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Genome sequencing reveals new drug candidates for rhabdomyosarcoma
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A gene sequencing project carried out by researchers in US centres including St. Jude’s Children’s Research Hospital in Memphis, Tennessee, the Washington University School of Medicine in St. Louis, Missouri, UT Southwestern Medical Centre in Dallas, Texas and Seattle Children’s Hospital has shed new light on reasons for recurrence and potential treatments for rhabdomyosarcoma. Rhabdomyosarcoma is a cancer predominantly of childhood. It is a soft-tissue sarcoma and has two major histological subtypes, namely embryonal (approximately 60% of patients) and alveolar (approximately 25% of patients). These two subtypes have distinct features in terms of their clinical and genetic features.

The project exploited the experience of researchers in the Genome Institute at Washington University School of Medicine in whole-genome sequencing and analysis of tumour recurrence. The study, published this week in Cancer Cell describes the results of next generation, whole genome sequencing of both the tumour and the normal genomes of 16 tumours from 13 rhabdomyosarcoma patients and subsequent validation by more focussed sequencing of tumours from 37 further patients. The results showed that there were different genetic origins for the two tumour subtypes and that there were many more genomic alterations, including chromosomal rearrangements and mutations, in the embryonal compared to the alveolar subtype. Alveolar rhabdomyosarcoma indeed appeared to be the result of a single chromosomal rearrangement that fuses FOX01 with either PAX3 or PAX 7. In the embryonal rhabdomyosarcoma patients who were at high risk, it was observed that there were mutations in genes of the RAS pathway which by contrast were not observed in alveolar rhabdomyosarcoma. It was also observed that there was a high level of oxidative stress in the embryonal rhabdomyosarcoma tumours. A drug screen on tumour cells from three embryonal rhabdomyosarcoma patients, using primary cultures derived from xenografts, found that while RAS-targeting drugs had little effect, the use of oxidative stress-inducing drugs resulted in tumour cell death and enhancement of chemotherapeutic effects. The study’s authors concluded that the increase of oxidative stress on already stressed tumour cells was enough to push the balance towards cell death. These results offer a potentially new and exciting way to use existing oxidative stress-enhancing drugs to complement chemotherapy in embryonal rhabdomyosarcoma patients. It also gives a telling insight into why these tumours sometimes recur.

Sources

Chen, X. et al (2103). Targeting Oxidative Stress in Embryonal Rhabdomyosarcoma. Cancer Cell, 2013; 24 (6): 710 DOI: 10.1016/j.ccr.2013.11.002

St. Jude Children's Research Hospital. "Gene sequencing project finds drugs with promise for treating childhood tumor." ScienceDaily, 9 Dec. 2013. [Accessed 12 Dec. 2013]
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