Targeting the Thymic Stromal Lymphopoeitin Receptor Signaling Axis to Reduce Relapse of High Risk Pediatric Acute Lymphoblastic Leukemia
Pediatric acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Although the cure rate for this disease is greater than 85%, ALL remains a primary cause of cancer-related deaths in children due to relapse of disease. Importantly, there has been little progress in improving outcomes for patients with relapsed or refractory disease. Recently, a subset of pediatric ALL patients whose leukemic cells express high levels of thymic stromal lymphopoietin receptor (TSLPR/CRLF2) have been shown to have higher rates of relapse, shorter disease free survival, and poorer overall survival. The mechanism by which Thymic Stromal Lymphopoietin (TLSP) signaling contributes to increased risk of relapse is unknown.
We hypothesize that patients with high TSLPR levels relapse more frequently because their leukemia cells are more responsive to TSLP secreted in the local environment where they grow called niches. These niches are made up of specific cell types that secrete factors like TSLP and support the growth of normal developing blood cells, but in the context of ALL have been hijacked to support growth and survival of ALL. We believe that this interaction between ALL and its niche provides a survival advantage for high TLSPR expressing ALL during treatment and that these patients have higher rates of relapse due to survival of leukemic cells that can re-initiate leukemia. Therefore, we propose that blockade of TSLPR signaling will enhance existing therapies for leukemia by reducing the risk of relapse in patients with high TSLPR expression.
"In this time of decreased funding for biomedical research, foundations like Alex’s Lemonade Stand are critical to help young investigators such as myself to continue working on projects that have the potential to make a significant impact on childhood cancer. I am extremely glad to have received a Young Investigator Grant from such a fantastic organization committed to finding a solution to the problem of pediatric cancers." ~ Christopher Chien, PhD