New Targeted Therapies for Pediatric Acute Myeloid Leukemia
Kimberly Stegmaier
MDDana-Farber Cancer Institute
Project Term: July 1, 2023 - June 30, 2025
Our research focuses on the preclinical evaluation of new targeted therapies for high-risk subtypes of childhood AML. We are deploying screening approaches to delete each gene, one-by-one, to identify genes whose deletion leads to death of the leukemia cells. We will evaluate drugs developed against these targets in state-of-the-art models of pediatric AML. Our goal is to translate the most promising findings to clinical trials for children with these very poor outcome subsets of AML.
Leukemia remains the leading cause of cancer in children and the second leading cause of cancer related death in this age group. Remarkable progress has been made in the treatment of the most common type of leukemia in children, acute lymphoblastic leukemia (ALL). In contrast, cure rates for children with acute myeloid leukemia (AML) have lagged behind. One of the more common genetic abnormalities in childhood leukemia, including AML, involves a process known as a translocation in which a chromosome breaks and the fragmented pieces re-attach to a different chromosome. Often these translocations result in the production of a cancer-promoting protein known as a fusion oncoprotein. These fusion oncoproteins, which are only present in the leukemia cells and not in the normal cells, are responsible for the development of the leukemia and needed for the ongoing growth of the leukemia cells. Some of these fusion oncoproteins are associated with a particularly bad prognosis and resistance to standard chemotherapy treatment regimens. This proposal will focus on these subsets of pediatric AML with high-risk fusion oncoproteins and the identification and validation of new targeted drugs for these children.
Our laboratory has used an approach known as CRISPR-Cas9 to delete each gene, one-by-one, in the genome in over twenty AML cell line models and to study the impact of deletion of that gene in the AML cells. In doing so, we have identified genes that when deleted lead to the inability of AML cells to grow. Using this approach, we have identified several candidate drug targets for high-risk, fusion positive childhood AMLs and will focus on two high priority candidates. Both targets have chemical inhibitors developed against them, including FDA-approved drugs. In this proposal, we will use both genetic and chemical approaches to evaluate the impact of removing or inhibiting these targets on state-of-the-art models of childhood AML. It is our goal to translate promising findings from these studies to next-generation clinical trials for children with these devastating subtypes of pediatric AML.