Invited Speaker

Development of a New Class of Anti-Cancer Chemotherapeutics which Target the Actin Cytoskeleton
Peter Gunning, Galina Schevzov, Sarah Creed, Jason Coombes, Teresa Bonello, Loretta Lau, Elizabeth Musgrove, Adam McCluskey, Stephen Palmer, Edna Hardeman, Munif Allanson, Vivienne Reeve, Ian Dixon and Justine Stehn
Australia

The actin cytoskeleton is a high priority chemotherapy target in cancer cells because of its central role in cell growth, proliferation and motility. Drugs developed to date which target the actin cytoskeleton via its core constituent, actin, have been unsuccessful due to failure of the actin based contractile system responsible for cardiac and respiratory function. Studies in our lab have previously shown that tropomyosin (Tm), the second core component of the actin cytoskeleton, defines functionally distinct populations of actin filaments. We have now identified a specific Tm isoform common to all tumour cells which regulates cell proliferation and have designed a new class of compounds to target this filament population. Tm5NM1 is one of only two Tms which are common to all tumour cells. Elevated expression of Tm5NM1 in rat neuroblastoma-derived B35 cells accelerates cell proliferation and enhances anchorage independent growth in soft agar assays. Conversely, cell proliferation in response to serum is significantly reduced in primary mouse embryo fibroblasts isolated from a Tm5NM1 knockout mouse. siRNA knockdown of Tm5NM1 in the neuroblastoma tumour cell line (SHEP) also results in decreased cell growth. Tm5NM1 containing actin filaments regulate proliferation via modulation of cyclin D levels. We have developed a novel class of anti-Tm compounds that target Tm5NM1 containing filaments but not those representative of muscle Tms. Our lead compound, TR100, is effective against a panel of neuroblastoma and melanoma cell lines (average LC50 ~2-3uM) and significantly reduced tumour growth in the murine B16/F10 melanoma model with elimination of 20% of the tumours. In vivo experiments demonstrate that cardiac function is not impacted by TR100. We conclude that it is possible to generate chemotherapeutic compounds which target specific actin filaments which regulate cell growth and proliferation based on their Tm isoform composition. This has far reaching implications for the treatment of cancer.