Leukemia-specific delivery of mutant NOTCH1 targeted therapy

J Exp Med. 2018 Jan 2;215(1):197-216. doi: 10.1084/jem.20151778. Epub 2017 Nov 20.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / administration & dosage*
  • Biological Transport
  • Cell Line, Tumor
  • Disease Models, Animal
  • Drug Delivery Systems*
  • Endocytosis
  • Folate Receptor 2 / genetics
  • Folate Receptor 2 / metabolism
  • Folic Acid / chemistry
  • Gene Expression
  • Humans
  • Leukemia / drug therapy
  • Leukemia / genetics*
  • Leukemia / metabolism
  • Leukemia / pathology
  • Mice
  • Mutation*
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / metabolism
  • Protein Binding
  • Receptor, Notch1 / antagonists & inhibitors*
  • Receptor, Notch1 / genetics*
  • Receptor, Notch1 / metabolism
  • Signal Transduction / drug effects
  • Thapsigargin / chemistry
  • Xenograft Model Antitumor Assays


  • Antineoplastic Agents
  • Folate Receptor 2
  • Receptor, Notch1
  • Thapsigargin
  • Folic Acid