Abstract B17: Targeting the oncogenic TBX3 and its co-factors in anti-cancer drug development

Abstract

Abstract Sarcomas are heterogeneous neoplasms of mesenchymal origin whose clinical management is compromised due to inadequate diagnostic markers and limited therapeutic options. While the incidence rates for sarcomas in Africa remain uncertain, there is a widely held view that they are common in black African children and adolescents. Indeed, according to a Nigerian study, soft tissue sarcomas make up as much as 11.3% of all childhood cancers. We recently reported that the transcription factor, TBX3, is overexpressed in a diverse range of sarcoma subtypes where it plays a direct oncogenic role and it has been proposed as a novel target for their treatments. Direct targeting of transcription factors for therapies however continues to represent a serious challenge and therefore the molecular mechanisms that mediate its biological activity may be more amenable as anti-cancer drug targets. To address this, affinity purifications coupled with mass spectrometry was performed to identify TBX3 protein co-factors that regulate its oncogenic activity in sarcomas. Here we describe the validation of nucleolin as TBX3 co-factor by co-immunoprecipitation assays and confocal microscopy/co-localization analysis. The effect of nucleolin on TBX3 function was determined using RNAi rescue experiments coupled with growth curve and scratch motility assays to assess cell proliferation and migration respectively. Finally, the effect of the nucleolin targeting aptamer, AS1411, on the cell viability of a range of sarcoma subtypes was tested. Results show that the overexpression of TBX3 and nucleolin are common in a number of sarcoma subtypes. We provide compelling evidence that nucleolin interacts with and co-operates with TBX3 to promote proliferation and migration of chondrosarcoma, liposarcoma and rhabdomyosarcoma cells. Furthermore, AS1411 exhibits potent anti-cancer activity in these sarcomas whilst it has no effect on normal cells. In conclusion, we propose that TBX3 and nucleolin can be used in combination as biomarkers for the diagnosis and targeted therapy of a diverse range of sarcomas which are highly aggressive and treatment resistant cancers. Citation Format: Tarryn Willmer, Shannon Smyly, Danica Smuts, Sharon Prince. Targeting the oncogenic TBX3 and its co-factors in anti-cancer drug development [abstract]. In: Proceedings of the AACR International Conference: New Frontiers in Cancer Research; 2017 Jan 18-22; Cape Town, South Africa. Philadelphia (PA): AACR; Cancer Res 2017;77(22 Suppl):Abstract nr B17.