Rhabdomyosarcoma: development of molecular therapeutics under the microscope

Rhabdomyosarcoma (RMS), predominantly diagnosed in children, represents 3% of the pediatric solid tumors. RMS has characteristics of skeletal muscle, although the cell of origin remains controversial. Cytotoxic therapeutics, radiation treatment and surgery remain the standard of care; however, outcomes for advanced disease have not changed for several decades. Major research advances over the past two decades have defined molecular subtypes and driver mutations that could provide new therapeutic targets.

Due to the small number of patients diagnosed with RMS, progress in testing novel agents has been slow and, although many drugs with 'molecular targets' have been identified as 'active' in preclinical models, there remains a lack of standardization for evaluating efficacy. Molecular therapeutics identified in model systems include kinase inhibitors, antibody-drug conjugates (ADCs), chimeric antigen receptor T-cells (CAR T-cells), and drugs that target the genetic/epigenetic drivers of RMS. More recently, immune checkpoint inhibitors have entered clinical trials.

RMS represents a set of diseases with unique molecular drivers that will each necessitate the development of targeted therapeutics. For efficient development of effective treatments, novel approaches to preclinical testing and standardization of efficacy assessments need to be developed in conjunction with molecularly guided clinical trials in patients earlier in their disease before drug resistance develops.