Overcoming Glucocorticoid Resistance in Lymphoid Cancers
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.
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.