Network-Based Drug Discovery Identifies Statins as a Repurposing Agent to Improve Activity of Current Therapies in Chronic Lymphocytic Leukemia.

Abstract

Background: Chronic lymphocytic leukemia (CLL) is a B lymphoid malignancy highly dependent on the microenvironment. CLL cell interactions with the supportive tissue microenvironment play a critical role in disease pathogenesis. Despite new targeted therapies such as ibrutinib and venetoclax, disease progression and relapse remain an issue. The present study aimed to identify drugs targeting key proteins described to have a role in the microenvironment.Methods: We used a platform for drug discovery based on systems biology and artificial intelligence. Bioactive compounds have been screened in silico and selected compounds were evaluated in CLL cell lines in the presence of stromal cells to mimic the microenvironment and validated the best candidates in primary CLL cells. Results: Our results showed that the commercial drug simvastatin was the most effective and selective out of the tested compounds. Simvastatin decreased CLL cell survival and proliferation as well as cell adhesion. Importantly, this drug enhanced the antitumor effect of venetoclax and ibrutinib. Conclusions: We proposed that systems biology approaches combined with pharmacology screening could help to find new drugs for CLL treatment and to predict new combinations with current therapies. Our results highlight the possibility of repurposing widely used drugs such as statins to target the microenvironment and to improve the efficacy of ibrutinib or venetoclax in CLL cells.

A Multi-Objective Approach for Drug Repurposing in Preeclampsia

“…This indicates that, despite the uncertain match between the gene signature in preeclampsia and the gene signature of drugs, we can use our 55 models to define a compound-protein interaction network or target interaction signature of all drugs used in preeclampsia management. A similar idea based on a multi-target approach obtained from system biology was successfully applied to identify statins as potential therapies in chronic lymphocytic leukemia in vitro [ 40 ]. In preeclampsia, the recent work of Shuyu Zhao et al [ 12 ] also identify a set of targets which later involve a drug-target network approach for repurposing.…”