Mechanisms and targeting of SWI/SNF alterations in pancreatic cancer

描述(申请人提供)：SWI/SNF是一种多亚单位染色质重塑复合体，它重新定位核小体以控制对DNA的访问，从而调节基因表达。最近，我们在超过三分之一的人胰腺癌中发现了针对SWI/SNF亚单位的局灶性DNA缺失和有害突变，这一频率接近于TP53突变。SWI/SNF再表达研究支持生长抑制功能，我们的初步数据提名多梳抑制复合体2(PRC2)拮抗和转化生长因子β信号通路可能是下游的效应通路。SWI/SNF也被报道在DNA损伤修复中发挥作用，我们的初步数据显示SWI/SNF缺失使胰腺细胞对DNA损伤敏感。根据这些发现，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，并确定可能选择性地针对SWI/SNF缺陷的胰腺癌的治疗方法。为了实现这些目标，在目标1中，我们将通过在SWI/SNF缺陷的胰腺癌细胞和重组的胰腺癌细胞以及在原发胰腺肿瘤中对PRC2的分子研究，来研究PRC2拮抗作为SWI/SNF生长抑制的媒介的作用。在目标2中，我们将类似地评估转化生长因子信号在介导SWI/SNF生长抑制中的作用。在目标3中，我们将确定残留的SWI/SNF复合体(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，在目标4中，我们将评估针对SWI/SNF缺陷的胰腺癌的可能治疗方法，首先是DNA损伤剂(以探索已报道的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缺陷的胰腺癌的治疗策略。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)，以及胰腺癌是一种如此毁灭性的疾病，拟议中的研究有望对该领域做出重大贡献。此外，这些发现很可能扩展到其他带有SWI/SNF突变的癌症类型。

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.