Tumor subtypes and therapy response in pancreatic cancer

摘要 我们发现了两种新的肿瘤特异性胰腺癌亚型，我们称之为“经典”和“基础”。 就像“。几个发现说明了我们的发现的力量。我们的亚型不仅对我们自己的预后有影响 数据集，但也独立验证了我们的亚型在 最近发布的国际癌症基因组联合会(ICGC)PDAC微阵列数据集以及 来自癌症基因组图谱(TCGA)的未公布的公开数据。重要的是，来自 “基底样”因子，包括层粘连蛋白和角蛋白，也与先前定义的基本亚型一致 在膀胱癌和乳腺癌中，这让我们假设，尽管这两种癌症的基本亚型都一样 反之，更具侵略性的患者对细胞毒疗法更敏感。我们还发现，这两个 基因工程小鼠模型和细胞系不能完全代表我们的经典亚型 患者来源的异种移植(PDX)肿瘤显示两者的表现。最后我们也确认了， 自从我们最初提交以来，加强了我们之前在Kinome激活配置文件之间的关联。我们的两个 亚型提示新的激酶抑制剂方法可以针对每种亚型量身定做。因此，我们将使用 新的蛋白质组学方法来评估我们每一个亚型和每个亚型的基准线激活状态 使用PDX模型来确定我们的亚型是否与对新的激酶抑制剂的反应有关 和细胞毒疗法。此外，为了促进我们的研究结果的翻译，我们建议开始评估 我们的亚型与现有的来自两个已确认的患者样本的治疗反应之间的关系 不同的机构(Dana-Farber癌症研究所和印第安纳大学)。

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subtypes in the recently published International Cancer Genome Consortium (ICGC) PDAC microarray dataset as well as the unpublished publically available data from The Cancer Genome Atlas (TCGA).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).