Adenosine A2A and beta-2 adrenergic receptor agonists: Novel selective and synergistic multiple myeloma targets discovered through systematic combination screening

Richard J. Rickles, Winnie F. Tam, Thomas P. Giordano, Laura T. Pierce, Melissa Farwell, Douglas W. McMillin, Antoaneta Necheva, David Crowe, Mei Chen, William Avery, Vikram Kansra, Steffan T. Nawrocki, Jennifer S. Carew, Francis J. Giles, Constantine S. Mitsiades, Alexis A. Borisy, Kenneth C. Anderson, Margaret S. Lee

Research output: Contribution to journalArticlepeer-review

14 Scopus citations

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 b2AR agonists for use in multi-drug combination therapy for multiple myeloma. Furthermore, use of cHTS for the discovery and evaluation ofnew targets and combination therapies has the potential to improve cancer treatment paradigms and patient outcomes.

Original languageEnglish (US)
Pages (from-to)1432-1442
Number of pages11
JournalMolecular cancer therapeutics
Volume11
Issue number7
DOIs
StatePublished - Jul 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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