Targeting leukemia stem cells by disrupting translational fidelity
The Regents of the University of California, San Diego
Project Term: July 1, 2020 - June 30, 2023
Dr. Signer is investigating how the process of building defective proteins (inaccurate protein synthesis) plays a role in the development of a type of blood cancer called acute myeloid leukemia (AML) in the hopes of developing targeted therapies to treat this condition.
Leukemia stem cells are a subset self-sustaining leukemia cells that maintain and propagate malignant disease. Unfortunately, leukemia stem cells are resistant to most therapies and their persistence leads to disease relapse. This is particularly evident amongst patients with acute myeloid leukemia (AML). AML is the most common form of adult leukemia, and because of a failure to target and eliminate AML stem cells, the five-year survival rate for AML patients is just 26%. The goal of our research is to identify new strategies to target leukemia stem cells and to develop curative therapies for AML patients. The current strategy that we are investigating is to target the machinery that produces proteins within AML stem cells. Proteins are the functional products of genes and perform virtually all of the specialized tasks within cells. We recently discovered that stem cells are highly dependent on producing proteins slowly and accurately, and increasing assembly errors within proteins preferentially impairs stem cell maintenance. Now, we are using genetic interventions and newly modified therapeutics to reduce the fidelity of protein synthesis in order to deliberately increase protein assembly errors within AML stem cells. Our studies will examine if this new approach can slow or prevent the progression of AML by disrupting the function of AML stem cells, and whether it can enable patients’ own immune systems to more readily recognize and eliminate AML stem cells. These studies could ultimately lead to new therapies for AML and other blood cancer patients.
This Discovery award is sponsored through a partnership between LLS, the Mark Foundation for Cancer Research and The Paul G. Allen Frontiers Group.