The role of pyruvate kinase as a therapeutic target in pediatric leukemia
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic malignancy recognized as a high-risk leukemia group. The introduction of intensified chemotherapy protocols has led to a progressive improvement in outcome in this disease, however, about 20% of children and 50% of adults with T-ALL fail to achieve a sustained complete remission and salvage therapies rarely work, so the prognosis for patients with primary resistant disease or relapsed leukemia remains dismal. In addition, the long-term effects of intensified chemotherapy in survivors of T-ALL show that gains in leukemia-free survival have been achieved at the cost of significant increases in rates of life-threatening and debilitating toxicities. Thus, further advances in the treatment of T-ALL are not likely to come from the intensification of existing agents or strategies, but from the development of novel molecularly targeted antileukemic drugs. In this context, our preliminary results highlight the critical relevance in T-ALL of pyruvate kinase (PKM), an enzyme that controls glucose metabolism. However, the role of PKM in pediatric T-ALL is largely unexplored. Thus, we propose to use our cutting-edge tools to dissect the role and mechanisms of PKM in leukemia in vivo. The results from this innovative project will ultimately lead to the development of novel combination therapies that might translate into improved treatments with fewer chances of relapse for pediatric T-ALL patients and, potentially, for other pediatric tumor types that might be dependent on PKM activity.
Project Goals:
This research proposal seeks to exploit our novel genetic tools, in which we can eliminate PKM from already established leukemias in mice in vivo, so that we can understand better the mechanisms behind its therapeutic effects using cutting-edge profiling technologies. In addition, we will also explore the potential toxicities associated to inhibiting PKM in the whole body (a critical step for any therapy to be used in pediatric patients), as well as identify potential synergistic effects of PKM loss with standard-of-care antileukemic treatments. Our results will unequivocally address the impact of inhibiting PKM in leukemia in vivo, and will identify PKM as a novel therapeutic target in this disease.
Project Update 2025
In this first year, using different genetic tricks, we have verified the antileukemic effects of targeting PKM in leukemic mice. We have started dissecting the mechanisms leading to these therapeutic effects, but more research is needed to fully understand why PKM is important for T-ALL cells. In addition, we have also identified a critical role for PKM in the development of normal T-cells, so further analyzing potential toxicities upon PKM inhibition will be critical for any future translation into patients. Our results support the development of clinical-grade PKM inhibitors, as such drugs should have very significant antileukemic effects.
