A Strategy To Identify Therapeutic Candidates For Chronic Lymphocytic Leukemia From A Library Of Fda Approved Drugs

Chronic lymphocytic leukemia (CLL) is an adult lymphoid malignancy with a variable clinical course. There is considerable interest in the identification of new treatments, as most current approaches are not curative. While most patients respond to initial chemotherapy, relapsed disease is often resistant to the drugs commonly used in CLL and are left without limited therapeutic options. In this study, we used a luminescent cell viability assay based on ATP levels (CellTiter-Glo, Promega) to find compounds that were potent and efficacious in killing CLL cells. We employed an in-house process of quantitative high throughput screening (qHTS) to assess 8-9 concentrations of each member of a 2,816 compound library (including FDA-approved drugs and those known to be bio-active from commercial suppliers). Using qHTS we generated potency values on each compound in lymphocytes donated from each of six individuals with CLL and five unaffected individuals. We found 102 compounds efficacious against cells from all six individuals with CLL (“consensus” drugs) with seven of these showing no efficacy on lymphocytes from a majority of unaffected donors, suggesting some degree of specificity for the leukemic cells. Furthermore, to determine if we could save time and cost we screened the same library using CLL cells pooled from these individuals. We found that over 90% of the 102 drugs identified as efficacious on cells from individuals were also efficacious in the pooled experiment. Importantly, a near perfect correlation was observed in potency values between the single and pooled studies. The results of this “pooling” approach suggests it is rationale to apply pooling and qHTS when screening CLL cells against much larger collections (>300,000 unapproved compounds) where novel compounds could be identified as starting points for drug discovery and development. 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 3685.