Investigation of CYP2W1 as a therapeutic target in childhood rhabdomyosarcoma

Rhabdomyosarcoma (RMS) is rare, but the most common type of soft tissue cancer (a ‘sarcoma’) to occur in childhood, with around 70 new cases every year in the UK.

RMS can arise virtually anywhere in the body and is currently treated with chemotherapy drugs that cause severe side effects for patients. Treatment options include cyclophosphamide and ifosamide, drugs that are ‘activated’ once inside the body (‘prodrugs’), where they then damage the DNA of cancer cells and kills them. The problem is that this activation is not selective inside the tumour – it happens nonselectively in the liver by enzymes known as cytochromes P450 (CYP), which causes toxicity. To overcome this problem, we have developed new prodrugs of powerful DNA-damaging agents termed duocarmycins that eradicate tumours expressing a new type of CYP enzyme called CYP2W1 (not expressed in normal tissue). The new type of prodrug is only activated directly in cancer cells where they are needed, preventing harmful side‐effects in the rest of the body. Ultimately, we believe a duocarmycin prodrug could be trialled in patients alongside other treatments to further prevent tumour growth or spread in the body (the process called ‘metastasis’) in patients with advanced disease.