PSEN1-selective gamma-secretase inhibition for the treatment of T-cell acute lymphoblastic leukemia

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. We 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 aim to: (1)
determining the relationship between the efficacy of PSEN1-selective gammasecretase
inhibition and NOTCH1 pathway mutations in vitro and in vivo; (2)
identifying synergistic drug combinations between PSEN1-selective gammasecretase
inhibitors and currently used drugs for T-ALL treatment; (3)
identifying mutations that confer resistance to PSEN1-selective gammasecretase
inhibition.