Biomarkers and mechanisms in cancer associated thrombosis

摘要 血栓形成是癌症的常见和高度病态的并发症。肿瘤类型是目前最好的 癌症相关血栓形成和胰腺导管腺癌（PDAC）的可用预测因子是 血栓形成性最强的癌症我们的基本前提是肿瘤本身的因素 导致癌症中血栓的形成。从这一断言产生的具体假设，形成我们的基础， 项目(1)评估癌症患者的血浆蛋白可以准确预测癌症相关性 血栓形成为了评估这一假设，我们将进行一个高通量的蛋白质组学分析的大群体 癌症患者的血浆蛋白比较患者谁随后发展凝块相比， 没有血凝块该项目采用了新的邻近延伸分析技术。(2)如果肿瘤 血栓形成，那么癌症血栓形成的散发性质可以解释为： 甚至在单一类型的癌症中也存在肿瘤的异质性。我们预测，PDAC来自不同的 患者将显示出与其分子水平一致的其产生血栓前因子的能力的变化。 子分类为了评估这一预测，我们将使用患者来源的类器官，它们保留了遗传基因， 和原发性肿瘤的表型特征，以便对个体肿瘤进行深入分析 相对于体外和体内的促血栓形成潜力。(3)事实上，血栓形成更常见于 侵袭性、晚期癌症表明肿瘤进展增强了肿瘤的血栓形成性。 我们将在分子水平上评估这一前提，通过检验以下假设： 蛋白反应（UPR）有助于PDAC中的血栓形成。具体来说，我们将确定 PDAC中的UPR信号导致血栓前因子如胰腺特异性蛋白的加工 二硫键异构酶、组织因子和促血栓形成微粒。这些研究利用了 BIDMC胰腺疾病登记和生物储存库的资源，其中包括>150名患者来源的 异种移植模型。这些PDAC模型与相关的患者病史、transciptome和 蛋白质组数据和相关的血浆样品。拟议的研究具有重大临床意义， 因为他们将使用大型临床队列来发现和验证生物标志物， 患者将从积极的抗血栓治疗中获益最多。这些实验也将提高我们的 基本了解导致癌症进展的途径，如普遍定期审议， PDAC的血栓前表型。干扰蛋白质二硫键异构酶（PDI）作为一种免疫抑制剂的效用 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 II/III试验，评估晚期癌症患者中PDI活性的小分子抑制剂。因此这些 研究对癌症的基础知识和治疗都有重要和直接的影响- 相关血栓形成

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.