Adenosine A2A and Beta-2 Adrenergic Receptor Agonists: Novel Selective and Synergistic Multiple Myeloma Targets Discovered through Systematic Combination Screening

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

来源：Molecular Cancer Therapeutics, 2012, 11(7): 1432-1442.

DOI：10.1158/1535-7163.MCT-11-0925

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 beta-2 adrenergic receptor (beta 2AR) agonists were shown to be highly synergistic, selective, and novel agents that enhance glucocorticoid activity in B-cell malignancies. Unexpectedly, A2A and beta 2AR 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 beta 2AR 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. Mol Cancer Ther; 11(7); 1432-42.

• 出版日期2012-7