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Tumor subtypes and therapy response in pancreatic cancer

胰腺癌的肿瘤亚型和治疗反应

基本信息

批准号：
9176967
负责人：
Lee M Graves
金额：
$ 60万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-09-01 至 2021-07-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9176967
关键词：
Adjuvant Therapy Biological Assay Cancer Patient Cancer cell line Cell Line Cellularity Clinic Clinical Trials Computing Methodologies Consensus Curative Surgery Cytotoxic Chemotherapy Cytotoxic agent Dana-Farber Cancer Institute Data Data Set Development Disease Dissection Distant Epithelium Exhibits Frequencies Future Gene Expression Gene Expression Profile Genes Genetic Engineering Genetically Engineered Mouse Indiana Institution International KRAS2 gene Keratin Laminin Malignant - descriptor Malignant Neoplasms Malignant neoplasm of pancreas Malignant neoplasm of urinary bladder Mass Spectrum Analysis Modeling Mutation Neoplasm Metastasis Normal tissue morphology Paclitaxel Pancreas Patients Pharmaceutical Preparations Phosphotransferases Primary Neoplasm Proteomics Publishing RNA Regimen Sampling Site Technology Testing The Cancer Genome Atlas Therapeutic Tissues Translating Translations Tumor Subtype Universities Vertebral column Work Xenograft Model Xenograft procedure abstracting base cancer genome clinical biomarkers cohort cytotoxic gemcitabine in vitro Model in vivo Model inhibitor/antagonist kinase inhibitor leukemia malignant breast neoplasm mouse model novel pancreatic cancer cells patient subsets predicting response predictive modeling prevent prognostic prognostic significance response three dimensional cell culture treatment response triple-negative invasive breast carcinoma tumor tumor xenograft virtual

项目摘要

Abstract We have identified two novel tumor-specific subtypes of pancreatic cancer which we call “classical” and “basal- like”. Several findings illustrate the power of our findings. Our subtypes were not only prognostic in our own dataset but also independently validated the presence and prognostic significance of our subtypes in the recently published International Cancer Genome Consortium (ICGC) PDAC microarray dataset as well as the unpublished publically available data from The Cancer Genome Atlas (TCGA). Importantly, genes from the “basal-like” factor, including laminins and keratins, were also consistent with basal subtypes previously defined in bladder and breast cancers, leading us to hypothesize that like both these cancers basal subtypes although more aggressive, are conversely more sensitive to cytotoxic therapies. We have also found that both genetically engineered mouse models and cell lines inadequately represent our classical subtype with only patient-derived xenograft (PDX) tumors showing representation of both. Finally we have also confirmed and strengthened our previous association between kinome activation profiles since our initial submission. Our two subtypes suggesting that novel kinase inhibitor approaches may be tailored to each subtype. Thus we will use novel proteomic approaches to assess the baseline activation state of the kinome in each of our subtypes and use PDX models to determine whether our subtypes are associated with response to novel kinases inhibitor and cytotoxic therapies. Furthermore to advance the translation of our findings we propose to begin to evaluate the association of our subtypes with treatment response in existing deidentified patient samples from two different institutions (Dana-Farber Cancer Institute and Indiana University).

摘要