New approaches to target T-ALL

Abstract

Acute lymphoblastic leukemia is the most common malignancy in children. Although it is now curable in 80-90% of cases, patients with T-cell acute lymphoblastic leukemia (T-ALL) experience a higher frequency of induction failure and early relapse. Despite aggressive treatment approaches, including transplantation and new salvage regimens, most children with relapsed T-ALL will not be cured. As such, we are in need of new targeted therapies for the disease. Recent advances in the molecular characterization of T-ALL have uncovered a number of new therapeutic targets. This review will summarize recent advancements in the study of inhibiting the NOTCH1, PI3K-AKT, and Cyclin D3:CDK4/6 pathways as therapeutic strategies for T-ALL. We will focus on pre-clinical studies supporting the testing of small-molecule inhibitors targeting these proteins and the rationale of combination therapies. Moreover, epigenetic approaches to modulate T-ALL are rapidly emerging. Here, we will discuss the data supporting the role of bromodomain and extra-terminal bromodomain inhibitors in human T-ALL. While cure rates for children with acute lymphoblastic leukemia (ALL) have dramatically improved over the last several decades, ALL still remains a leading cause of cancer-related death in children. For adults with ALL, progress has been rather modest. One high-risk ALL subtype, T-cell acute lymphoblastic leukemia (T-ALL), accounts for 10-15% of pediatric and 25% of adult ALL cases. Although treatment of T-ALL has improved, early relapse is common and is almost invariably associated with poor prognosis. Furthermore, a major challenge remains the lifelong morbidity suffered by patients treated with current chemotherapy regimens. We are in need of more effective and selective treatment strategies. In this review, we will focus on emerging druggable opportunities in T-ALL: NOTCH1, BRD4/MYC, Cyclin D3:CDK4/6, and the PI3K pathway. © 2014 Roti and Stegmaier.