Applying Small Molecule Signal Transducer and Activator of Transcription-3 (STAT3) Protein Inhibitors as Pancreatic Cancer Therapeutics.
Applying Small Molecule Signal Transducer and Activator of Transcription-3 (STAT3) Protein Inhibitors as Pancreatic Cancer Therapeutics.
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DOI：
10.1158/1535-7163.mct-15-0003
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发表时间：
2016-05
影响因子：
5.7
通讯作者：
Fishel ML
中科院分区：
文献类型：
--
作者：
Arpin CC;Mac S;Jiang Y;Cheng H;Grimard M;Page BD;Kamocka MM;Haftchenary S;Su H;Ball DP;Rosa DA;Lai PS;Gómez-Biagi RF;Ali AM;Rana R;Hanenberg H;Kerman K;McElyea KC;Sandusky GE;Gunning PT;Fishel ML
组成性激活的信号转导和转录激活因子3（STAT 3）蛋白已被发现是胰腺癌的关键调节因子和分子治疗干预的靶点。在本研究中，发现PG-S3-001（一种源自SH-4-54类STAT 3抑制剂的小分子）在体外和体内低μM范围内抑制患者源性胰腺癌细胞增殖。PG-S3-001有效结合STAT 3蛋白，通过SPR测定Kd = 324 nM，在激酶组筛选中显示无作用（> 100种癌症相关激酶）。体外研究表明，在胰腺癌细胞中有效的细胞杀伤以及STAT 3活化的抑制。为了更好地模拟肿瘤及其微环境，我们在不存在和存在癌症相关成纤维细胞（CAF）的情况下利用患者来源的胰腺癌细胞的三维（3D）培养物。在该共培养模型中，在CAF存在下，在STAT 3抑制后维持对肿瘤生长的抑制。共聚焦显微镜用于验证用PG-S3-001处理3D共培养物后的肿瘤细胞死亡。3D模型可预测体内疗效，因为PG-S3-001给药后观察到显著的肿瘤生长抑制。这些研究表明，STAT 3的抑制能够影响相关3D模型以及使用患者来源细胞的异种移植模型中肿瘤细胞的存活。
Constitutively activated Signal Transducer and Activator of Transcription 3 (STAT3) protein has been found to be a key regulator of pancreatic cancer and a target for molecular therapeutic intervention. In this study PG-S3-001, a small molecule derived from the SH-4-54 class of STAT3 inhibitors, was found to inhibit patient-derived pancreatic cancer cell proliferation in vitro and in vivo in the low μM range. PG-S3-001 binds the STAT3 protein potently, Kd = 324 nM by SPR, showed no effect in a kinome screen (> 100 cancer-relevant kinases). In vitro studies demonstrated potent cell killing as well as inhibition of STAT3 activation in pancreatic cancer cells. To better model the tumor and its microenvironment, we utilized 3-Dimensional (3D) cultures of patient-derived pancreatic cancer cells in the absence and presence of cancer-associated fibroblasts (CAFs). In this co-culture model, inhibition of tumor growth is maintained following STAT3 inhibition in the presence of CAFs. Confocal microscopy was used to verify tumor cell death following treatment of 3D co-cultures with PG-S3-001. The 3D model was predictive of in vivo efficacy as significant tumor growth inhibition was observed upon administration of PG-S3-001. These studies showed that the inhibition of STAT3 was able to impact the survival of tumor cells in a relevant 3D model, as well as in a xenograft model using patient-derived cells.