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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：
10418754
负责人：
Sita Kugel
金额：
$ 40.26万
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/10418754
关键词：
Automobile Driving Binding Biological Markers Cancer Etiology Cell Line ChIP-seq 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.

项目总结