Grant: Doctoral Award - Frederick Banting and Charles Best Canada Graduate Scholarships

Current treatment for chronic myeloid leukemia (CML) relies on inhibitors such as Imatinib Mesylate (IM) and newer iteration tyrosine kinase inhibitors (TKIs) to target the fusion protein, BCR-ABL1, which characterizes CML as a disease. However, BCR-ABL1 does not always act independently in persisting cell survival, which is why therapeutic resistance and disease relapse often occurs. Moreover, there is no promising detection strategy to identify patients who are unlikely to benefit from TKI monotherapy. One critical pathway involved in many cancers, including CML, is the cellular recycling process known as autophagy. Several key autophagy genes are expressed differently in leukemia stem cells - the cells responsible for the repopulating the cancer cells after treatment. The most substantial change is the increased presence of the core autophagy protein ATG4B. The expression of ATG4B is also increased in CML cells when compared to normal bone marrow cells, and importantly even more so in drug resistant CML cells. Stable reduction of ATG4B thus reduces autophagy within the cell, impairs survival of CML cells, and sensitizes these cells to TKI treatment. It appears targeting autophagy through ATG4B has clinical benefits, so I hypothesize that combination therapy with drugs targeting BCR-ABL1 and ATG4B can overcome TKI-resistance in CML. To investigate this I will test the use of novel ATG4B inhibitors in combination with TKIs within immortalized CML cell lines, real patient samples, and multiple mouse models. Simultaneously, I will explore the molecular mechanisms that cause ATG4B overexpression and how it contributes to CML drug resistance. Many other cancer types have identified ATG4B as a cancerous target, so this study will provide insight into the origin of its role in drug resistance and the feasibility of targeting ATG4B in treatment.