PAIS experiment. Homo sapiens

Intimal sarcoma (IS) is a rare, malignant and aggressive tumor that shows a relentless course with a concomitant low survival rate, for which no effective treatment is available. In this study, 21 cases of large arterial blood vessel IS were analyzed by immunohistochemistry and fluorescent in situ hydridisation (FISH), and selectively by karyotyping, array-CGH, sequencing, phospho-kinase antibody arrays and Western immunoblotting, in search for the novel diagnostic markers and potential molecular targets. Ex vivo immunoassays were applied to test the sensitivity of IS primary tumor cells to the receptor tyrosine kinase (RTK) inhibitors imatinib and dasatinib.We demonstrated that amplification of the platelet-derived growth factor receptor alpha (PDGFRA) is a common finding in IS, and might be considered as a cytogenetic hallmark of this entity. This amplification is consistently associated with PDGFRA activation. Furthermore, the tumors reveal persistent activation of the epidermal growth factor receptor (EGFR), concurrent to PDGFRA activation. Activated PDGFRA and EGFR frequently co-exist with amplification and overexpression of MDM2. Ex vivo immunoassays on primary cells showed the potency of dasatinib to inhibit PDGFRA and downstream effectors in IS. Our findings provide a rationale for investigating therapies that target PDGFRA, EGFR or MDM2 in IS. Given the molecular heterogeneity of this tumor type and the potential crosstalk between PDGFRA and EGFR signaling pathways, targeting multiple RTKs and aberrant downstream effectors might be required to improve therapeutic outcome for patients with this disease. Key words: intimal sarcoma, PDGFRA, EGFR, MDM2, targeted therapy, amplification Overall design: Genomic profiling of 8 PAIS cases for detection of chormosomal aberrations Individual sample Against a normal control

内膜肉瘤（Intimal sarcoma，IS）是一种罕见的恶性侵袭性肿瘤，病程迁延且生存率低下，目前尚无有效的治疗手段。本研究通过免疫组织化学（immunohistochemistry）、荧光原位杂交（fluorescent in situ hybridization，FISH）对21例大血管内膜肉瘤病例进行分析，并选择性采用核型分析、阵列比较基因组杂交（array-CGH）、测序、磷酸化激酶抗体芯片以及蛋白质免疫印迹（Western immunoblotting）技术，旨在探索新型诊断标志物与潜在分子靶点。此外，本研究采用体外免疫检测方法，评估IS原代肿瘤细胞对受体酪氨酸激酶（receptor tyrosine kinase，RTK）抑制剂伊马替尼（imatinib）与达沙替尼（dasatinib）的敏感性。本研究证实，血小板衍生生长因子受体α（platelet-derived growth factor receptor alpha，PDGFRA）扩增是IS的常见分子特征，可作为该肿瘤的细胞遗传学标志性事件，且该扩增与PDGFRA的激活持续相关。进一步研究发现，肿瘤同时存在表皮生长因子受体（epidermal growth factor receptor，EGFR）的持续性激活，且与PDGFRA激活常同时发生。激活的PDGFRA与EGFR常与MDM2的扩增及过表达共存。体外原代细胞免疫检测实验证实，达沙替尼可有效抑制IS细胞中PDGFRA及其下游效应通路的活性。本研究结果为针对IS的PDGFRA、EGFR或MDM2靶向治疗提供了理论依据。鉴于该肿瘤的分子异质性以及PDGFRA与EGFR信号通路间潜在的交互串扰，同时靶向多种受体酪氨酸激酶及异常下游效应分子，或可改善该疾病患者的治疗预后。关键词：内膜肉瘤，PDGFRA，EGFR，MDM2，靶向治疗，扩增整体实验设计：对8例PAIS病例开展基因组谱分析，以检测染色体畸变，实验采用个体样本并以正常样本作为对照。