Adenosine A2A and Beta-2 Adrenergic Receptor Agonists: Novel Selective and Synergistic Multiple Myeloma Targets Discovered through Systematic Combination Screening
Menée sur des lignées cellulaires, à l'aide de xénogreffes et d'échantilllons prélevés sur des patients atteints de myélome multiple, cette étude met en évidence une activité antitumorale de la combinaison d'agonistes du récepteur A2A et du récepteur bêta-2-adrénergique
The use of combination drug regimens has dramatically improved the clinical outcome for multiple myeloma (MM) patients. 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 agonists were shown to be highly synergistic, selective and novel agents that enhance glucocorticoid activity in B-cell malignancies. Unexpectedly, A2A and beta-2 adrenergic receptor agonists also synergize with melphalan, lenalidomide, bortezomib and doxorubicin. An analysis of agonists in combination with dexamethasone (Dex) or melphalan in 83 cell lines reveals substantial activity in MM and diffuse large B cell lymphoma cell lines. Combination effects are also observed with Dex as well as bortezomib, using MM patient samples and mouse MM xenograft assays. Our results provide compelling evidence in support of development of A2A and beta-2 adrenergic receptor agonists for use in multi-drug combination therapy for MM. 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.
http://mct.aacrjournals.org/content/early/2012/04/03/1535-7163.MCT-11-0925.abstract