Targeting KDM6B in Pediatric Leukemia
Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer and the leading cause of death in kids with cancer. About 15% of these cases are a subtype called T cell ALL (T-ALL) and these patients are historically linked with poor prognosis. While clinical outcomes have improved with intense chemotherapy, ultimately about a quarter of these patients will relapse. In these cases, the survival prognosis is abysmal. In addition, intensive chemotherapy produces significant side effects associated with the toxicity of these approaches. The design of tumor-specific therapies to improve outcomes and reduce off-target toxicity is vital. Our laboratory investigations have identified a novel therapeutic target in pediatric T-ALL–a protein called KDM6B. Genetic suppression of KDM6B in murine models inhibits the development of pediatric T-ALL but is much less detrimental to healthy blood-forming stem cells. This suggests KDM6B is a good drug target because inhibition is harmful to cancer cells, but should be less toxic for the patient.
In this proposal, we will use leukemia cells from pediatric T-ALL patients to translate our findings from murine models into a more clinical setting. We will also use genetic tools to identify the precise regions of the KDM6B protein that facilitate its cancer-promoting functions. We will use this information to design a new, more specific drug to target this protein. We hope this work will lead to the development of a new therapy for high-risk pediatric T-ALL patients who have a high likelihood of treatment failure or have suffered a relapse.
Project Update - June 1, 2020
In year one of this project, we showed for the first time that inhibition of KDM6B also inhibits the growth of leukemia cells taken directly from pediatric T-ALL patients, in agreement with our previous mouse studies. We also developed and acquired new tools to understand how KDM6B supports the growth of these particular leukemia cells. In year two, we are poised to identify the precise function of KDM6B in these leukemias so that we can identify the important regions of the protein to design new drugs. These studies show that unlike its family member KDM6A, the gene KDM6B is needed for pediatric T-ALL in humans and is a good candidate for drug development to help these patients. We hope this work will lead to the development of a new therapy for high-risk pediatric T-ALL patients who have a high likelihood of treatment failure or have suffered a relapse.