Target Stat3 in pancreatic cancer using novel small molecule inhibitors

描述（由申请人提供）：美国每年约有32,000人被诊断为胰腺癌，预后通常被认为很差，胰腺癌很难治愈。对于晚期癌症患者，5年的总生存率低于1%，大多数患者在1年内死亡。因此，迫切需要开发更有效的胰腺癌治疗方法。Stat3的持续激活在包括胰腺癌在内的人类癌症中经常被检测到，但在正常细胞中却没有。Stat3显性阴性突变体或反义Stat3寡核苷酸阻断Stat3信号传导可显著抑制癌细胞生长，使癌细胞对常规细胞毒性药物变得敏感，表明Stat3可能对癌细胞生长和耐药性至关重要。我们最近开发了抑制Stat3活性的新型小分子化合物，为可能更有效地治疗胰腺癌打开了新的大门。我们的初步结果表明，我们的小分子是有效的抑制剂，可以阻断Stat3转录，Stat3 DNA结合活性，抑制细胞活力，诱导具有持续Stat3信号的胰腺癌细胞系凋亡。本提案的目的是在体外和小鼠肿瘤模型中测试药物样Stat3抑制剂对胰腺癌细胞的抑制效果。这项初步研究是首次尝试使用非肽小分子Stat3抑制剂靶向Stat3治疗胰腺癌。这些前期研究应该为未来使用靶向Stat3的新型药理化合物进行临床研究奠定基础，最终目的是治疗和提高人类胰腺癌的总体生存率，延长我国和全世界人民的健康生活质量。将研究以下具体目标：目标1。设计、合成和测试专门针对Stat3 SH2二聚化位点的新型小分子。目标2。研究胰腺癌细胞中靶向Stat3通路的新型小分子抑制剂的抑制作用。目标3。在小鼠肿瘤模型中评估靶向Stat3的小分子抑制剂的抑制效果。公共卫生相关性：胰腺癌是最严重的癌症之一。迫切需要开发更有效的胰腺癌治疗方法。Stat3的持续激活在胰腺癌中经常被检测到，并有助于癌细胞的生长、肿瘤血管生成和耐药性。我们最近开发了新的小分子化合物STA-21， LLL-3及其结构类似物LLL-12，可以抑制Stat3的活性，并为表达Stat3的持续激活的胰腺癌的更有效治疗开辟了新的途径。我们的初步结果表明，我们的新型Stat3抑制剂在抑制表达Stat3持续激活的癌细胞的细胞活力方面表现出效力。我们拟在胰腺癌细胞和小鼠肿瘤模型中测试LLL-12及其新型类似物的抑制作用。我们的长期目标是利用新型小分子抑制剂靶向Stat3作为胰腺癌的新治疗方法，最终目标是提高人类胰腺癌的总体生存率。

DESCRIPTION (provided by applicant): Each year about 32,000 individuals in the United States are diagnosed with pancreatic cancer and the prognosis is generally regarded as poor and the cancer of the pancreas is rarely curable. For patients with advanced cancers, the overall survival rate of all stages is less than 1% at 5 years with most patients dying within 1 year. Therefore, there is a critical need to develop more effective treatments for pancreatic cancer. The persistent activation of Stat3 is frequently detected in human cancers including pancreatic cancer but not in normal cells. Blocking signaling to Stat3 by dominant negative Stat3 mutants or antisense Stat3 oligonucleotides significantly inhibits cancer cell growth and renders cancer cells become sensitive to conventional cytotoxic agents, demonstrating that Stat3 may be crucial to the growth and drug resistance of cancer cells. We have recently developed novel small molecule compounds that inhibit Stat3 activities and opened a new door for possibly more effective treatment of pancreatic cancer. Our preliminary results demonstrated that our small molecules are potent inhibitors that blocks Stat3 transcription, Stat3 DNA binding activities, inhibits cell viability and induces apoptosis in pancreatic cancer cell lines with persistent Stat3 signaling. The objective of this proposal is to test inhibitory efficacy of the drug-like Stat3 inhibitors in pancreatic cancer cells in vitro and in a mouse tumor model. This pilot study is the first attempt to target Stat3 using non-peptide small molecule Stat3 inhibitors in pancreatic cancer. The pilot studies should establish the basis for future clinical study using novel pharmacological compounds that target Stat3, with the ultimate goal of treatment and improve the overall survival rate for human pancreatic carcinoma and extending the quality of healthy life for people in this country and around the world. The following specific aims will be studied: Aim 1. Design, synthesize, and test novel small molecules specifically targeting Stat3 SH2 dimerization site. Aim 2. Examine the inhibitory effects of the novel small molecule inhibitors that target Stat3 pathway in pancreatic cancer cells. Aim 3. Evaluate the inhibitory efficacy of the small molecule inhibitors that target Stat3 in a mouse tumor model. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is one of the most serious of cancers. There is an urgent need to develop more effective treatments for pancreatic cancer. The persistent activation of Stat3 is frequently detected in pancreatic cancer and contributes to the growth, tumor angiogenesis, and drug resistance of cancer cells. We have recently developed novel small molecule compounds, STA-21, LLL-3, and their structural analogue, LLL-12 that inhibit Stat3 activities and opened a new avenue for more effective therapy for pancreatic cancer that express persistent activation of Stat3. Our preliminary results indicate that our novel Stat3 inhibitors demonstrated potency in inhibiting cell viability of cancer cells expressing persistent activation of Stat3. We proposed to test the inhibitory effects of LLL-12 and its novel analogues in pancreatic cancer cells and in mouse tumor model. Our long-term goal is to target Stat3 as a new therapeutic approach for pancreatic cancer using novel small molecule inhibitors with the ultimate goal of improving the overall survival rate for human pancreatic cancer.