The Anti-Tumour Efficacy Of The Novel Peptide Inhibitor Of Angiogenesis Alm-201

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Neovascularization is critical to tumour growth and metastasis and this has led to the development of a number of marketed anti-angiogenic agents which target VEGF/VEGFR2 receptors, for clinical use in specific types of cancer. However, incomplete responses and/or resistance to these therapies has highlighted the need for new agents targeting alternative pathways. Here we describe the characterisation of a novel peptide derived from the natural protein FKBP-like binding protein (FKBPL), which has extremely potent anti-angiogenic activity, is very effective in mouse xenograft models at low doses, and exerts its effects through microtubule binding using CD44 as a cell-entry mechanism. ALM-201 has been profiled in a range of human microvascular endothelial cell (HMEC-1) assays and potently inhibited migration, tubule formation and microvessel formation in vitro and in vivo. Although the peptide has a marked effect on migration, ALM-201 does not inhibit proliferation in a range of growth factor stimulated proliferation assays. Importantly, there is a significant disconnect between the pharmacokinetic and pharmacodynamic profiles of ALM-201 which allows for 3 q.d. dosing in mouse xenograft models. The peptide is well tolerated with no signs of toxicity observed in mouse xenograft models up to 80 days of dosing. The mechanism by which ALM-201 inhibits angiogenesis involves the cell surface receptor CD44, as determined by siRNA depletion of the receptor in migration assays. Furthermore, the peptide potently inhibits microtubule assembly and downstream signalling, thus promoting the anti-migratory phenotype. In summary, ALM-201 is a novel, targeted microtubule binding agent which exhibits potent anti-angiogenic activity in vitro and in vivo. Pre-clinical development is in progress with a Phase 1 clinical study planned for 2011. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3288. doi:10.1158/1538-7445.AM2011-3288