Novel targeting approach for pediatric B-cell malignancies
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.
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.