Overcoming Glucocorticoid Resistance in Lymphoid Cancers
Background: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with T lineage ALL (T-ALL) accounting for approximately 15% of cases. Many patients with T-ALL present with "high risk" clinical features and are treated with chemotherapy drugs that kill the leukemia cells, but also damage normal tissues. This causes long-term adverse health effects in some pediatric cancer survivors. Glucocorticoids (also called steroids) are an essential type of chemotherapy drug that has been used to treat pediatric ALL and lymphoma for almost 50 years. ALL cells that respond poorly to glucocorticoids have a much higher chance of causing disease relapse and death. For this reason, drugs that can make glucocorticoids work better would significantly improve the treatment of pediatric ALL and lymphoma patients. We generated T-ALLs in mice, showed that these leukemias have many of the same mutations found in pediatric T-ALL patients, and treated them with a glucocorticoid called dexamethasone. This drug was very effective, and we also unexpectedly discovered that when T-ALLs relapsed after prolonged treatment they were frequently missing the receptor that glucocorticoids bind. This revealed a novel way that leukemia cells use to become resistant to glucocorticoid treatment, and we showed that this also happens in human T-ALL cells at relapse.
Project Goal: Our goals are to understand how leukemia cells become resistant by turning off the glucocorticoid receptor and to use this knowledge in order to devise new ways of killing them.
Project Update 2021: Our recent work has uncovered new mechanisms of steroid resistance using T-ALL cells isolated from mice that were treated with this drug until relapse. These mechanisms include disruption of a region of DNA that is thought to affect expression and function of the glucocorticoid receptor, and increased expression of a protein with multiple functions that was shown to cause tumor formation and steroid resistance in another model system. We cultured human leukemia cell lines and manipulated them in order to determine how the alterations we found in mouse T-ALLs after they stopped responding to steroids can cause drug resistance. This information will allow us to identify drugs we can combine with steroids to overcome resistance, which we can test by treating mice with relapsed T-ALL that no longer respond to steroids. The goal of our work is to find drug combinations that will provide new treatment strategies for children with relapsed/refractory T-ALL or other lymphoid cancers.
