In the era of Precision Medicine, the treatment of Acute Myeloid Leukemia (AML) remains a significant challenge with fewer than 50% of patients having long term disease-free survival. Yet, the explosion of genomic information has allowed us to refine our knowledge of the genetic changes that result in the development of the many subsets of AML and has provided us insights into new and potentially groundbreaking clinical advances. One of the most common subsets of AML that affects both children and adults is characterized by mutations in a gene important for normal blood cell growth and development known as FLT3. The FLT3 gene is mutated or abnormally expressed in up to 25% of cases of AML and this abnormal expression results in an aberrantly active FLT3 kinase that results in a rapidly proliferating AML with a poor treatment outcome in all patient age groups. Therefore, specific therapies for FLT3 mutant leukemias are needed urgently. Attempts to target the mutant FLT3 with targeted FLT3 kinase inhibitors is an area of active research but a major breakthrough has not yet been made; in part, this is due to the rapid emergence of resistance to the targeted FLT3 kinase inhibitors that have thus far been tested. In this application, we propose the development of a new agent to treat leukemias with mutation or over-expression of FLT3. Recently, our group identified that a protein kinase, known as TOPK, which is abnormally expressed in many cancers (but not in normal tissues) is also expressed in high levels in AML, particularly in AML cells with mutations of FLT3. The laboratory of Dr. Yusuke Nakamura, one of the principal investigators of this grant identified a specific inhibitor of TOPK which is now being developed in partnership with a Japanese company, OncoTherapy Science. They are now completing toxicity and large animal model feasibility testing. Importantly, Dr. Nakamura’s laboratory has developed other successful new protein kinase inhibitors in collaboration with OncoTherapy Science, including a MELK protein kinase inhibitor that is currently being tested for the first time in patients with a variety of solid tumor malignancies here at the University of Chicago. We have tested the TOPK inhibitor OTS514 in many AML cell lines and in cells from patients with AML. Interestingly, this TOPK inhibitor has tremendous activity against AML cells, particularly in those with FLT3 mutations, resulting in their cell death using clinically achievable concentrations of the drug. Importantly, the TOPK inhibitor, OTS514, does not impair the survival of normal early blood cells. The goal of our grant is to understand how it is that the TOPK inhibitor kills FLT3 driven leukemias, to perform pre-clinical testing of OTS514 in mouse models of FLT3 leukemias and, using these insights, to design and perform a first in human trial of this TOPK inhibitor in patients with AML, focusing on those with mutations in FLT3. Our proposal is a comprehensive bench to bedside approach! The ability to shut down FLT3 expression with TOPK inhibition also provides the potential for circumventing the resistance that occurs with targeted FLT3 kinase inhibitors. Thus, we are optimistic that understanding of the mechanism by which TOPK impairs FLT3 driven leukemia cell growth and survival and the performance of a phase I “first in human” trial will provide us with the insights needed for future successful development of this TOPK inhibitor, with the ultimate goal of using a Precision Medicine approach to improving the survival of patients with FLT3 mutated AML.
