Target Stat3 in pancreatic cancer using novel small molecule inhibitors

使用新型小分子抑制剂靶向胰腺癌中的 Stat3

基本信息

批准号：
7661258
负责人：
Chenglong Li
金额：
$ 20.28万
依托单位：
RESEARCH INST NATIONWIDE CHILDREN'S HOSP
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-03-01 至 2011-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7661258
关键词：
Advanced Malignant Neoplasm Apoptosis Binding Breast Cancer Cell Cancer Cell Growth Cancer Prognosis Cancer cell line Cell Survival Chimera organism Clinical Research Clinical Trials Complex Country Crystallography Cytotoxic agent DNA Binding Development Diagnosis Dimerization Docking Dominant-Negative Mutation Drug resistance Event Future Genetic Transcription Goals Growth Hot Spot Human In Vitro Individual Laboratories Life Malignant Neoplasms Malignant neoplasm of pancreas Modeling Molecular Molecular Models Molecular Weight Mus Normal Cell Oligonucleotides Pancreas Pancreatic carcinoma Pathway interactions Patients Peptides Pharmaceutical Chemistry Pharmaceutical Preparations Pilot Projects Principal Investigator Proteins Reporting Roentgen Rays STAT3 gene Side Signal Transduction Site Staging Stat3 Signaling Pathway Stat3 protein Structure Survival Rate Testing Time Tumor Angiogenesis United States X-Ray Crystallography Xenograft Model analog base cancer cell cell growth design drug efficacy effective therapy improved in vivo inhibitor/antagonist innovation iterative design molecular modeling mutant neoplastic cell new therapeutic target novel novel therapeutic intervention outcome forecast pancreatic neoplasm pre-clinical public health relevance simulation small molecule small molecule libraries src Homology Region 2 Domain tumor tumor growth tumor progression

项目摘要

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.

描述（申请人提供）：美国每年约有 32,000 人被诊断患有胰腺癌，通常认为预后很差，而且胰腺癌很少能治愈。对于晚期癌症患者，5年各期总生存率低于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 的持续激活经常在包括胰腺癌在内的人类癌症中检测到，但在正常细胞中却未检测到。通过显性失活 Stat3 突变体或反义 Stat3 寡核苷酸阻断 Stat3 信号传导，可显着抑制癌细胞生长，并使癌细胞对常规细胞毒性药物变得敏感，这表明 Stat3 可能对癌细胞的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，可通过持续的 Stat3 信号传导阻断 Stat3 转录、Stat3 DNA 结合活性、抑制细胞活力并诱导胰腺癌细胞系凋亡。该提案的目的是在体外和小鼠肿瘤模型中测试类药物 Stat3 抑制剂对胰腺癌细胞的抑制功效。这项试点研究是首次尝试使用非肽小分子 Stat3 抑制剂来靶向治疗胰腺癌中的 Stat3。试点研究应该为未来使用针对 Stat3 的新型药理化合物进行临床研究奠定基础，最终目标是治疗和提高人类胰腺癌的总体生存率，并延长本国和世界各地人民的健康生活质量。世界。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 二聚位点的新型小分子。目标 2. 检查靶向 Stat3 通路的新型小分子抑制剂对胰腺癌细胞的抑制作用。目标 3. 评估针对 Stat3 的小分子抑制剂在小鼠肿瘤模型中的抑制功效。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。我们最近开发了新型小分子化合物 STA-21、LLL-3 及其结构类似物 LLL-12，可抑制 Stat3 活性，并为表达 Stat3 持续激活的胰腺癌更有效的治疗开辟了新途径。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具有效力。我们建议测试 LLL-12 及其新型类似物在胰腺癌细胞和小鼠肿瘤模型中的抑制作用。我们的长期目标是将 Stat3 作为一种使用新型小分子抑制剂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。