Experimental Therapeutics in Lymphoid Malignancies Group, Institut d' Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain.
Sci Rep. 2020 Dec 17;10(1):22153. doi: 10.1038/s41598-020-78315-0.
Chronic lymphocytic leukemia (CLL) is a B lymphoid malignancy highly dependent on the microenvironment. Despite new targeted therapies such as ibrutinib and venetoclax, disease progression and relapse remain an issue. CLL cell interactions with the supportive tissue microenvironment play a critical role in disease pathogenesis. We used a platform for drug discovery based on systems biology and artificial intelligence, to identify drugs targeting key proteins described to have a role in the microenvironment. The selected compounds were screened in CLL cell lines in the presence of stromal cells to mimic the microenvironment and validated the best candidates in primary CLL cells. 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. We proposed that systems biology approaches combined with pharmacological 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.
慢性淋巴细胞白血病（CLL）是一种高度依赖于微环境的 B 淋巴细胞恶性肿瘤。尽管有伊布替尼和维奈托克等新的靶向治疗方法，但疾病的进展和复发仍然是一个问题。CLL 细胞与支持组织微环境的相互作用在疾病发病机制中起着关键作用。我们使用了一个基于系统生物学和人工智能的药物发现平台，来识别针对微环境中具有作用的关键蛋白的药物。选择的化合物在存在基质细胞的情况下在 CLL 细胞系中进行筛选，以模拟微环境，并在原代 CLL 细胞中验证最佳候选物。我们的结果表明，在测试的化合物中，商业药物辛伐他汀是最有效和最具选择性的。辛伐他汀降低了 CLL 细胞的存活和增殖以及细胞黏附。重要的是，这种药物增强了 venetoclax 和伊布替尼的抗肿瘤作用。我们提出，系统生物学方法与药理学筛选相结合，可以帮助寻找治疗 CLL 的新药，并预测与现有疗法的新组合。我们的结果强调了重新利用广泛使用的药物（如他汀类药物）来靶向微环境并提高伊布替尼或 venetoclax 在 CLL 细胞中的疗效的可能性。
