Abstract B8: Selective inhibition of Stat3 Tyr705 phosphorylation inhibits angiogenesis in breast cancer xenografts.

Abstract Signal transducer and activator of transcription 3 (Stat3) is recruited, via its SH2 domain, to phosphotyrosine residues on growth factor and IL-6 family receptors at which time it is phosphorylated on Tyr705 by Janus kinases, Src, or the kinase activity of the receptor. Phosphorylation of Tyr705 (pStat3) leads to dimerization, translocation to the nucleus, and transcription of downstream genes. Stat3 is activated in several human cancers and is considered a drug target. Starting with pTyr-Leu-Pro-Gln, we have been developing phosphopeptide mimics to target the SH2 domain with the goal of blocking recruitment to receptors to uncouple Stat3 from its signaling role. We have developed cell-permeable, phosphatase-stable prodrugs that inhibit constitutive and IL-6-stimulated Tyr705 phosphorylation at concentrations of 0.5 − 1 μM in a variety of human cancer cell lines. They are selective for Stat3 over Stat1, Stat5, Src, and PI3K. At 5 μM they are not cytotoxic to a panel of human cancer cell lines. Higher concentrations lead to off-target effects and cytotoxicity. Recent reports indicate that Ser727 phosphorylated Stat3 participates in electron transfer in the mitochodria and unphosphorylated Stat3 participates with NF-κB-mediated transcription. As opposed to Stat3 knockdown techniques which cannot discriminate the multiple roles of Stat3, our prodrugs are potential tools to selectively probe Stat3 phosphorylation. Both intra-tumoral and intra-peritoneal administration of our lead prodrug, PM-73G, resulted in reduction of orthotopic breast tumor xenografts in mice. There was no evidence of apoptosis, reduction of cyclin D1 or survivin. Treated tumors exhibited significant reduction in microvessel density. Thus, selectively inhibiting Tyr705 phosphorylation is a potential antiangiogenic treatment modality. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B8.