Exploring the epigenetic control of pancreatic cancer subtypes

探索胰腺癌亚型的表观遗传控制

基本信息

批准号：
10667487
负责人：
Sita Kugel
金额：
$ 39.45万
依托单位：
FRED HUTCHINSON CANCER CENTER
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10667487
关键词：
Automobile Driving Binding Biological Markers Cancer Etiology Cell Line ChIP-seq Classification Clinical Combination Drug Therapy Coupled Cyclin-Dependent Kinase Inhibitor Cyclin-Dependent Kinases Cytogenetics Data Dependence Development Disease Dose Down-Regulation Drug resistance Endocrine Enhancers Epigenetic Process Gene Expression Profile Genes Genetic Genetic Transcription Genetically Engineered Mouse Genomics Goals HDAC4 gene High-Throughput Nucleotide Sequencing Histone Deacetylase Human Individual Induction of Apoptosis Intervention KRAS oncogenesis KRAS2 gene Knowledge MYC gene Maintenance Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mesenchymal Messenger RNA MicroRNAs Modeling Molecular Pancreas Pancreatic Ductal Adenocarcinoma Pathogenesis Pathway interactions Patients Pharmacologic Substance Phenotype Phosphotransferases Primary Neoplasm Prognosis Proteins Resistance Role Sampling Sirtuins Specificity Therapeutic Time Tumor Suppressor Genes Tumor Suppressor Proteins United States Work Xenograft procedure cancer cell cancer subtypes drug discovery drug sensitivity gain of function genetic signature immunogenic improved in vitro activity inhibitor innovation insight knock-down loss of function mortality neoplastic cell new therapeutic target novel novel therapeutic intervention novel therapeutics pancreatic ductal adenocarcinoma cell pancreatic ductal adenocarcinoma model patient derived xenograft model precision medicine preclinical development predictive marker progenitor programs repository standard of care targeted treatment transcriptome sequencing transcriptomics tumor

项目摘要

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.

项目概要胰腺导管腺癌（PDA）是美国癌症相关死亡的主要原因。不幸的是，PDA 的基因组和转录组分析均未能确定治疗相关性。目标。联合化疗仍然是大多数患有此病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。掌上电脑有被细分为 2-4 个转录子集，这些子集可以通过其独特的表观遗传状态来定义，而不是而非特定的遗传图谱。在这些亚型中，准间充质 (QM) 亚型的特点是最差的预后，从而凸显了寻找 QM PDA 新治疗途径的重要性。短- 该提案的长期目标是阐明调节 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 QM 疾病的靶向疗法。我们的初步数据表明 PDA 可能下调 PDA 中的一种新型表观遗传调节因子和肿瘤抑制因子为了实现这种更具侵略性的 QM PDA 表型，同时使肿瘤细胞更具攻击性对特定的靶向治疗敏感。这种表观遗传调节剂是一种名为 Sirtuin 6 的组蛋白脱乙酰酶 (SIRT6)，最近被证明在基因工程小鼠模型中可作为有效的肿瘤抑制因子 (GEMM) 的 PDA，并且与患者样本中的不良预后呈负相关。然而，SIRT6 是如何 PDA 中的下调及其在调节 PDA 亚型中的作用仍不清楚。这里我们提出三个具体目标：（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； (3) 开发新的治疗方法 PDA 肿瘤的 QM 子集。为了实现这些目标，我们将结合细胞遗传学、高通量测序、遗传功能获得和功能丧失方法以及制药对一组具有分子特征的 PDA GEMM、人类 PDA 细胞系和患者进行干预来自 NCI 患者衍生模型存储库的异种移植物。我们的方法还利用了创新的一类靶向治疗药物，其与靶蛋白上的特定残基共价结合以达到更大的抑制作用和特异性。我们工作的长期目标是改变临床这种癌症的范例从联合化疗转向基于精准医学的方法预测性生物标志物可为 PDA 患者量身定制更有效、毒性更小的疗法。