Inhibition of STAT3 signal transduction for human cancer therapy
Signal Transducer and Activator of Transcription (STAT) proteins have a fundamental role cell signaling, and are activated by a large number of cytokines and growth factors. One member of the STAT family, STAT3, has a critical role in oncogenesis. The present invention relates generally to disruption of the pathway of STAT3 signaling in the treatment of human cancer. STAT3 activation is shown to be present in diverse tumor cell lines and tumors, to promote oncogenesis, to inhibit apoptosis, and to reduce sensitivity to chemotherapeutic agents. Inhibition of STAT3 signaling induces apoptosis specifically in tumor cell lines, and increases sensitivity to chemotherapeutic agents. The invention relates more particularly to methods, compositions, means of administering such compositions, and means for identifying such compositions for the inhibition of STAT3 intracellular signaling in the treatment of human cancers.
1. An isolated peptide 3 to 12 amino acids in length that disrupts SH2-phosphotyrosine (pY) interactions between the SH2 domain of one STAT (signal transducer and activator of transcription) 3 polypeptide monomer and a pY on another STAT3 polypeptide monomer, or antagonizes STAT3 DNA binding, wherein said peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:35, and SEQ ID NO:36.
2. An isolated peptide 3 to 12 amino acids in length that disrupts SH2-phosphotyrosine (pY) interactions between the SH2 domain of one STAT (signal transducer and activator of transcription) 3 polypeptide monomer and a pY on another STAT3 polypeptide monomer, or antagonizes STAT3 DNA binding, wherein said peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:27, SEQ ID NO:28, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:34, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, and SEQ ID NO:38.
3. The isolated peptide of claim 1 , wherein said peptide comprises an amino acid sequence selected from the group consisting of SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:30, SEQ ID NO:32, SEQ ID NO:34, and SEQ ID NO:36.
4. The isolated peptide of claim 2 , wherein said peptide consists of an amino acid sequence selected from the group consisting of SEQ ID NO:17, SEQ ID NO:19, SEQ ID NO:22, SEQ ID NO:24, SEQ ID NO:25, SEQ ID NO:26, SEQ ID NO:30, SEQ ID NO:31, SEQ ID NO:32, SEQ ID NO:34, and SEQ ID NO:36.
5. A composition comprising said isolated peptide of claim 1 and a pharmaceutically acceptable carrier.
6. A composition comprising said isolated peptide of claim 2 and a pharmaceutically acceptable carrier.