Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York.
Mol Cancer Res. 2022 Feb;20(2):244-252. doi: 10.1158/1541-7786.MCR-21-0255. Epub 2021 Nov 2.
In this era of precision medicine, numerous workflows for the targeting of high-recurrent mutations in common tumor types have been developed, leaving patients with rare diseases with few options. Here, we implement a functional precision oncology approach utilizing comprehensive genomic profiling in combination with high-throughput drug screening, to identify tumor-specific drug sensitivities for patients with rare tumor types such as myxofibrosarcoma. From a patient with a high-grade myxofibrosarcoma, who was enrolled in the Englander Institute for Precision Medicine (EIPM) program, we established patient-derived 3D - and models for functional testing. In the absence of a large cohort of clinically similar cases, high-throughput drug screening was performed on the patient-derived cells, and compared with two other myxofibrosarcoma lines and a benign fibroblast line to functionally identify tumor-specific drug sensitivities. The addition of functional drug sensitivity testing to complement genomic profiling identified multiple therapeutic options that were further validated in patient derived xenograft models. Genomic analyses detected the frequently known codeletion of the tumor suppressors together with the methylthioadenosine phosphorylase () and a E286fs*50 mutation. High-throughput drug screening demonstrated tumor-specific sensitivity to compounds targeting the cell cycle. Based on genomic analysis and high-throughput drug screening, we show that targeting the cell cycle in these tumors is a powerful approach. IMPLICATIONS: This study demonstrates the potential of functional testing to aid clinical decision making for patients with rare or molecularly complex malignancies when combined with comprehensive genomic profiling.
在精准医学时代，针对常见肿瘤类型的高频突变已开发出许多靶向治疗方法，但这使得罕见病患者的选择有限。在这里，我们采用了一种功能性精准肿瘤学方法，利用全面的基因组分析与高通量药物筛选相结合，来确定罕见肿瘤类型（如黏液纤维肉瘤）患者的肿瘤特异性药物敏感性。我们对一名高级别黏液纤维肉瘤患者进行了研究，该患者参加了英格兰精准医学研究所（EIPM）的项目，我们建立了患者来源的 3D 模型和 进行功能测试。由于缺乏大量临床相似病例，我们对患者来源的细胞进行了高通量药物筛选，并与另外两条黏液纤维肉瘤细胞系和一条良性成纤维细胞系进行比较，以从功能上确定肿瘤特异性药物敏感性。将功能性药物敏感性测试添加到基因组分析中，可以确定多种治疗选择，并在患者来源的异种移植模型中进一步验证。基因组分析检测到了经常发生的肿瘤抑制因子 和甲基硫腺苷磷酸化酶 () 的共同缺失，以及一个 E286fs*50 突变。高通量药物筛选显示，这些肿瘤对靶向细胞周期的化合物具有肿瘤特异性敏感性。基于基因组分析和高通量药物筛选，我们表明靶向这些肿瘤的细胞周期是一种有效的治疗方法。意义：本研究表明，当与全面的基因组分析相结合时，功能测试具有为罕见或分子上复杂的恶性肿瘤患者提供临床决策辅助的潜力。
