New approaches for pediatric rhabdomyosarcoma drug discovery: targeting combinatorial signaling

Abstract

Introduction: Rhabdomyosarcomas (RMS) are rare heterogeneous pediatric tumors that are treated by surgery, chemotherapy and irradiation. New therapeutic approaches are needed, especially in the advanced stages to target the pro-oncogenic signals. Exploring the molecular interactions of the regulatory signals and their roles in the developmental aspects of different subtypes of RMS is essential to identify potential targets and develop new therapeutic drugs.

Areas covered: Insights into different drug discovery approaches are discussed with specific emphasis on gene expression profiling, fusion protein, role of small interfering RNA (siRNA)- and microRNA (miRNA)-based discovery approaches, targeting cancer stem cells, and in vitro and in vivo model systems. Targeting some overexpressed signals along with the possibilities of combination therapy of validated drug targets is discussed. Additionally, methods to overcome the limitations of discovery-based research are briefly discussed.

Expert opinion: Due to drug resistance, ineffective therapy in advanced stages and relapse, there is a demand to explore new drug targets and discovery approaches. Implementing miRNA-based profiling would reveal the extent of miR-based regulation, various biomarkers and potential targets in RMS. A suitable combination of innovative techniques and the use of model systems might assist the identification and validation of novel targets and drug discovery methods. Combining specific drugs along with type-specific target inhibition of overexpressed mRNAs through siRNA approaches would enable the development of personalized therapy.

Keywords:

• combined therapy
• drug discovery
• drug targets
• gene expression profile
• microRNA
• PAX-FOXO1a
• preclinical animal models
• rhabdomyosarcoma
• small interfering RNA

Acknowledgements

The authors would like to thank the peer reviewers for their critical comments and constructive suggestions, and Lakshmi Narayan for his insight and feedback during the preparation of this manuscript. The authors research is supported by grants from Translational Sarcoma Network2 (BMBF-01GM0875 to UK) and DFG grant (RO 1263/9-1 to VR and JR).

Notes

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