Blood Journal
Leading the way in experimental and clinical research in hematology

Preclinical activity, pharmacodynamic and pharmacokinetic properties of a selective HDAC6 inhibitor, ACY-1215, in combination with bortezomib in multiple myeloma

  1. Loredana Santo1,
  2. Teru Hideshima2,
  3. Andrew L. Kung3,
  4. Jen-Chieh Tseng3,
  5. David Tamang4,
  6. Min Yang4,
  7. Matthew Jarpe4,
  8. John H. van Duzer4,
  9. Ralph Mazitschek5,
  10. Walter C. Ogier4,
  11. Diana Cirstea2,
  12. Scott Rodig6,
  13. Homare Eda1,
  14. Tyler Scullen1,
  15. Miriam Canavese1,
  16. James Bradner2,
  17. Kenneth C. Anderson2,
  18. Simon S. Jones4, and
  19. Noopur Raje1,*
  1. 1 Division of Hematology and Oncology, Massachusetts General Hospital Cancer Center, Boston, MA, United States;
  2. 2 Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States;
  3. 3 Lurie Family Imaging Center and Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States;
  4. 4 Acetylon Pharmaceuticals Inc., Boston, MA, United States;
  5. 5 Center for Systems Biology, Massachusetts General Hospital, Boston, MA, United States;
  6. 6 Department of Pathology, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, United States
  1. * Corresponding author; email: nraje{at}partners.org

Abstract

Histone deacetylase (HDAC) enzymatic activity has been linked to the transcription of DNA in cancers including multiple myeloma (MM). Consequently, HDAC inhibitors, alone and in combination, are being actively studied as novel therapies in MM. Here we investigated the preclinical activity of an HDAC6 selective inhibitor ACY-1215 in MM, alone and in combination with bortezomib. Low doses of ACY-1215 combined with bortezomib triggered synergistic anti-MM activity, resulting in protracted ER stress and apoptosis via activation of caspase-3,-8,-9 and poly (ADP) ribosome polymerase. In vivo anti-MM activity of ACY-1215 in combination with bortezomib was confirmed using two different xenograft SCID mouse models: human MM injected subcutaneously (plasmacytoma model); and luciferase-expressing human MM injected intravenously (disseminated MM model). Tumor growth was significantly delayed and overall survival significantly prolonged in animals treated with combined therapy. Importantly, pharmacokinetic data showed peak plasma levels of ACY-1215 at 4 h following treatment coincident with an increase in acetylated-α tubulin, a marker of HDAC6 inhibition, by immunohistochemistry and Western blotting analysis. These studies provide preclinical rationale for acetylated-α tubulin use as a pharmacodynamic biomarker in future clinical trials.

  • Submitted October 21, 2011.
  • Accepted January 8, 2012.