Exploring the epigenetic control of pancreatic cancer subtypes

项目总结 胰腺导管腺癌(PDA)是美国癌症相关死亡的主要原因。 不幸的是，对PDA的基因组和转录组分析都未能确定与治疗相关。 目标。联合化疗仍然是大多数患者的标准护理方案 局部晚期或转移性疾病，导致中位总生存期不到一年。掌上电脑有 被细分为2-4个转录亚集，这可以由它们独特的表观遗传状态来定义 而不是特定的基因特征。在这些子集中，准间充质(QM)亚型的特征是 最糟糕的预后，因此强调了为QM PDA寻找新的治疗途径的重要性。简而言之- 本提案的术语目标是阐明控制qm pda亚型的遗传或表观遗传机制。 决心并利用这种理解来开发针对QM疾病的靶向治疗方法。 我们的初步数据表明，PDA可能下调PDA中一种新的表观遗传调节因子和肿瘤抑制因子 为了实现这种更具侵袭性的QM PDA表型，同时使肿瘤细胞 对特定的靶向治疗敏感。这种表观遗传调节因子是一种称为sirtuin 6的组蛋白脱乙酰基酶 (SIRT6)，最近在基因工程小鼠模型中被证明是一种有效的肿瘤抑制因子 在患者样本中，PDA的(GEMM)与预后不良呈负相关。然而，SIRT6是如何 在PDA中下调，其在PDA亚型中的调节作用尚不清楚。在这里，我们提出三个建议 具体目标：(1)确定PDA中SIRT6下调的新机制；(2)确定 SIRT6在调节PDA亚型中的功能作用；以及(3)为此开发新的治疗方法 PDA肿瘤的QM亚群。为了实现这些目标，我们将应用细胞遗传学、高密度的 产量测序、遗传功能获得和功能丧失方法与药物 干预一组强大的分子特征的PDA GEMM，人类PDA细胞系和患者- 来自NCI患者衍生模型资料库的衍生异种移植。我们的方法还利用了 创新的靶向治疗药物，它与目标蛋白上的特定残基共价结合 以达到更大的抑制性和特异性。我们工作的长期目标是将临床 这种癌症的范例从联合化疗转向基于精确医学的方法 预测性生物标记物为PDA患者量身定做更有效和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.