Targeted Inhibition of Leukemia Inhibitory Factor (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 and therapy resistance. In this DOD funded project, we developed a first-in-class inhibitor of LIFR, EC359, which binds to LIFR and block LIF/LIFR interactions. EC359 treatment exhibited antiproliferative effects, reduced stemness, and promoted apoptosis in triple-negative breast cancer (TNBC) cell lines. Treatment with EC359 attenuated the activation of LIF/LIFR driven pathways. EC359 also reduced the viability of therapy resistant TNBC models and synergized HDAC inhibitors. EC359 reduced the invasion and decreased metastases of TNBC cells. RNA-seq studies demonstrated oncogenic/survival signaling pathways were attenuated by the EC359 therapy. Importantly, EC359 inhibited the growth of TNBC patient derived explants ex vivo, cell derived xenografts and patient-derived xenografts in vivo. EC359 exhibits distinct pharmacologic advantages, including oral bioavailability, and in vivo stability. Collectively, these data supportEC359 as a novel targeted therapeutic that inhibits LIFR oncogenic signaling.
Document Details
- Document Type
- Technical Report
- Publication Date
- May 01, 2022
- Accession Number
- AD1190411
Entities
People
- Bindu Santhamma
- Ratna K Vadlamudi
Organizations
- Evestra (United States)
- University of Texas at San Antonio