title: Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist.
abstract: Histone deacetylase inhibitors (HDACi) and agents such as recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and agonistic anti-TRAIL receptor (TRAIL-R) antibodies are anticancer agents that have shown promise in preclinical settings and in early phase clinical trials as monotherapies. Although HDACi and activators of the TRAIL pathway have different molecular targets and mechanisms of action, they share the ability to induce tumor cell-selective apoptosis. The ability of HDACi to induce expression of TRAIL-R death receptors 4 and 5 (DR4/DR5), and induce tumor cell death via the intrinsic apoptotic pathway provides a molecular rationale to combine these agents with activators of the TRAIL pathway that activate the alternative (death receptor) apoptotic pathway. Herein, we demonstrate that the HDACi vorinostat synergizes with the mouse DR5-specific monoclonal antibody MD5-1 to induce rapid and robust tumor cell apoptosis in vitro and in vivo. Importantly, using a preclinical mouse breast cancer model, we show that the combination of vorinostat and MD5-1 is safe and induces regression of established tumors, whereas single agent treatment had little or no effect. Functional analyses revealed that rather than mediating enhanced tumor cell apoptosis via the simultaneous activation of the intrinsic and extrinsic apoptotic pathways, vorinostat augmented MD5-1-induced apoptosis concomitant with down-regulation of the intracellular apoptosis inhibitor cellular-FLIP (c-FLIP). These data demonstrate that combination therapies involving HDACi and activators of the TRAIL pathway can be efficacious for the treatment of cancer in experimental mouse models.
authors.affiliation: Cancer Immunology Program, The Peter MacCallum Cancer Centre, Trescowthick Research Laboratories, St. Andrews Place, East Melbourne 3002, Victoria, Australia.
authors.forename: Ailsa J
authors.initials: AJ
authors.lastname: Frew
authors.forename: Ralph K
authors.initials: RK
authors.lastname: Lindemann
authors.forename: Ben P
authors.initials: BP
authors.lastname: Martin
authors.forename: Christopher J P
authors.initials: CJ
authors.lastname: Clarke
authors.forename: Janelle
authors.initials: J
authors.lastname: Sharkey
authors.forename: Desiree A
authors.initials: DA
authors.lastname: Anthony
authors.forename: Kellie-Marie
authors.initials: KM
authors.lastname: Banks
authors.forename: Nicole M
authors.initials: NM
authors.lastname: Haynes
authors.forename: Pradnya
authors.initials: P
authors.lastname: Gangatirkar
authors.forename: Kym
authors.initials: K
authors.lastname: Stanley
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Bolden
authors.forename: Kazuyoshi
authors.initials: K
authors.lastname: Takeda
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: J Paul
authors.initials: JP
authors.lastname: Secrist
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Smyth
authors.forename: Ricky W
authors.initials: RW
authors.lastname: Johnstone
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000096:biosynthesis; D045744:Cell Line, Tumor; D015536:Down-Regulation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D056572:Histone Deacetylase Inhibitors; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D016513:Mice, SCID; D009363:Neoplasm Proteins / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000819:agonists* / Q000378:metabolism; D000077337:Vorinostat
chemical_list: D000911:Antibodies, Monoclonal; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506387:Cflar protein, mouse; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D009363:Neoplasm Proteins; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; C505640:Tnfrsf10b protein, mouse; D000077337:Vorinostat; D006655:Histone Deacetylases