Rhabdomyosarcoma (RMS), an aggressive childhood cancer caused by mutations in genes that control the development of skeletal muscle tissue, has often spread (metastasized) by the time it is diagnosed in children, leading to poor survival rates. Researchers have now identified mutations in the fibroblast growth factor receptor 4 (FGFR4) gene that are associated with metastasis and poor outcomes in patients with RMS.
The FGFR4 protein belongs to a family of proteins known as receptor tyrosine kinases, which are involved in cellular signaling processes that help regulate cell growth, maturation, and survival. The gene, the researchers believe, may provide a target for therapy. The results appeared online October 5 in the Journal of Clinical Investigation.
Researchers from NCI; the National Heart, Lung, and Blood Institute; The Children’s Hospital at Westmead, Australia; and the Nationwide Children’s Hospital in Columbus, OH, were involved in the project. Their previous research, and that of others, has shown that FGFR4 is highly expressed in RMS. Because the gene is active during muscle development and not in mature muscle, the team investigated whether expression of FGFR4 might contribute to RMS. Using mouse models, the researchers showed that the growth and spread of human RMS cells to the lungs was inhibited by suppressing FGFR4 expression. After sequencing the FGFR4 gene in human RMS tumor samples, they found that more than 7 percent of the tumors had mutations in the tyrosine kinase portion of the protein. Some of these mutations caused the protein to become overly active. Mutations that increase receptor tyrosine kinase activity have been found in other cancers, but the researchers note that this is the first time that mutations in a receptor tyrosine kinase have been found in RMS.
With a series of lab and animal studies, they confirmed that two of the FGFR4 mutations caused increased tumor growth, reduced RMS cell death, and enhanced the ability of RMS cells to metastasize.
The mutations, which were found in both types of RMS, alveolar and embryonal, appeared to act via the STAT3 pathway. Mouse RMS cells harboring these mutations were also more sensitive to treatment with drugs that inhibit FGFR4, which has “direct implications for personalized therapy and for patients with metastatic RMS, for whom long-term prognosis remains poor,” said lead author Dr. Javed Khan of NCI’s Pediatric Oncology Branch.
Researchers from NCI; the National Heart, Lung, and Blood Institute; The Children’s Hospital at Westmead, Australia; and the Nationwide Children’s Hospital in Columbus, OH, were involved in the project. Their previous research, and that of others, has shown that FGFR4 is highly expressed in RMS. Because the gene is active during muscle development and not in mature muscle, the team investigated whether expression of FGFR4 might contribute to RMS. Using mouse models, the researchers showed that the growth and spread of human RMS cells to the lungs was inhibited by suppressing FGFR4 expression. After sequencing the FGFR4 gene in human RMS tumor samples, they found that more than 7 percent of the tumors had mutations in the tyrosine kinase portion of the protein. Some of these mutations caused the protein to become overly active. Mutations that increase receptor tyrosine kinase activity have been found in other cancers, but the researchers note that this is the first time that mutations in a receptor tyrosine kinase have been found in RMS.
With a series of lab and animal studies, they confirmed that two of the FGFR4 mutations caused increased tumor growth, reduced RMS cell death, and enhanced the ability of RMS cells to metastasize.
The mutations, which were found in both types of RMS, alveolar and embryonal, appeared to act via the STAT3 pathway. Mouse RMS cells harboring these mutations were also more sensitive to treatment with drugs that inhibit FGFR4, which has “direct implications for personalized therapy and for patients with metastatic RMS, for whom long-term prognosis remains poor,” said lead author Dr. Javed Khan of NCI’s Pediatric Oncology Branch.
1 comment:
hi there - i read your post about RMS research with interest, as my brother is fighting this disease, diagnosed at the end of april. we are currently struggling to choose a treatment path, having started chemo should he have surgery first (as some doctors suggest), or stick with radiation. anyway, thank you for the post and i'll be back. also, i have been writing about my brother's experience from the caregiver's side at http://featsdontfailme.blogspot.com/.
thanks... jim
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