Rhabdomyosarcoma is the most common malignant soft tissue tumor in children and adolescence, which is further is divided into two major molecular categories: fusion-positive (FP-RMS) and fusion-negative (FN-RMS). FP-RMS is commonly driven by a balanced chromosomal translocation generating an oncogenic Pax3-FOXO1 or Pax7-FOXO1 fusion protein. FN-RMS encompasses tumors that do not contain PAX3/7-FOXO1 fusion-proteins, but exhibits significantly greater genomic instability such as copy number variations and gene amplifications. Despite decades of clinical and basic research, the outcome for children with metastatic or recurrent disease is still very poor, with overall survival at 3 years only o...

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Rhabdomyosarcoma is the most common malignant soft tissue tumor in children and adolescence, which is further is divided into two major molecular categories: fusion-positive (FP-RMS) and fusion-negative (FN-RMS). FP-RMS is commonly driven by a balanced chromosomal translocation generating an oncogenic Pax3-FOXO1 or Pax7-FOXO1 fusion protein. FN-RMS encompasses tumors that do not contain PAX3/7-FOXO1 fusion-proteins, but exhibits significantly greater genomic instability such as copy number variations and gene amplifications. Despite decades of clinical and basic research, the outcome for children with metastatic or recurrent disease is still very poor, with overall survival at 3 years only of 25-30%. This poor outlook has not improved despite many attempts to intensify chemotherapy with new agents. These challenges highlight the critical need to understand the mechanisms underlying the initiation and progression of the disease, which could lead to the identification of new prognostic and therapeutic approaches. We recently identified frequent copy number amplification of the TWIST2 loci, which in turn drives overexpression of TWIST2 in FN-RMS. Twist2 is a bHLH transcription factor that plays essential roles in tissue development and disease, and shares extensive homology and functional redundancy with Twist1, which controls cancer invasion, metastasis, initiation and stemness of cancer cells. We hypothesize that Twist2 is an oncogenic driver of FN-RMS and targeting Twist2 pathway is a novel therapeutic approach. Towards this goal, we will study the role of Twist2 in regulating tumor cell growth and maintenance in vitro and in vivo. We will also explore the new Twist2-regulated therapeutic targets in RMS patients and RMS mouse models. The ultimate successful completion of the proposed Aims will lead us to a deeper understanding of RMS biology and have a major impact on developing clinical trials for new RMS targeted therapies.

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