Abstract 5509: Identification of synergistic drugs using combination high-throughput screening

Abstract

Abstract Increased understanding of the complexity of biological networks is forcing us to reconsider traditional views of disease and treatment. This is particularly true for cancer, as tumor cells have a tremendous capacity to evade the effects of drugs by mutation and/or pathway adaptation. We have developed a combination high throughput screening (cHTS) platform (robotics and analytics) that systematically and efficiently identifies combination drugs with synergistic activity. Synergistic combination drugs can increase maximal drug effect, increase potency and/or circumvent chemoresistance. In addition, coordinated action at multiple molecular targets can provide unique therapeutic benefit not achievable with the “one-drug, one-target” paradigm, especially problematic for cancer. We describe the application of cHTS to the discovery of novel synergistic drug combinations for the treatment of cancer. Using cHTS we have made the surprising discovery that A2A and β2 adrenergic receptor agonists strongly synergize with glucocorticoids (GCs) to inhibit the proliferation of hematologic malignancies. Using an 83 cell line panel, we find that synergistic activity is specific for select B-cell malignancies (including some cell lines that are GC-insensitive). These dexamethasone-dependent synergies are observed across a large panel of multiple myeloma (MM) cell lines and in multiple complex preclinical models of MM disease. In general, chemoresistance is a recurrent problem for cancer drugs and development of resistance after chronic exposure can reduce drug efficacy and promote refractory disease. We therefore examined the effects of chronic exposure to either A2A or β2AR agonists. Exposure of MM cells (MM.1S) to CGS-21680 (A2A agonist) or salmeterol (β2AR agonist) for one month reduced single agent sensitivity >80%. Surprisingly, combinations of either agent with dexamethasone maintained similar amounts of synergy and cell killing as found with naïve untreated cells. Our studies demonstrate that synergistic combinations of A2A and β2AR agonists are highly selective for B-cell malignancies and support the notion that synergistic drug combinations can improve therapeutically relevant selectivity and circumvent drug resistance. These preclinical studies reinforce the rationale for investigation of A2A and β2AR agonists in the treatment of B-cell malignancies and in particular, patients who have MM. Furthermore, this work highlights the power of cHTS to interrogate combination activity across large panels of cancer cell lines with distinct molecular phenotypes and to identify novel mechanisms for therapeutic application. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5509.