilization of drug-screening technologies. We use a multi-platform approach to define the cell and molecular mechanism of selective toxicity and characterize pre-clinical efficacy in efforts to develop the novel nutraceutical into a clinical therapeutic. Through this approach, we identified avocatin B, a lipid from avocados, with potent and selective toxicity toward leukemia and leukemia stem cells. Avocatin B is a potent inhibitor of fatty acid oxidation, which was recently discovered to be important in leukemia cell survival. We have since partnered with the Centre for Commercialization of Regenerative Medicine and now looking to develop avocatin B into a drug suitable for human use.
Novel Probes to Understand Cellular Pathways
Once we have identified novel anti-cancer nutraceuticals we then use them as novel molecular probes to better understand the pathways that govern cancer cell survival and death. Understanding these processes enables the development of drugs with greater selectivity and potency at eliminating leukemia and leukemia stem cells. Through this approach, we are using avocatin B to understand the role of fatty acid metabolism and how it plays a pivotal role in leukemia cell survival. Interrogation of these pathways has allowed for the development of a second generation of avocatin B-like molecules with a greater ability of killing leukemia cells.