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.
Project Goals:
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.
Project Update 2024:
Our original hypothesis was that blocking the protein choline kinase A (CHKA) would increase sensitivity of leukemia cells to a class of chemotherapeutic drugs call alkylating agents. Alkylating agents are often used as part of hematopoietic stem cell transplant regimens for relapsed and high-risk childhood leukemias. Unfortunately, despite the fact that blocking CHKA dramatically increases sensitivity of leukemia cells to these drugs in the laboratory, this approach had much more modest effects in a whole organism. This argues that something that is present in the body, but missing in a laboratory dish, allows leukemia cells to survive chemotherapy treatment even when the protein CHKA is blocked. While these results were disappointing from the point of view of immediate clinical translation, we are now working to understand \ the factor present in the body that allows leukemia cells to survive. We believe that understanding the biology for this unexpected observation will allow us to better understand how leukemias survive chemotherapy, and ultimately develop better therapies.
