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.
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.
|Yu, Wenying; Xiao, Hui; Lin, Jiayuh et al. (2013) Discovery of novel STAT3 small molecule inhibitors via in silico site-directed fragment-based drug design. J Med Chem 56:4402-12|
|Lin, Li; Benson Jr, Don M; DeAngelis, Stephanie et al. (2012) A small molecule, LLL12 inhibits constitutive STAT3 and IL-6-induced STAT3 signaling and exhibits potent growth suppressive activity in human multiple myeloma cells. Int J Cancer 130:1459-69|
|Li, Huameng; Liu, Aiguo; Zhao, Zhenjiang et al. (2011) Fragment-based drug design and drug repositioning using multiple ligand simultaneous docking (MLSD): identifying celecoxib and template compounds as novel inhibitors of signal transducer and activator of transcription 3 (STAT3). J Med Chem 54:5592-6|
|Liu, Aiguo; Liu, Yan; Li, Pui-Kai et al. (2011) LLL12 inhibits endogenous and exogenous interleukin-6-induced STAT3 phosphorylation in human pancreatic cancer cells. Anticancer Res 31:2029-35|
|Park, In-Hee; Li, Chenglong (2011) Characterization of molecular recognition of STAT3 SH2 domain inhibitors through molecular simulation. J Mol Recognit 24:254-65|
|Li, Huameng; Li, Chenglong (2010) Multiple ligand simultaneous docking: orchestrated dancing of ligands in binding sites of protein. J Comput Chem 31:2014-22|
|Lin, Li; Hutzen, Brian; Zuo, Mingxin et al. (2010) Novel STAT3 phosphorylation inhibitors exhibit potent growth-suppressive activity in pancreatic and breast cancer cells. Cancer Res 70:2445-54|
|Liu, Yan; Li, Pui-Kai; Li, Chenglong et al. (2010) Inhibition of STAT3 signaling blocks the anti-apoptotic activity of IL-6 in human liver cancer cells. J Biol Chem 285:27429-39|
|Lin, Li; Hutzen, Brian; Li, Pui-Kai et al. (2010) A novel small molecule, LLL12, inhibits STAT3 phosphorylation and activities and exhibits potent growth-suppressive activity in human cancer cells. Neoplasia 12:39-50|
|Friedman, Lauren; Lin, Li; Ball, Sarah et al. (2009) Curcumin analogues exhibit enhanced growth suppressive activity in human pancreatic cancer cells. Anticancer Drugs 20:444-9|