title: Synergistic anti-myeloma activity of the proteasome inhibitor marizomib and the IMiD immunomodulatory drug pomalidomide.
abstract: The proteasome inhibitor bortezomib is an effective therapy for the treatment of relapsed and refractory multiple myeloma (RRMM); however, prolonged treatment can be associated with toxicity, peripheral neuropathy and drug resistance. Our earlier studies showed that the novel proteasome inhibitor marizomib is distinct from bortezomib in its chemical structure, mechanisms of action and effects on proteasomal activities, and that it can overcome bortezomib resistance. Pomalidomide, like lenalidomide, has potent immunomodulatory activity and has been approved by the US Food and Drug Administration for the treatment of RRMM. Here, we demonstrate that combining low concentrations of marizomib with pomalidomide induces synergistic anti-MM activity. Marizomib plus pomalidomide-induced apoptosis is associated with: (i) activation of caspase-8, caspase-9, caspase-3 and PARP cleavage, (ii) downregulation of cereblon (CRBN), IRF4, MYC and MCL1, and (iii) suppression of chymotrypsin-like, caspase-like, and trypsin-like proteasome activities. CRBN-siRNA attenuates marizomib plus pomalidomide-induced MM cells death. Furthermore, marizomib plus pomalidomide inhibits the migration of MM cells and tumour-associated angiogenesis, as well as overcomes cytoprotective effects of bone marrow microenvironment. In human MM xenograft model studies, the combination of marizomib and pomalidomide is well tolerated, inhibits tumour growth and prolongs survival. These preclinical studies provide the rationale for on-going clinical trials of combined marizomib and pomalidomide to improve outcome in patients with RRMM.
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Deepika S
authors.initials: DS
authors.lastname: Das
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Arghya
authors.initials: A
authors.lastname: Ray
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Song
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Richardson
authors.affiliation: Triphase Accelerator, San Diego, CA, USA.
authors.forename: Mohit
authors.initials: M
authors.lastname: Trikha
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Dharminder
authors.initials: D
authors.lastname: Chauhan
authors.affiliation: LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004357:Drug Synergism; D006801:Humans; D007783:Lactones / Q000008:administration & dosage / Q000494:pharmacology; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000188:drug therapy*; D010447:Peptide Hydrolases / Q000378:metabolism; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism; D061988:Proteasome Inhibitors / Q000494:pharmacology; D011758:Pyrroles / Q000008:administration & dosage / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000378:metabolism; D013792:Thalidomide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D014183:Transplantation, Heterologous; D044767:Ubiquitin-Protein Ligases
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020533:Angiogenesis Inhibitors; C502543:CRBN protein, human; D007783:Lactones; D061988:Proteasome Inhibitors; D011758:Pyrroles; D034741:RNA, Small Interfering; D013792:Thalidomide; C475865:marizomib; C467566:pomalidomide; D044767:Ubiquitin-Protein Ligases; D011065:Poly(ADP-ribose) Polymerases; D010447:Peptide Hydrolases; D020169:Caspases
keywords: cancer and drug therapy; marizomib; multiple myeloma; pomalidomide