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Genomics, morphoproteomics, and treatment patterns of alveolar soft part sarcoma patients and response to multiple experimental therapies
Molecular Cancer Therapeutics ( IF 5.3 ) Pub Date : 2020-03-03 , DOI: 10.1158/1535-7163.mct-19-0579
Roman Groisberg 1 , Jason Roszik 2 , Anthony P Conley 3 , Alexander J Lazar 4 , Daniella E Portal 1 , David S Hong 5 , Aung Naing 5 , Cynthia E Herzog 6 , Neeta Somaiah 3 , Maria A Zarzour 3 , Shreyaskumar Patel 3 , Robert E Brown 7 , Vivek Subbiah 5, 6
Affiliation  

Overexpression of transcription factor 3 in alveolar soft part sarcoma(ASPS) results in upregulation of cell proliferation pathways. No standard treatment algorithm exists for ASPS; multikinase inhibitors[tyrosine kinase inhibitor (TKI)] and immune checkpoint inhibitors (ICI) have shown clinical benefit. To date, no studies have reported on management strategies or sequencing of therapy. We evaluated ASPS treatment patterns and responses in an experimental therapeutics clinic. Genomic and morphoproteomic analysis was performed to further elucidate novel targets. We retrospectively reviewed patients with ASPS treated on clinical trials. Demographic and clinical next-generation sequencing (NGS) profiles were collected. AACR GENIE database was queried to further evaluate aberrations in ASPS. Morphoproteomic analysis was carried out to better define the biology of ASPS with integration of genomic and proteomic findings. Eleven patients with ASPS were identified; 7 received NGS testing and mutations in CDKN2A (n = 1) and hepatocyte growth factor (n = 1) were present. Ten patients were treated with TKIs with stable disease as best response and 4 patients with ICI (three partial responses). Within GENIE, 20 patients were identified harboring 3 called pathogenic mutations. Tumor mutation burden was low in all samples. Morphoproteomic analysis confirmed the expression of phosphorylated c-Met. In addition, fatty acid synthase and phosphorylated-STAT3 were detected in tumor cell cytoplasm and nuclei. Patients with ASPS have a quiescent genome and derive clinical benefit from VEGF-targeting TKIs. Morphoproteomic analysis has provided both additional correlative pathways and angiogenic mechanisms that are targetable for patients with ASPS. Our study suggests that sequential therapy with TKIs and immune checkpoint inhibitors is a reasonable management strategy.

中文翻译:

肺泡软部肉瘤患者的基因组学、形态蛋白质组学和治疗模式以及对多种实验疗法的反应

肺泡软部肉瘤 (ASPS) 中转录因子 3 的过度表达导致细胞增殖途径的上调。没有针对ASPS 的标准处理算法;多激酶抑制剂 [酪氨酸激酶抑制剂 (TKI)] 和免疫检查点抑制剂 (ICI) 已显示出临床益处。迄今为止,尚无关于管理策略或治疗顺序的研究报告。我们在实验性治疗诊所评估了 ASPS 治疗模式和反应。进行基因组和形态蛋白质组学分析以进一步阐明新目标。我们回顾性审查了在临床试验中接受治疗的 ASPS 患者。收集了人口统计学和临床​​下一代测序 (NGS) 资料。查询 AACR GENIE 数据库以进一步评估 ASPS 中的像差。进行形态蛋白质组学分析以通过整合基因组和蛋白质组学发现更好地定义 ASPS 的生物学。确定了 11 名 ASPS 患者;7 人接受了 NGS 检测,出现 CDKN2A(n = 1)和肝细胞生长因子(n = 1)突变。10 名患者接受 TKI 治疗,病情稳定是最佳反应,4 名患者接受 ICI(3 名部分反应)。在 GENIE 中,确定了 20 名患者携带 3 种称为致病突变。所有样本中的肿瘤突变负荷都很低。形态蛋白质组学分析证实了磷酸化 c-Met 的表达。此外,在肿瘤细胞的细胞质和细胞核中检测到脂肪酸合酶和磷酸化-STAT3。ASPS 患者的基因组处于静止状态,并从靶向 VEGF 的 TKI 中获得临床益处。形态蛋白质组学分析为 ASPS 患者提供了额外的相关通路和血管生成机制。我们的研究表明,使用 TKI 和免疫检查点抑制剂进行序贯治疗是一种合理的管理策略。
更新日期:2020-03-03
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