Exploring the epigenetic control of pancreatic cancer subtypes

项目摘要 胰腺导管腺癌（PDA）是美国癌症相关死亡率的主要原因。 不幸的是，PDA的基因组和转录组学分析都未能确定治疗相关的， 目标的联合化疗仍然是大多数存在以下症状的患者的标准治疗： 局部晚期或转移性疾病，导致中位总生存期不到一年。PDA具有 被细分为2-4个转录子集，这可以通过其独特的表观遗传状态来定义，而不是 而不是特定的基因图谱在这些亚群中，准间充质（QM）亚型的特征在于： 最差的预后，从而突出了确定新的治疗途径QM PDA的重要性。短- 该建议的长期目标是阐明调节QM PDA亚型的遗传或表观遗传机制 确定并利用这种理解发展QM疾病的靶向治疗。 我们的初步数据表明，PDA可能下调了一种新的表观遗传调节因子和肿瘤抑制因子 为了获得这种更具侵袭性的QM PDA表型，同时使肿瘤细胞更具侵袭性， 对特定的靶向治疗敏感。这种表观遗传调节因子，一种叫做sirtuin 6的组蛋白去乙酰化酶， SIRT 6最近被证明在基因工程小鼠模型中作为一种有效的肿瘤抑制因子 （GEMM），并且与患者样品中的不良预后负相关。然而，SIRT 6是如何 其在PDA中下调，并且其在调节PDA亚型中的作用仍然未知。在这里，我们提出三个 具体目标：（1）确定PDA中SIRT 6下调的新机制;（2）确定PDA中SIRT 6的表达水平;（3）确定PDA中SIRT 6的表达水平。 SIRT 6在调节PDA亚型中的功能作用;和（3）开发新的治疗方法 PDA肿瘤的QM子集。为了实现这些目标，我们将应用细胞遗传学，高- 通量测序、功能的遗传获得和功能丧失方法以及药物 干预的强大面板的分子特征的PDA GEMM，人PDA细胞系和患者- 来自NCI患者衍生模型库的异种移植物。我们的方法还利用了 创新的靶向治疗剂，其共价结合到其靶蛋白上的特定残基， 以实现更大的抑制和特异性。我们工作的长期目标是将临床 从联合化疗到基于精确医学的方法， 预测性生物标志物，为PDA患者定制更有效、毒性更低的治疗方法。

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDA) is a leading cause of cancer-related mortality in the United States. Unfortunately, both genomic and transcriptomic analyses of PDA have failed to identify therapeutically relevant targets. Combination chemotherapy remains the standard of care for the majority of patients who present with locally advanced or metastatic disease, resulting in a median overall survival of less than one year. PDA has been subclassified into 2-4 transcriptional subsets, which can be defined by their unique epigenetic states rather than a specific genetic profile. Of these subsets, the quasi-mesenchymal (QM) subtype is characterized by the worst prognosis, thus highlighting the importance of identifying new therapeutic avenues for QM PDA. The short- term goals of this proposal are to elucidate the genetic or epigenetic mechanisms regulating QM PDA subtype determination and to leverage that understanding toward the development of targeted therapies for QM disease. Our preliminary data suggest PDA may downregulate a novel epigenetic regulator and tumor suppressor in PDA in order to achieve this more aggressive QM PDA phenotype, while at the same time rendering tumor cells more sensitive to specific targetable therapies. This epigenetic regulator, a histone deacetylase called sirtuin 6 (SIRT6), was recently shown to act as a potent tumor suppressor in genetically engineered mouse models (GEMMs) of PDA, and inversely correlates with poor prognosis in patient samples. However, how SIRT6 is downregulated in PDA and its role in regulating PDA subtypes remains unknown. Here we propose three specific aims: (1) To identify novel mechanisms of SIRT6 downregulation in PDA; (2) To determine the functional role of SIRT6 in regulating PDA subtypes; and (3) To develop novel therapeutic approaches for this QM subset of PDA tumors. To accomplish these aims, we will apply a combination of cytogenetics, high- throughput sequencing, genetic gain of function and loss of function approaches and pharmaceutical interventions to a robust panel of molecularly characterized PDA GEMMs, human PDA cell lines and patient- derived xenografts from the NCI Patient-Derived Models Repository. Our approach also takes advantage of an innovative class of targeted therapeutics, which bind covalently to a specific residue on their target protein in order to achieve greater inhibition and specificity. The long-term goal of our work is to transform the clinical paradigm for this cancer from combination chemotherapy, toward a precision medicine-based approach utilizing predictive biomarkers to tailor more effective and less toxic therapies for PDA patients.