title: Adenosine A2A and beta-2 adrenergic receptor agonists: novel selective and synergistic multiple myeloma targets discovered through systematic combination screening.
abstract: The use of combination drug regimens has dramatically improved the clinical outcome for patients with multiple myeloma. However, to date, combination treatments have been limited to approved drugs and a small number of emerging agents. Using a systematic approach to identify synergistic drug combinations, combination high-throughput screening (cHTS) technology, adenosine A2A and β-2 adrenergic receptor (β2AR) agonists were shown to be highly synergistic, selective, and novel agents that enhance glucocorticoid activity in B-cell malignancies. Unexpectedly, A2A and β2AR agonists also synergize with melphalan, lenalidomide, bortezomib, and doxorubicin. An analysis of agonists, in combination with dexamethasone or melphalan in 83 cell lines, reveals substantial activity in multiple myeloma and diffuse large B-cell lymphoma cell lines. Combination effects are also observed with dexamethasone as well as bortezomib, using multiple myeloma patient samples and mouse multiple myeloma xenograft assays. Our results provide compelling evidence in support of development of A2A and β2AR agonists for use in multi-drug combination therapy for multiple myeloma. Furthermore, use of cHTS for the discovery and evaluation of new targets and combination therapies has the potential to improve cancer treatment paradigms and patient outcomes.
authors.affiliation: Zalicus Inc., Cambridge, Massachusetts 02142, USA. rrickles@zalicus.com
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rickles
authors.forename: Winnie F
authors.initials: WF
authors.lastname: Tam
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Giordano
authors.forename: Laura T
authors.initials: LT
authors.lastname: Pierce
authors.forename: Melissa
authors.initials: M
authors.lastname: Farwell
authors.forename: Douglas W
authors.initials: DW
authors.lastname: McMillin
authors.forename: Antoaneta
authors.initials: A
authors.lastname: Necheva
authors.forename: David
authors.initials: D
authors.lastname: Crowe
authors.forename: Mei
authors.initials: M
authors.lastname: Chen
authors.forename: William
authors.initials: W
authors.lastname: Avery
authors.forename: Vikram
authors.initials: V
authors.lastname: Kansra
authors.forename: Steffan T
authors.initials: ST
authors.lastname: Nawrocki
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Carew
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Giles
authors.forename: Constantine S
authors.initials: CS
authors.lastname: Mitsiades
authors.forename: Alexis A
authors.initials: AA
authors.lastname: Borisy
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Anderson
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Lee
mesh_terms: D058917:Adenosine A2 Receptor Antagonists / Q000494:pharmacology*; D058672:Adrenergic beta-2 Receptor Antagonists / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D005260:Female; D020869:Gene Expression Profiling; D057166:High-Throughput Screening Assays; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000235:genetics / Q000378:metabolism*; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays
chemical_list: D058917:Adenosine A2 Receptor Antagonists; D058672:Adrenergic beta-2 Receptor Antagonists; D000970:Antineoplastic Agents