Co-funded by the Dick Vitale Pediatric Cancer Research Fund and the Jeff Gordon Children’s Foundation
Children with cancer are typically treated with chemotherapy to kill all dividing cells, including tumor cells. This general treatment causes side-effects, including damaging the normal healthy cells children need to grow and thrive. An additional, devastating, long-term side-effect of the use of chemotherapy is the risk of developing a second cancer. To circumvent these toxicities, we propose a targeted treatment tailored for a subset of pediatric patients with blood cancer. We identified a gene called “CUX1” that is deleted in the blood cells of patients with certain types of leukemia. Loss of one copy of CUX1 causes blood cells to grow too fast and stop maturing. In the current proposal, we predict that a drug that increases CUX1 levels will prevent leukemia growth and restore normal blood cell maturation. The objectives of the current proposal are to identify druggable regulators of CUX1 and to use these compounds to restore CUX1 in leukemias with CUX1 loss. We have identified one candidate regulator, named GSK3. We hypothesize that inhibition of GSK3 will increase CUX1 levels, halt leukemia growth, and restore normal blood development. We will accomplish these studies using innovative genetic screening, novel mouse models of childhood leukemia, and patient leukemia samples. Accomplishing the proposed studies will aid in the development of non-toxic therapies for children. This work will help us achieve our long-term goal of devising urgently needed treatments to improve the outcome for high-risk leukemias of childhood.