Mechanisms and targeting of SWI/SNF alterations in pancreatic cancer

胰腺癌中 SWI/SNF 改变的机制和靶向

• 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
• 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

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（由申请人提供）：SWI/SNF是一种多亚基染色质重塑复合体，通过重新定位核小体来控制DNA的获取，从而调节基因表达。最近，我们在超过三分之一的人类胰腺癌中发现了针对SWI/SNF亚基的局灶性DNA缺失和有害突变，其频率接近TP53突变。SWI/SNF再表达研究支持其生长抑制功能，我们的初步数据表明多梳抑制复合体2 （PRC2）拮抗和TGF¿信号传导可能是下游效应途径。SWI/SNF也被报道在DNA损伤修复中起作用，我们的初步数据显示SWI/SNF缺失使胰腺细胞对DNA损伤敏感。基于这些发现，拟议研究的主要目标是确定SWI/SNF改变导致胰腺癌的途径和机制，并确定可能选择性靶向SWI/SNF缺陷胰腺癌的治疗方法。为了实现这些目标，在Aim 1中，我们将通过对SWI/SNF缺陷和重组胰腺癌细胞以及原发性胰腺肿瘤中PRC2的分子研究，研究PRC2拮抗剂作为SWI/SNF生长抑制介质的作用。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，我们将评估选择性治疗SWI/SNF缺陷胰腺癌的可能疗法，首先在细胞活力测定中使用DNA损伤剂（利用SWI/SNF在DNA损伤修复中的作用）。这些研究的完成将建立SWI/SNF改变驱动胰腺癌的途径和机制，并确定SWI/SNF缺陷胰腺癌的治疗策略。鉴于SWI/SNF改变在胰腺癌中很常见，其后果几乎一无所知（例如与TP53突变相比），并且胰腺癌是一种毁灭性的疾病，预计拟议的研究将对该领域做出高影响力的贡献。此外，研究结果可能可扩展到其他具有SWI/SNF突变的癌症类型。