Pediatric Cancer Genome Project finds promising family of drugs for rhabdomyosarcoma
Drugs that enhance oxidative stress were found to kill rhabdomyosarcoma tumor cells growing in the laboratory and possibly bolstered the effectiveness of chemotherapy against this aggressive tumor of muscle and other soft tissue. These are the latest findings from the St. Jude Children's Research Hospital-Washington University Pediatric Cancer Genome Project, and they were published in Cancer Cell (2013; doi:10.1016/j.ccr.2013.11.002).
Oxidative stress is caused when oxygen-free radicals and other byproducts of cell metabolism build up in cells. This study offers the first evidence that rhabdomyosarcoma patients might benefit from drugs that harness the mechanism to kill cancer cells, including medications that are on the market or in development.
The results followed next-generation, whole-genome sequencing of the tumor and normal genomes of 16 tumors from 13 rhabdomyosarcoma patients. The findings were validated with more focused sequencing of tumors from an additional 37 patients. The analysis also provided new clues about why tumors recur.
“Overall, survival for patients with recurrent rhabdomyosarcoma is just 17%, and until now, nothing was known about how tumors evolve in response to therapy,” said corresponding author Michael Dyer, PhD, a member of the St. Jude Department of Developmental Neurobiology in Memphis, Tennessee, and a Howard Hughes Medical Institute investigator. “Clinically, we know that chemotherapy will kill the vast majority of tumor cells. This analysis suggests that a rare subset of tumor cells harbor different genetic alterations and that those cells serve as the seeds for the recurrence of rhabdomyosarcoma.”
Based on the results, St. Jude plans to expand biopsies to include recurrent rhabdomyosarcoma tumors and possibly other solid tumors. Researchers said the importance of collecting tissue samples from recurrent tumors will grow as more targeted therapies become available.
“Studies like the current one involving rhabdomyosarcoma are giving us a close-up look at the way cancer evolves in response to treatment,” said study coauthor Richard K. Wilson, PhD, director of The Genome Institute at Washington University School of Medicine in St. Louis, Missouri, where scientists have extensive expertise analyzing tumor recurrence using whole-genome sequencing. “When cancer comes back, it's genetically very similar to the original tumor but often with additional mutations that may give cancer cells new strategies to survive attack by whatever drugs are thrown at them. This makes a lot of sense but it's been hard to prove without whole-genome sequencing.”
About 60% of rhabdomyosarcoma patients have tumors of the embryonal subtype, and about 25% have the alveolar subtype. This study showed the two subtypes have different genetic origins and involve a dramatically different number of chromosomal rearrangements, mutations, and other gene variations.
When researchers screened a library of more than 200 drugs and related compounds for activity against embryonal subtype tumor cells from three patients, the most promising results involved drugs that increased oxidative stress in tumor cells. The drugs killed cancer cells and also enhanced the effectiveness of chemotherapy. Drugs that targeted the RAS pathway showed little activity against the tumor cells.