Choline Kinase and Alkylating Agent Resistance in Refractory Childhood Leukemias
Alkylating agents are a class of chemotherapeutics important for children with high-risk or relapsed leukemias. These are given during what we call conditioning regimens just before bone marrow transplantation (BMT). The goal of conditioning regimens is to eliminate all leukemia cells, before the bone marrow is replaced by BMT. However, the failure of these conditioning regimens to ablate all leukemia cells is a major problem that leads to relapse after BMT. Leukemic relapse is the most common cause of treatment failure of BMT regimens, and these patients have a very poor prognosis. How leukemia cells become resistant to these drugs is not well understood, which prevents development of improved treatments. New effective therapies are urgently needed for these patients.
We recently used a technique called CRISPR/Cas9 to systematically inactivate every gene in drug-resistant leukemia cells. This approach allowed us to discover genes that cause chemotherapy resistance. We found that blocking an enzyme of choline metabolism reverses resistance to alkylating agents in drug-resistant leukemias. However, our studies to date have only been performed on laboratory-derived leukemia cells.
We do not know whether this approach can effectively kill leukemias from children that relapsed after chemotherapy. We also do not understand how this enzyme controls chemotherapy resistance. These knowledge gaps are major obstacles to the translation of these findings to the clinic, and to further improving efficacy and safety of this approach.
We propose to investigate these knowledge gaps as follows: 1) Test the therapeutic utility of inhibition of this enzyme of choline metabolism and alkylating agents in leukemic samples from children with relapsed/refractory T-cell acute lymphoblastic leukemia and acute myeloid leukemia. 2) Define precisely how this enzyme of choline metabolism controls chemotherapy resistance. Successful completion of this proposal is expected to provide a compelling rationale for development of clinical-grade drugs to test this approach in the clinic.