Biomarkers and mechanisms in cancer associated thrombosis

摘要 血栓形成是一种常见且高度病态的癌症并发症。肿瘤类型是目前最好的之一 癌症相关血栓形成和胰腺导管腺癌(PDAC)的可用预测指标是 血栓形成程度最高的癌症。我们的基本前提是肿瘤本身所阐述的因素 促进癌症中血栓的形成。从这一断言中产生了特定的假设，这些假设构成了我们 项目。(1)评估癌症患者的血浆蛋白可准确预测癌症相关因素 血栓形成。为了评估这一假说，我们将对大型队列进行高通量蛋白质组学分析。 癌症患者的血浆蛋白与随后形成血栓的患者的血浆蛋白进行比较 保持无凝块状态。该项目利用了新的邻近延伸分析技术。(2)如果肿瘤驱使 在癌症中形成血栓，那么癌症血栓形成的零星性质可以用 肿瘤的异质性，即使在单一类型的癌症中也是如此。我们预测，PDAC源自不同的 患者将表现出不同的能力，他们制定血栓前因子与他们的分子保持一致 子分类。为了评估这一预测，我们将使用患者衍生的有机化合物，它保留了基因 和原发肿瘤的表型特征，以便对个别肿瘤进行深入分析 相对于体内和体外血栓形成潜能。(3)血栓形成更常见的事实是 侵袭性的晚期癌症表明肿瘤进展增强了肿瘤的血栓形成能力。 我们将在分子水平上评估这一前提，通过测试未折叠的激活的假设 蛋白反应(UPR)参与了PDAC血栓的形成。具体来说，我们将确定是否 PDAC中的UPR信号导致血栓前因子的形成，如胰腺特异性蛋白 二硫键异构酶、组织因子和血栓前微粒。这些研究利用了独特的 BIDMC胰腺疾病登记和生物库的资源，其中包括来自150名患者的 异种移植模型。这些PDAC模型与相关的患者病史、Transciptome和 蛋白质组数据，以及相关的血浆样本。拟议的研究具有实质性的临床意义， 因为他们将使用大型临床队列来发现和验证生物标记物，目标是识别哪些 患者将从积极的血栓预防中受益最多。这些实验还将增强我们的 对UPR等导致癌症进展的途径如何促进 PDAC的血栓前表型。干扰蛋白二硫键异构酶(PDI)作为一种 癌症进展和血栓形成之间的机制联系将使用我们阶段的样本进行评估 在晚期癌症患者中评估PDI活性的小分子抑制剂的II/III试验。因此，这些 研究对癌症的基本知识和治疗都有重要而直接的影响- 伴发血栓形成。

Abstract Thrombosis is a common and highly morbid complication of cancer. Tumor type is among the best currently available predictors of cancer-associated thrombosis and pancreatic ductal adenocarcinoma (PDAC) is among the most highly thrombogenic cancers. Our underlying premise is that factors elaborated by the tumor itself drive thrombus formation in cancer. From this assertion arise specific hypotheses that form the basis of our project. (1) Evaluation of plasma proteins from patients with cancer can accurately predict cancer-associated thrombosis. To evaluate this hypothesis, we will perform a high throughput proteomic analysis of large cohorts of cancer patients comparing plasma proteins in patients who subsequently develop clots compared to those who remain clot free. This project utilizes novel proximity extension assay technologies. (2) If the tumor drives clot formation in cancer, then the sporadic nature of cancer thrombosis could be explained by the heterogeneity of tumors even within a single type of cancer. We predict that PDACs derived from different patients will show variation in their ability to elaborate prothrombotic factors in keeping with their molecular subclassification. To evaluate this prediction, we will use patient-derived organoids, which retain the genetic and phenotypic signatures of the primary tumor in order to perform in-depth analysis of individual tumors relative to prothrombotic potential in vitro and in vivo. (3) The fact that thrombosis is more common in aggressive, advanced stage cancers indicates that tumor progression enhances the thrombogenicity of tumors. We will evaluate this premise at the molecular level by testing the hypothesis that activation of the unfolded protein response (UPR) contributes to thrombus formation in PDAC. Specifically, we will determine whether UPR signaling in PDAC leads to the elaboration of prothrombotic factors such as pancreatic-specific protein disulfide isomerase, tissue factor, and prothrombotic microparticles. These studies leverage the unique resource of the BIDMC Pancreatic Disease Registry and Biorepository, which includes a >150 patient-derived xenograft models. These PDAC models are fully curated with associated patient history, transciptome and proteome data, and correlated plasma samples. The proposed studies are of substantial clinical significance, since they will discover and validate biomarkers using large clinical cohorts with the goal of identifying which patients will benefit most from aggressive thromboprophyhlaxis. These experiments will also enhance our fundamental understanding of how pathways leading to cancer progression such as the UPR contribute to the prothrombotic phenotype of PDAC. The utility of interfering with protein disulfide isomerase (PDI) as a mechanistic link between cancer progression and thrombosis will be evaluated using samples from our phase II/III trial of evaluating a small-molecule inhibitor of PDI activity in advanced cancer patients. Thus, these studies have important and immediate implications for both basic knowledge and treatment of cancer- associated thrombosis.