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

The use of combination drug regimens has dramatically improved the clinical outcome for patients with multiplemyeloma.However,todate,combinationtreatmentshavebeenlimitedtoapproveddrugsandasmall number of emerging agents. Using a systematic approach to identify synergistic drug combinations, combination high-throughput screening (cHTS) technology, adenosine A2A and b-2 adrenergic receptor (b2AR) agonistswereshowntobehighlysynergistic,selective,andnovelagentsthatenhanceglucocorticoidactivityin B-cell malignancies. Unexpectedly, A2A and b2AR agonists also synergize with melphalan, lenalidomide, bortezomib, and doxorubicin. Ananalysis of agonists, in combination with dexamethasone ormelphalan 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,useofcHTSforthediscoveryandevaluationofnewtargetsandcombinationtherapies has the potential to improve cancer treatment paradigms and patient outcomes. Mol Cancer Ther; 1–11. � 2012 AACR.