Targeting Beta-catenin Nuclear Export and Protein Degradation in High-Risk Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and while most children are cured, many who relapse or do not respond to treatment face very poor outcomes. Many children who fail newer targeted drugs must return to intensive chemotherapy, which can cause serious short- and long-term side effects. New, less toxic treatment options are urgently needed. Our team recently discovered a surprising weakness in leukemia cells: unlike many other cancers, ALL cells must constantly remove a protein called beta-catenin to stay alive. If beta-catenin builds up, it shuts down MYC, a gene leukemia cells need for survival, causing the cancer cells to die. We also found that ALL cells rely on a transport protein, XPO1, to move beta-catenin out of the cell, preventing this toxic buildup. Together, these findings reveal a completely new vulnerability that exists only in leukemia cells, not in normal cells or other cancer cells, offering an opportunity to design safer, more precise therapies for children with relapsed or high-risk ALL.
Project Goals
This project aims to develop a new, less-toxic treatment strategy for children with high-risk leukemia by taking advantage of the unique way ALL cells handle the protein beta-catenin. Our goal is to force leukemia cells into a state where beta-catenin builds up in the cell, shutting down MYC and causing the cancer cells to die, while sparing healthy cells. To do this, we will test combinations of medicines that block key leukemia survival systems. We can target beta-catenin using drugs that inhibit GSK3, NAE1, or the immunoproteasome and then combine these with an FDA-approved drug called Selinexor which blocks transport of beta-catenin out of the cell through XPO1. All of these medicines already exist and some have been tested in children, allowing quick translation into early-phase clinical trials if our results are successful. Ultimately, this work aims to deliver a new, targeted therapy that can improve survival and reduce treatment-related toxicity for children facing the most aggressive forms of leukemia.
