2. Academic Validation
  3. KDM4 Inhibition Targets Breast Cancer Stem-like Cells

KDM4 Inhibition Targets Breast Cancer Stem-like Cells

  • Cancer Res. 2017 Nov 1;77(21):5900-5912. doi: 10.1158/0008-5472.CAN-17-1754.
Eric Metzger 1,  Stella S Stepputtis 2 3,  Juliane Strietz 2,  Bogdan-Tiberius Preca 2,  Sylvia Urban 1,  Dominica Willmann 1,  Anita Allen 1,  Fides Zenk 4,  Nicola Iovino 4,  Peter Bronsert 3 5,  Amelie Proske 6,  Marie Follo 7,  Melanie Boerries 3 8,  Elmar Stickeler 9,  Jiangchun Xu 10,  Michael B Wallace 10,  Jeffrey A Stafford 10,  Toufike Kanouni 10,  Jochen Maurer 11 3,  Roland Schüle 12 3 13
Affiliations

Affiliations

  • 1 Urologische Klinik und Zentrale Klinische Forschung, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany.
  • 2 Department of General and Visceral Surgery and Comprehensive Cancer Center, University Medical Center Freiburg, Freiburg, Germany.
  • 3 Deutsches Konsortium für Translationale Krebsforschung, Standort Freiburg, Freiburg, Germany.
  • 4 Department of Chromatin Regulation, Max Planck Institute of Immunobiology and Epigenetics, Stübeweg and University of Freiburg, Freiburg, Germany.
  • 5 Department of Surgical Pathology, University Medical Center Freiburg, Freiburg, Germany.
  • 6 Department of Hematology/Oncology, University Medical Center Freiburg, Freiburg, Germany.
  • 7 Department of Internal Medicine I, University Medical Center Freiburg, Freiburg, Germany.
  • 8 Institute of Molecular Medicine and Cell Research, University of Freiburg, Freiburg, Germany.
  • 9 Department of OBGYN, University Clinic Aachen (UKA), Aachen, Germany.
  • 10 Celgene Quanticel Research, San Diego, California.
  • 11 Department of General and Visceral Surgery and Comprehensive Cancer Center, University Medical Center Freiburg, Freiburg, Germany. [email protected] [email protected].
  • 12 Urologische Klinik und Zentrale Klinische Forschung, Universitätsklinikum Freiburg, Medizinische Fakultät, Albert-Ludwigs-Universität Freiburg, Freiburg, Germany. [email protected] [email protected].
  • 13 BIOSS Centre for Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
PMID: 28883001 DOI: 10.1158/0008-5472.CAN-17-1754
Abstract

Traditional treatments for breast Cancer fail to address therapy-resistant Cancer stem-like cells that have been characterized by changes in epigenetic regulators such as the lysine demethylase KDM4. Here, we describe an orally available, selective and potent KDM4 Inhibitor (QC6352) with unique preclinical characteristics. To assess the antitumor properties of QC6352, we established a method to isolate and propagate breast Cancer stem-like cells (BCSC) from individual triple-negative tumors resected from patients after neoadjuvant chemotherapy. Limiting-dilution orthotopic xenografts of these BCSCs regenerated original patient tumor histology and gene expression. QC6352 blocked BCSC proliferation, sphere formation, and xenograft tumor formation. QC6352 also abrogated expression of EGFR, which drives the growth of therapy-resistant triple-negative breast Cancer cells. Our findings validate a unique BCSC culture system for drug screening and offer preclinical proof of concept for KDM4 inhibition as a new strategy to treat triple-negative breast Cancer. Cancer Res; 77(21); 5900-12. ©2017 AACR.

Figures
Products