Mechanisms and Targeted Inhibition of NT5C2 Mutations in Relapsed ALL
Resistance to chemotherapy is a major clinical challenge in pediatric acute leukemias. This project seeks to develop new drugs targeting NT5C2, a gene mutated in relapsed leukemias responsible for the development of resistance to chemotherapy.
Over the last decade, molecular and cytogenetic studies have uncovered multiple genes and pathways in the pathogenesis of T-ALL(2). However, the genetic drivers of drug resistance, therapeutic failure, disease progression and relapse in this disease remain largely unknown. Thus, mapping the genetic landscape of relapse leukemias, defining the mechanism of action of relapse-associated mutations and developing effective strategies to reverse chemotherapy resistance have become major research imperatives in the field.
This research proposal stems from our original identification of activating mutations in he NT5C2 nucleotidase gene as a major driver of chemotherapy resistance in T-ALL. The fundamental importance of NT5C2 mutations is highlighted not only by their prevalence (20% of relapsed T-ALLs) but also by their potential role as biomarkers to detect chemotherapy resistant subclones potentially associated with increased relapse risk and most importantly as therapeutic targets for the treatment of relapsed ALLs.
This research proposal follows on our detailed structural and functional characterization of activated mutant forms of NT5C2 identified in relapsed ALL and seeks to set the basis for the development of mutant specific NT5C2 inhibitors for the treatment of this disease.