Tumor subtypes and therapy response in pancreatic cancer

摘要 我们已经确定了两种新的胰腺癌肿瘤特异性亚型，我们称之为“经典型”和“基底型”， 喜欢”。几个发现说明了我们发现的力量。我们的亚型不仅在我们自己的 数据集，但也独立验证了我们的亚型在 最近发表的国际癌症基因组联盟（ICGC）PDAC微阵列数据集以及 癌症基因组图谱（TCGA）中未发表的临床可用数据。重要的是， “基底样”因子，包括层粘连蛋白和角蛋白，也与先前定义的基底亚型一致 在膀胱癌和乳腺癌中，这使我们假设，像这两种癌症一样， 更积极，相反对细胞毒性疗法更敏感。我们还发现， 基因工程小鼠模型和细胞系不足以代表我们的经典亚型， 患者来源的异种移植（PDX）肿瘤显示两者的代表性。最后我们也确认了， 自我们最初提交以来，加强了我们先前在激酶组激活谱之间的关联。我们两 这表明新的激酶抑制剂方法可以针对每个亚型进行定制。因此，我们将使用 新的蛋白质组学方法来评估我们的每种亚型中激酶组的基线激活状态， 使用PDX模型来确定我们的亚型是否与对新型激酶抑制剂的反应相关 和细胞毒性疗法。此外，为了推进我们的研究结果的翻译，我们建议开始评估 我们的亚型与来自两个研究中心的现有去识别患者样本中的治疗反应之间的关联 不同的机构（Dana-Farber癌症研究所和印第安纳州大学）。

Abstract We have identified two novel tumor-specific subtypes of pancreatic cancer which we call “classical” and “basal- like”. Several findings illustrate the power of our findings. Our subtypes were not only prognostic in our own dataset but also independently validated the presence and prognostic significance of our subtypes in the recently published International Cancer Genome Consortium (ICGC) PDAC microarray dataset as well as the unpublished publically available data from The Cancer Genome Atlas (TCGA). Importantly, genes from the “basal-like” factor, including laminins and keratins, were also consistent with basal subtypes previously defined in bladder and breast cancers, leading us to hypothesize that like both these cancers basal subtypes although more aggressive, are conversely more sensitive to cytotoxic therapies. We have also found that both genetically engineered mouse models and cell lines inadequately represent our classical subtype with only patient-derived xenograft (PDX) tumors showing representation of both. Finally we have also confirmed and strengthened our previous association between kinome activation profiles since our initial submission. Our two subtypes suggesting that novel kinase inhibitor approaches may be tailored to each subtype. Thus we will use novel proteomic approaches to assess the baseline activation state of the kinome in each of our subtypes and use PDX models to determine whether our subtypes are associated with response to novel kinases inhibitor and cytotoxic therapies. Furthermore to advance the translation of our findings we propose to begin to evaluate the association of our subtypes with treatment response in existing deidentified patient samples from two different institutions (Dana-Farber Cancer Institute and Indiana University).