title: Antitumor activities and on-target toxicities mediated by a TRAIL receptor agonist following cotreatment with panobinostat.
abstract: The recent development of novel targeted anticancer therapeutics such as histone deacetylase inhibitors (HDACi) and activators of the TRAIL pathway provide opportunities for the introduction of new treatment regimens in oncology. HDACi and recombinant TRAIL or agonistic anti-TRAIL receptor antibodies have been shown to induce synergistic tumor cell apoptosis and some therapeutic activity in vivo. Herein, we have used syngeneic preclinical models of human solid cancers to demonstrate that the HDACi panobinostat can sensitize tumor cells to apoptosis mediated by the anti-mouse TRAIL receptor antibody MD5-1. We demonstrate that the combination of panobinostat and MD5-1 can eradicate tumors grown subcutaneously and orthotopically in immunocompetent mice, while single agent treatment has minimal effect. However, escalation of the dose of panobinostat to enhance antitumor activity resulted in on-target MD5-1-mediated gastrointestinal toxicities that were fatal to the treated mice. Studies performed in mice with knockout of the TRAIL receptor showed that these mice could tolerate doses of the panobinostat/MD5-1 combination that were lethal in wild type mice resulting in superior tumor clearance. Given that clinical studies using HDACi and activators of the TRAIL pathway have been initiated, our preclinical data highlight the potential toxicities that could limit the use of such a treatment regimen. Our studies also demonstrate the power of using syngeneic in vivo tumor models as physiologically relevant preclinical systems to test the antitumor effects and identify potential side effects of novel anticancer regimens.
authors: Cancer Therapeutics Program, The Peter MacCallum Cancer Centre, East Melbourne, Victoria, Australia.
authors: Ben P
authors: BP
authors: Martin
authors: Ailsa J
authors: AJ
authors: Frew
authors: Michael
authors: M
authors: Bots
authors: Stephen
authors: S
authors: Fox
authors: Fenella
authors: F
authors: Long
authors: Kazuyoshi
authors: K
authors: Takeda
authors: Hideo
authors: H
authors: Yagita
authors: Peter
authors: P
authors: Atadja
authors: Mark J
authors: MJ
authors: Smyth
authors: Ricky W
authors: RW
authors: Johnstone
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D017209:Apoptosis; D015153:Blotting, Western; D003131:Combined Modality Therapy; D004357:Drug Synergism; D056572:Histone Deacetylase Inhibitors / Q000627:therapeutic use; D006655:Histone Deacetylases / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000627:therapeutic use*; D020287:In Situ Nick-End Labeling; D007211:Indoles; D008325:Mammary Neoplasms, Experimental / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D000077767:Panobinostat; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D000077767:Panobinostat; D006655:Histone Deacetylases