Targeted Inhibition of Leukemia Inhibitory Factory (LIF)/LIFR Axis for the Treatment of Triple-Negative Breast Cancer

Abstract

Leukemia inhibitory factor receptor (LIFR) and its ligand LIF play a critical role in cancer progression. Here, we describe a rationally designed first-in-class inhibitor of LIFR, EC359 that directly interacts with LIFR and effectively block LIF/LIFR interactions. The results from first year studies showed that EC359 treatment exhibit anti-proliferative effects, reduce invasiveness and promote apoptosis of TNBC cells. The activity of EC359 is dependent on LIFR expression and treatment with EC359 attenuated the activation of LIF/LIFR driven pathways including STAT3, mTOR, and AKT. EC359 significantly reduced tumor progression in TNBC xenografts. EC359 exhibited good ADME characteristics. Collectively, these data support EC359 as a novel targeted therapeutic that inhibits LIFR oncogenic signaling that occur in TNBC.

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Document Details

Document Type
Technical Report
Publication Date
Feb 01, 2019
Accession Number
AD1095858

Entities

People

  • Klaus Nickisch
  • Ratna K Vadlamudi

Organizations

  • University of Texas Health Science Center at San Antonio

Tags

DTIC Thesaurus Topics

  • Apoptosis
  • Breast Cancer
  • Cancer
  • Cells
  • Chemical Synthesis
  • Chemistry
  • Department Of Defense
  • Epithelial Cells
  • Inhibition
  • Inhibitors
  • Medical Personnel
  • Molecular Biology
  • Neoplasms
  • Small Molecules
  • Students
  • Surface Plasmon Resonance
  • Therapy

Fields of Study

  • Chemistry

Readers

  • Oncology (Cancer Research).