Mechanisms and targeting of SWI/SNF alterations in pancreatic cancer

胰腺癌中 SWI/SNF 改变的机制和靶向

基本信息

批准号：
8719605
负责人：
JONATHAN R POLLACK
金额：
$ 33.31万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2019-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8719605
关键词：
ATP Hydrolysis ATP phosphohydrolase Biological Assay Biology Cancer Cell Growth Cancer cell line Cell Survival Cells Chromatin Chromatin Remodeling Factor Complex DNA DNA Binding DNA Damage DNA Repair Data Disease EZH2 gene Embryonic Development Engineering Epithelial Cells Frequencies Gene Expression Gene Targeting Goals Growth Human Knowledge Laboratories Malignant Neoplasms Malignant neoplasm of pancreas Mediating Mediator of activation protein Molecular Mutation Nucleosomes Oncogenic Pancreas Pathway interactions Pattern Pharmaceutical Preparations Phenotype Point Mutation Polycomb Qualifying Reporting Residual state Role SMARCA2 gene SMARCA4 gene Signal Transduction Survival Rate TP53 gene Testing Therapeutic cancer genomics cancer type cell growth combat drug sensitivity gain of function overexpression pancreatic cancer cells pancreatic neoplasm programs public health relevance reconstitution transcription factor tumor

项目摘要

DESCRIPTION (provided by applicant): SWI/SNF is a multi-subunit chromatin remodeling complex that repositions nucleosomes to control access to DNA, thus regulating gene expression. Recently, we discovered focal DNA deletions and deleterious mutations that target SWI/SNF subunits in more than one-third of human pancreatic cancers, a frequency approaching that of TP53 mutation. SWI/SNF re-expression studies support a growth-suppressive function, and our preliminary data nominate polycomb repressive complex 2 (PRC2) antagonism and TGF¿ signaling as possible downstream effector pathways. SWI/SNF has also been reported to function in DNA damage repair, and our preliminary data show SWI/SNF loss sensitizes pancreatic cells to DNA damage. Building from these findings, the broad goals of the proposed studies are to define the pathways and mechanisms by which SWI/SNF alterations contribute to pancreatic cancer, and to identify therapies that might selectively target SWI/SNF-deficient pancreatic cancers. To achieve these goals, in Aim 1 we will investigate the role of PRC2 antagonism as a mediator of SWI/SNF growth suppression, by molecular studies of PRC2 in SWI/SNF-deficient and reconstituted pancreatic cancer cells, and in primary pancreatic tumors. In Aim 2, we will similarly assess the role of TGF¿ signaling in mediating SWI/SNF growth suppression. In Aim 3, we will determine whether residual SWI/SNF complexes (remnants of SWI/SNF alteration) contribute to growth phenotypes in pancreatic cancer cells. Finally, in Aim 4 we will evaluate possible therapies selective to SWI/SNF-deficient pancreatic cancers, starting with DNA damaging agents (to exploit the reported role of SWI/SNF in DNA damage repair) in cell viability assays. Completion of these studies should establish the pathways and mechanisms by which SWI/SNF alterations drive pancreatic cancer, and define therapeutic strategies for SWI/SNF-deficient pancreatic cancers. Given that SWI/SNF alterations are commonplace in pancreatic cancer, that almost nothing is known of their consequence (for example compared to TP53 mutations), and that pancreatic cancer is such a devastating disease, the proposed studies are expected to make a high-impact contribution to the field. Moreover, findings are likely to be extendable to other cancer types with SWI/SNF mutations.

描述（由适用提供）：SWI/SNF是一种多生育染色质重塑复合物，它重新定位核商品以控制对DNA的访问，从而调节基因表达。最近，我们发现了焦点DNA缺失和有害突变，这些突变靶向SWI/SNF亚基，超过三分之一的人类胰腺癌，这是TP53突变的频率方法。 SWI/SNF重新表达研究支持了生长抑制功能，我们的初步数据提名Polycomb反射复合物2（PRC2）拮抗作用和TGF？信号传导可能是下游效应途径。 SWI/SNF还据报道在DNA损伤修复中起作用，我们的初步数据表明SWI/SNF损失敏感的胰腺细胞对DNA损伤。根据这些发现的建立，拟议的研究的广泛目标是定义SWI/SNF改变会导致胰腺癌的途径和机制，并确定可能有选择性地靶向SWI/SNF缺乏胰腺胰腺癌的疗法。为了实现这些目标，在AIM 1中，我们将通过对SWI/SNF缺乏症和重构胰腺癌细胞的分子研究以及原发性胰腺肿瘤来研究PRC2拮抗作用作为SWI/SNF生长抑制的介体。在AIM 2中，我们将类似地评估TGF信号在介导SWI/SNF生长抑制中的作用。在AIM 3中，我们将确定残留的SWI/SNF复合物（SWI/SNF改变的残留物）是否有助于胰腺癌细胞的生长表型。最后，在AIM 4中，我们将评估对SWI/SNF缺乏胰腺胰腺癌选择性的可能疗法，从DNA损伤剂（以利用SWI/SNF在DNA损伤修复中的作用）在细胞活力测定中的作用开始。这些研究的完成应建立SWI/SNF改变驱动胰腺癌的途径和机制，并为SWI/SNF缺乏胰腺胰腺癌定义理论策略。鉴于SWI/SNF改变在胰腺癌中是司空见惯的，因此几乎一无所知的后果（例如，与TP53突变相比），并且胰腺癌是一种毁灭性的疾病，因此拟议的研究预计将对该领域做出高度影响。此外，发现可能扩展到具有SWI/SNF突变的其他癌症类型。