Bioinformatics and Computational Biology, University of Minnesota, Minneapolis, Minnesota, USA.
Department of Experimental and Clinical Pharmacology, University of Minnesota, Minneapolis, Minnesota, USA.
Clin Transl Sci. 2024 Sep;17(9):e70030. doi: 10.1111/cts.70030.
Neuroendocrine prostate cancer (NEPC) is an aggressive advanced subtype of prostate cancer that exhibits poor prognosis and broad resistance to therapies. Currently, few treatment options are available, highlighting a need for new therapeutics to help curb the high mortality rates of this disease. We designed a comprehensive drug discovery pipeline that quickly generates drug candidates ready to be tested. Our method estimated patient response to various therapeutics in three independent prostate cancer patient cohorts and selected robust candidate drugs showing high predicted potency in NEPC tumors. Using this pipeline, we nominated NAMPT as a molecular target to effectively treat NEPC tumors. Our in vitro experiments validated the efficacy of NAMPT inhibitors in NEPC cells. Compared with adenocarcinoma LNCaP cells, NAMPT inhibitors induced significantly higher growth inhibition in the NEPC cell line model NCI-H660. Moreover, to further assist clinical development, we implemented a causal feature selection method to detect biomarkers indicative of sensitivity to NAMPT inhibitors. Gene expression modifications of selected biomarkers resulted in changes in sensitivity to NAMPT inhibitors consistent with expectations in NEPC cells. Validation of these markers in an independent prostate cancer patient dataset supported their use to inform clinical efficacy. Our findings pave the way for new treatments to combat pervasive drug resistance and reduce mortality. Furthermore, this research highlights the use of drug sensitivity-related biomarkers to understand mechanisms and potentially indicate clinical efficacy.
神经内分泌前列腺癌（NEPC）是一种侵袭性的晚期前列腺癌亚型，预后不良，对治疗广泛耐药。目前，可用的治疗选择很少，这突显了需要新的治疗方法来帮助遏制这种疾病的高死亡率。我们设计了一个全面的药物发现管道，可以快速生成准备好进行测试的药物候选物。我们的方法估计了三种独立的前列腺癌患者队列中各种治疗方法对患者的反应，并选择了在 NEPC 肿瘤中显示出高预测效力的稳健候选药物。使用该管道，我们将 NAMPT 确定为有效治疗 NEPC 肿瘤的分子靶标。我们的体外实验验证了 NAMPT 抑制剂在 NEPC 细胞中的疗效。与腺癌 LNCaP 细胞相比，NAMPT 抑制剂在 NEPC 细胞系模型 NCI-H660 中诱导的生长抑制作用明显更高。此外，为了进一步协助临床开发，我们实施了一种因果特征选择方法来检测对 NAMPT 抑制剂敏感的生物标志物。选定生物标志物的基因表达修饰导致对 NAMPT 抑制剂的敏感性发生变化，与 NEPC 细胞中的预期一致。在独立的前列腺癌患者数据集验证这些标志物支持将其用于告知临床疗效。我们的研究结果为对抗普遍耐药性和降低死亡率的新治疗方法铺平了道路。此外，这项研究强调了使用与药物敏感性相关的生物标志物来了解机制并可能指示临床疗效。
