Pediatric blood cancers, B-cell acute lymphoblastic leukemia and B-cell lymphomas, comprise a quarter of all childhood cancers. Treatments for these aggressive malignancies includes intensive chemotherapy, which has significant toxicities and can cause complications in patients in the short- and long-term. Those children that are refractory to current treatments or that relapse have limited treatment options and have a poor prognosis. Specific alterations in the cancerous B cells at diagnosis or that develop with treatment contribute to its aggressiveness and treatment resistance. Therefore, better, less toxic targeted therapies are needed for pediatric B-cell malignancies, particularly those that relapse or that are resistant to treatment. Utilizing engineered mouse models, we recently discovered a previously unknown vulnerability of lymphoma cells that have a common alteration that confers treatment resistance. We then generated new targeted compounds specifically for this vulnerability and propose to investigate their effectiveness on three different pediatric B-cell malignancies.

Project Goals:

The goal of this proposal is to evaluate a novel targeted approach to eliminate pediatric B-cell leukemia and B-cell lymphoma cells, and particularly those that are difficult to treat. Our innovative approach includes evaluating new compounds we generated to specifically target and degrade a protein that our preliminary data indicate is required for the survival of malignant pediatric B cells, causing their death. Importantly, based on a discovery we recently made, our targeted degraders should also cause the death of pediatric B-cell leukemia and B-cell lymphoma cells that contain mutations in a gene that make them resistant to many current therapies. Completion of the research proposed will result in increased understanding of a new vulnerability in pediatric B-cell malignancies and pre-clinical evaluation on pediatric B-cell leukemia and lymphoma cells of our novel compounds that target this vulnerability. The long-term goal of these studies is to have an improved, more effective treatment avenue for pediatric B-cell malignancies, particularly those that are resistant to current therapies, to improve care and survival of children with these cancers. Results from our studies may also be able to be translated to other childhood cancers.

Project Update 2024:

We have made significant progress this year on our research project focused on targeting pediatric B-cell malignancies with novel compounds. We evaluated two compounds we designed and generated that target at a protein we hypothesized was required for the growth and survival of Burkitt lymphoma and B-cell acute lymphocytic leukemia (B-ALL). Our data show that our hypothesis was correct, and this year we further tested the first compound and also tested a new compound that targets the same protein. Both compounds showed they were effective at causing the death of Burkitt lymphoma and B-ALL cells. We also identified the specific cell death pathway that was activated by our compounds inside the pediatric cancerous B cells, including those that carry a mutation that allow them to resist many treatments. We also tested our compounds for their ability to kill human Burkitt lymphoma cells growing in mice, and both were quite effective, increasing the survival of the mice without toxic effects on normal cells. Our results continue to show that the previously unrecognized vulnerability in pediatric B-cell malignancies we discovered can be targeted with our novel compounds. With additional testing and optimization of the compounds, this may lead to a new treatment avenue for pediatric B-cell cancers, including those that are treatment resistant. Our ultimate goal is to provide an improved treatment approach for pediatric B-cell malignancies, leading to an increased survival rate for children with these cancers.