New experiments in mice have revealed a potential therapeutic target in alveolar rhabdomyosarcoma, a rare and aggressive paediatric cancer.
The findings, published in Science Translational Medicine, found that inhibiting this target boosted the effects of traditional chemotherapy and led to tumour regression in mice.
The researchers, based at St. Jude Children’s Research Hospital in the USA, suggested that a similar strategy could offer a much needed treatment option for patients with aggressive tumours.
Rhabdomyosarcomas typically occur in children and develop from soft tissue cells, generally in skeletal muscle. About 3% of all childhood cancers are rhabdomyosarcomas. Alveolar rhabdomyosarcoma is one of two main forms of rhabdomyosarcoma and can have varying outcomes depending on its characteristics.
Alveolar rhabdomyosarcoma occurs most often in the arms, legs, chest or abdomen and is slightly more common in children with genetic disorders, including Li-Fraumeni syndrome, Beckwith-Wiedemann syndrome and Costello syndrome. Treatment typically requires a mix of chemotherapy, surgery and radiotherapy.
The Paired Box 3–Forkhead Box O1 (PAX3-FOXO1) fusion protein helps to promote oncogenic growth by remodelling super-enhancers. Alveolar rhabdomyosarcomas that originate from foetal cells bearing PAX3-FOXO1 are more aggressive and more likely to metastasize than fusion-negative rhabdomyosarcomas.
The authors noted, “Patients with PAX3-FOXO1 fusion-positive alveolar rhabdomyosarcoma face dismal outcomes, and the few who are cured face long-term side effects from aggressive chemotherapy.”
Enhancing chemotherapy effectiveness without side effects
The team identified a new vulnerability in fusion-positive alveolar rhabdomyosarcoma in the form of an enzyme called KDM4B. They demonstrated that epigenetic histone alterations of KDM4B was necessary for the growth of PAX3-FOXO1. They proposed that KDM4B was required for the spread of alveolar rhabdomyosarcoma cells and tumour growth.
A small molecule inhibitor of KDM4B, QC6352, was tested. The team discovered that suppression of KDM4 proteins inhibited the expression of core oncogenic transcription factors.
QC6352, in combination with cytotoxic chemotherapy, decelerated tumour growth and prolonged survival in a mouse model. It also enhanced the cell-killing power of the chemotherapy drugs vincristine and irinotecan.
Of note, QC6352 achieved this without causing side effects.
The authors stated, “Our findings indicate that selectively inhibiting KDM4B by small molecules has translational potential in the context of a disease that is driven by a currently undruggable fusion oncoprotein.”
Written by Poppy Jayne Morgan, Front Line Genomics
Image Credit: Canva