Jahchan Nadine S, Dudley Joel T, Mazur Pawel K, Flores Natasha, Yang Dian, Palmerton Alec, Zmoos Anne-Flore, Vaka Dedeepya, Tran Kim Q T, Zhou Margaret, Krasinska Karolina, Riess Jonathan W, Neal Joel W, Khatri Purvesh, Park Kwon S, Butte Atul J, Sage Julien
Departments of 1Pediatrics, 2Genetics, and 5Medicine-Oncology, 3Vincent Coates Mass Spectrometry Laboratory, Stanford University, Stanford; and 4Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis Cancer Center, University of California Davis School of Medicine, Sacramento, California.
Cancer Discov. 2013 Dec;3(12):1364-77. doi: 10.1158/2159-8290.CD-13-0183. Epub 2013 Sep 26.
Small cell lung cancer (SCLC) is an aggressive neuroendocrine subtype of lung cancer with high mortality. We used a systematic drug repositioning bioinformatics approach querying a large compendium of gene expression profiles to identify candidate U.S. Food and Drug Administration (FDA)-approved drugs to treat SCLC. We found that tricyclic antidepressants and related molecules potently induce apoptosis in both chemonaïve and chemoresistant SCLC cells in culture, in mouse and human SCLC tumors transplanted into immunocompromised mice, and in endogenous tumors from a mouse model for human SCLC. The candidate drugs activate stress pathways and induce cell death in SCLC cells, at least in part by disrupting autocrine survival signals involving neurotransmitters and their G protein-coupled receptors. The candidate drugs inhibit the growth of other neuroendocrine tumors, including pancreatic neuroendocrine tumors and Merkel cell carcinoma. These experiments identify novel targeted strategies that can be rapidly evaluated in patients with neuroendocrine tumors through the repurposing of approved drugs.
Our work shows the power of bioinformatics-based drug approaches to rapidly repurpose FDA-approved drugs and identifies a novel class of molecules to treat patients with SCLC, a cancer for which no effective novel systemic treatments have been identified in several decades. In addition, our experiments highlight the importance of novel autocrine mechanisms in promoting the growth of neuroendocrine tumor cells.
小细胞肺癌（SCLC）是一种侵袭性神经内分泌亚型肺癌，死亡率高。我们采用系统的药物重新定位生物信息学方法，查询大量基因表达谱，以确定美国食品药品监督管理局（FDA）批准的治疗SCLC的候选药物。我们发现三环类抗抑郁药及相关分子在体外培养的初治和耐药SCLC细胞、移植到免疫缺陷小鼠体内的小鼠和人SCLC肿瘤以及人SCLC小鼠模型的内源性肿瘤中均能有效诱导细胞凋亡。这些候选药物激活应激通路并在SCLC细胞中诱导细胞死亡，至少部分是通过破坏涉及神经递质及其G蛋白偶联受体的自分泌存活信号实现的。这些候选药物抑制其他神经内分泌肿瘤的生长，包括胰腺神经内分泌肿瘤和默克尔细胞癌。这些实验确定了新的靶向策略，可通过重新利用已批准药物在神经内分泌肿瘤患者中快速进行评估。
我们的工作展示了基于生物信息学的药物方法在快速重新利用FDA批准药物方面的力量，并确定了一类新的分子用于治疗SCLC患者，这是一种几十年来尚未发现有效新型全身治疗方法的癌症。此外，我们的实验突出了新型自分泌机制在促进神经内分泌肿瘤细胞生长中的重要性。
