Target Stat3 in pancreatic cancer using novel small molecule inhibitors

描述(申请人提供)：美国每年约有32,000人被诊断出患有胰腺癌，一般认为预后较差，胰腺癌很少能治愈。对于晚期癌症患者，所有阶段的总存活率在5年内不到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。在包括胰腺癌在内的人类肿瘤中经常检测到STAT3的持续激活，但在正常细胞中检测不到。显性负性STAT3突变体或反义STAT3寡核苷酸阻断STAT3信号通路可显著抑制癌细胞生长，并使癌细胞对常规细胞毒药物敏感，表明STAT3可能在癌细胞的生长和耐药性中起关键作用。我们最近开发了抑制STAT3活性的新型小分子化合物，并为可能更有效地治疗胰腺癌打开了一扇新的大门。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转录和STAT3DNA结合活性，抑制细胞活力，并诱导具有持续STAT3信号的胰腺癌细胞株的凋亡。这项建议的目的是测试类药物STAT3抑制剂在体外和小鼠肿瘤模型中对胰腺癌细胞的抑制效果。这项先导性研究是首次尝试在胰腺癌中使用非肽小分子STAT3抑制剂来靶向STAT3。试点研究应该为未来使用针对STAT3的新型药理化合物的临床研究奠定基础，最终目标是治疗和提高人类胰腺癌的总体存活率，并延长美国和世界各地人民的健康生活质量。目标1.设计、合成和测试针对STAT3SH2二聚化位点的新型小分子。目的2.检测靶向STAT3通路的新型小分子抑制剂对胰腺癌细胞的抑制作用。目的3.评价以STAT3为靶点的小分子抑制剂对小鼠肿瘤模型的抑制作用。公共卫生相关性：胰腺癌是最严重的癌症之一。目前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，并与肿瘤细胞的生长、肿瘤血管生成和耐药有关。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，它们可以抑制STAT3的活性，并为更有效地治疗表达STAT3持续激活的胰腺癌开辟了一条新的途径。我们的初步结果表明，我们的新型STAT3抑制剂显示出抑制表达STAT3持续激活的癌细胞的细胞活力的效力。我们建议测试LLL-12及其新的类似物在胰腺癌细胞和小鼠肿瘤模型中的抑制作用。我们的长期目标是以STAT3为靶点，使用新型小分子抑制剂作为治疗胰腺癌的新方法，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.