PSEN1-selective gamma-secretase inhibition for the treatment of T-cell acute lymphoblastic leukemia (T-ALL)
NOTCH1 gain-of-function mutations are present in the majority of T-ALL cases and mediate enhanced proliferation and survival of the leukemia cells. Importantly, mutant NOTCH1 still requires cleavage by the gamma-secretase complex to become active, making the gamma-secretase complex an important therapeutic target in T-ALL. The Laboratorium for Molecular Biology of Leukemia (Jan Cools) have recently shown that PSEN1-selective gamma-secretase inhibition could be an attractive novel avenue to target T-ALL since this is less toxic than broad gamma-secretase inhibition. In this project, we aim to perform pre-clinical studies of PSEN1-selective gamma-secretase inhibition for the treatment of T-ALL with the purpose of: (1) determining the relationship between the efficacy of PSEN1-selective gamma-secretase inhibition and NOTCH1 pathway mutations in vitro and in vivo; (2) identifying synergistic drug combinations between PSEN1-selective gamma-secretase inhibitors and currently used drugs for T-ALL treatment; (3) identifying mutations that confer resistance to PSEN1-selective gamma-secretase inhibition.