title: Preclinical screening of histone deacetylase inhibitors combined with ABT-737, rhTRAIL/MD5-1 or 5-azacytidine using syngeneic Vk*MYC multiple myeloma.
abstract: Multiple myeloma (MM) is an incurable malignancy with an unmet need for innovative treatment options. Histone deacetylase inhibitors (HDACi) are a new class of anticancer agent that have demonstrated activity in hematological malignancies. Here, we investigated the efficacy and safety of HDACi (vorinostat, panobinostat, romidepsin) and novel combination therapies using in vitro human MM cell lines and in vivo preclinical screening utilizing syngeneic transplanted Vk*MYC MM. HDACi were combined with ABT-737, which targets the intrinsic apoptosis pathway, recombinant human tumour necrosis factor-related apoptosis-inducing ligand (rhTRAIL/MD5-1), that activates the extrinsic apoptosis pathway or the DNA methyl transferase inhibitor 5-azacytidine. We demonstrate that in vitro cell line-based studies provide some insight into drug activity and combination therapies that synergistically kill MM cells; however, they do not always predict in vivo preclinical efficacy or toxicity. Importantly, utilizing transplanted Vk*MYC MM, we report that panobinostat and 5-azacytidine synergize to prolong the survival of tumor-bearing mice. In contrast, combined HDACi/rhTRAIL-based strategies, while efficacious, demonstrated on-target dose-limiting toxicities that precluded prolonged treatment. Taken together, our studies provide evidence that the transplanted Vk*MYC model of MM is a useful screening tool for anti-MM drugs and should aid in the prioritization of novel drug testing in the clinic.
authors.affiliation: Gene Regulation Laboratory, Cancer Therapeutics, Peter MacCallum Cancer Centre, St Andrews Place, East Melbourne, Victoria, Australia. geoff.matthews@petermac.org
authors.forename: G M
authors.initials: GM
authors.lastname: Matthews
authors.forename: M
authors.initials: M
authors.lastname: Lefebure
authors.forename: M A
authors.initials: MA
authors.lastname: Doyle
authors.forename: J
authors.initials: J
authors.lastname: Shortt
authors.forename: J
authors.initials: J
authors.lastname: Ellul
authors.forename: M
authors.initials: M
authors.lastname: Chesi
authors.forename: K M
authors.initials: KM
authors.lastname: Banks
authors.forename: E
authors.initials: E
authors.lastname: Vidacs
authors.forename: D
authors.initials: D
authors.lastname: Faulkner
authors.forename: P
authors.initials: P
authors.lastname: Atadja
authors.forename: P L
authors.initials: PL
authors.lastname: Bergsagel
authors.forename: R W
authors.initials: RW
authors.lastname: Johnstone
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001374:Azacitidine / Q000494:pharmacology / Q000627:therapeutic use*; D001713:Biphenyl Compounds / Q000494:pharmacology / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology / Q000627:therapeutic use; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D009596:Nitrophenols / Q000494:pharmacology / Q000627:therapeutic use*; D000077767:Panobinostat; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D053218:Receptors, Death Domain / Q000378:metabolism; D011994:Recombinant Proteins; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: C501332:ABT-737; D001713:Biphenyl Compounds; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D009596:Nitrophenols; D010879:Piperazines; D019253:Proto-Oncogene Proteins c-bcl-2; D016271:Proto-Oncogene Proteins c-myc; D053218:Receptors, Death Domain; D011994:Recombinant Proteins; D013449:Sulfonamides; D053221:TNF-Related Apoptosis-Inducing Ligand; D000077767:Panobinostat; D001374:Azacitidine
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