Multiple myeloma, the second-most common hematopoietic malignancy in the United States, still remains an incurable disease with dose-limiting toxicities and resistance to primary drugs like proteasome inhibitors (PIs) and Immunomodulatory drugs (IMiDs). We have created a computational pipeline that uses pharmacogenomics data-driven optimization-regularization/greedy algorithm to predict novel drugs (“secDrugs”) against drug-resistant myeloma. Next, we used single-cell RNA sequencing (scRNAseq) as a screening tool to predict top combination candidates based on the enrichment of target genes. For in vitro validation of secDrugs, we used a panel of human myeloma cell lines representing drug-sensitive, innate/refractory, and acquired/relapsed PI- and IMiD resistance. Next, we performed single-cell proteomics (CyTOF or Cytometry time of flight) in patient-derived bone marrow cells (ex vivo), genome-wide transcriptome analysis (bulk RNA sequencing), and functional assays like CRISPR-based gene editing to explore molecular pathways underlying secDrug efficacy and drug synergy. Finally, we developed a universally applicable R-software package for predicting novel secondary therapies in chemotherapy-resistant cancers that outputs a list of the top drug combination candidates with rank and confidence scores. Thus, using 17AAG (HSP90 inhibitor) + FK866 (NAMPT inhibitor) as proof of principle secDrugs, we established a novel pipeline to introduce several new therapeutic options for the management of PI and IMiD-resistant myeloma.
多发性骨髓瘤是美国第二常见的造血系统恶性肿瘤，目前仍是一种无法治愈的疾病，存在剂量限制性毒性，并对蛋白酶体抑制剂（PIs）和免疫调节药物（IMiDs）等一线药物产生耐药性。我们开发了一种计算流程，利用药物基因组学数据驱动的优化-正则化/贪心算法来预测针对耐药性骨髓瘤的新型药物（“二级药物”）。接着，我们采用单细胞RNA测序（scRNAseq）作为筛选工具，依据靶基因富集程度预测最佳联合用药候选方案。为在体外验证二级药物，我们使用一组代表药物敏感型、先天/难治性以及获得性/复发型PI和IMiD耐药的人类骨髓瘤细胞系进行测试。随后，我们在患者来源的骨髓细胞（离体）中进行了单细胞蛋白质组学分析（飞行时间质谱流式细胞术），全基因组转录组分析（批量RNA测序）以及基于CRISPR基因编辑的功能实验，以探索二级药物疗效和协同作用的分子通路。最后，我们开发了一个普适性R软件包，用于预测化疗耐药癌症的新型二级疗法，该软件可输出带有排名和置信度评分的顶级联合用药候选列表。因此，以17AAG（HSP90抑制剂）+ FK866（NAMPT抑制剂）作为原理验证性二级药物，我们建立了一套全新流程，为治疗PI和IMiD耐药性骨髓瘤提供了多种新治疗选择。
肿瘤(癌症)患者之家