Abstract A44: Proprotein convertase furin in rhabdomyosarcoma progression: A potential target for pediatric sarcomas therapy?

Abstract

Abstract To improve therapies for embryonal pediatric tumors such as rhabdomyosarcoma (RMS), the most common soft tissue sarcoma in children, we have selected, by in vivo phage display, for peptides that bind to RMS with high specificity. We have shown that coupling of doxorubicin to RMS-P3, our lead RMS-targeting peptide, increases its therapeutic impact in a xenograft mouse model for RMS. We have identified furin as potential target for RMS binding peptide RMS-P3. Furin is a member of the proprotein convertases (PC), a family of ten serine proteases, which convert inactive proproteins into their active form. We have found consistent expression of furin in a panel of RMS cell lines and in RMS biopsies at the mRNA level. To elucidate the contribution of furin to RMS growth we have generated a panel of RMS cell lines either overexpressing furin, or a specific intrinsic PC inhibitor called α1-PDX, as well as RMS cell lines were expression of furin has been stably reduced by shRNA. These cells have been tested for their growth, migration and invasion potential in vitro as well as for their growth in vivo as subcutaneous xenografts. The results suggest a direct correlation between furin activity and RMS cells migration and invasive properties in vitro as well as RMS tumor growth in vivo. Interestingly, alveolar RMS cells display a higher furin activity compared to embryonal RMS cells. Alveolar RMS cells growth in vivo cannot be further enhanced by furin overexpression, in contrast to embryonal RMS cells, suggesting a causal link between high furin activity and alveolar RMS malignant phenotype. Among the known furin substrates, which are processed and activated by furin, and involved in tumor growth, migration and invasion, we found a direct correlation between furin activity and IGFR1 activation. Our results suggest that furin plays a relevant role in RMS progression through enhanced activation of the IGF1R pathway, among others, and that it might represent a viable target for therapeutic intervention in RMS. This warrants further studies in the development of novel therapeutic approaches for RMS based both on specific inhibition of its activity and on targeted drug delivery by furin targeting peptides. Citation Format: Patricia Jaaks, Valentina D'Alessandro, Beat W. Schäfer, Michele Bernasconi.{Authors}. Proprotein convertase furin in rhabdomyosarcoma progression: A potential target for pediatric sarcomas therapy? [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A44.