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

Leukemia-specific delivery of mutant NOTCH1 targeted therapy.

Author information

1
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA.
2
Division of Hematology/Oncology, Boston Children's Hospital, Boston, MA.
3
Department of Medicine and Surgery, University of Parma, Italy.
4
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA.
5
Institute of Cancer Genetics, Columbia University, New York, NY.
6
Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY.
7
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA james.bradner@novartis.com.
8
Department of Medicine, Harvard Medical School, Boston, MA.
9
Novartis Institutes for Biomedical Research, Cambridge, MA.
10
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA kimberly_stegmaier@dfci.harvard.edu.
11
Broad Institute, Cambridge, MA.

Abstract

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.

PMID:
29158376
PMCID:
PMC5748843
DOI:
10.1084/jem.20151778
[Indexed for MEDLINE]
Free PMC Article

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