On-target drug delivery remains a challenge in cancer precision medicine; it is difficult to deliver a targeted therapy to cancer cells without incurring toxicity to normal tissues. The SERCA (sarco-endoplasmic reticulum Ca2+ATPase) inhibitor thapsigargin inhibits mutant NOTCH1 receptors compared with wild type in T cell acute lymphoblastic leukemia (T-ALL), but its administration is predicted to be toxic in humans. Leveraging the addiction of ALL to folic acid, we conjugated folate to an alcohol derivative of thapsigargin via a cleavable ester linkage. JQ-FT is recognized by folate receptors on the plasma membrane and delivered into leukemia cells as a potent antileukemic agent. In mechanistic and translational models of T-ALL, we demonstrate NOTCH1 inhibition in vitro and in vivo. These proof-of-concept studies support the further optimization of this first-in-class NOTCH1 inhibitor with dual selectivity: leukemia over normal cells and NOTCH1 mutants over wild-type receptors. Furthermore, tumor-specific disruption of Notch signaling may overcome legitimate concerns associated with the tumor suppressor function of nontargeted Notch pathway inhibitors.
Leukemia-specific delivery of mutant NOT CH1 targeted therapy / Roti, Giovanni; Qi, Jun; Kitara, Samuel; Sanchez-Martin, Marta; Conway, Amy Saur; Varca, Anthony C.; Su, Angela; Wu, Lei; Kung, Andrew L.; Ferrando, Adolfo A.; Bradner, James E.; Stegmaier, Kimberly. - In: JOURNAL OF EXPERIMENTAL MEDICINE. - ISSN 0022-1007. - 215:1(2018), pp. 197-216. [10.1084/jem.20151778]
|Appare nelle tipologie:||1.1 Articolo su rivista|