3 min readGene Sequencing Project Finds Family of Drugs With Promise for Treating Childhood Tumour

Memphis, TN – Drugs that enhance a process called oxidative stress were found to kill rhabdomyosarcoma tumour cells growing in the laboratory and possibly bolstered the effectiveness of chemotherapy against this aggressive tumour of muscle and other soft tissue.

The findings are the latest from the St. Jude Children’s Research Hospital–Washington University Pediatric Cancer Genome Project and appear in the December 9 edition of the scientific journal Cancer Cell.

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 tumour and normal genomes of 16 tumours from 13 rhabdomyosarcoma patients. The findings were validated with more focused sequencing of tumours from an additional 37 patients. The analysis also provided new clues about why tumours recur.

“Overall, survival for patients with recurrent rhabdomyosarcoma is just 17 percent, and until now nothing was known about how tumours evolve in response to therapy,” said corresponding author Dr. Michael Dyer, a member of the St. Jude Department of Developmental Neurobiology and a Howard Hughes Medical Institute Investigator. “Clinically, we know that chemotherapy will kill the vast majority of tumour cells. This analysis suggests that a rare subset of tumour cells harbour 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 tumours and possibly other solid tumours. Researchers said the importance of collecting tissue samples from recurrent tumours 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 co-author Dr. Richard K. Wilson, director of The Genome Institute at Washington University School of Medicine in St. Louis, where scientists have extensive expertise analyzing tumour recurrence using whole-genome sequencing. “When cancer comes back, it’s genetically very similar to the original tumour 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.”

The study was part of the Pediatric Cancer Genome Project. Since its launch in 2010, the project has sequenced the complete normal and cancer genomes of 700 young cancer patients with some of the most aggressive and least understood cancers. The project has advanced understanding of the genetic origins of childhood cancers and helped to build a foundation for the next generation of cancer diagnostic and treatment tools.

About 350 new cases of rhabdomyosarcoma are identified each year in the U.S., making it the most common soft tissue tumour in children. Current therapies cure more than 75 percent of patients whose tumours have not spread widely. The prognosis is worse, however, for other patients, including those with recurrent disease.

About 60 percent of rhabdomyosarcoma patients have tumours of the embryonal subtype, and about 25 percent 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.

Embryonal rhabdomyosarcoma included far more genomic alterations than alveolar subtype tumours. The results support the hypothesis that alveolar rhabdomyosarcoma is driven by a single chromosomal rearrangement. The result is a new gene created by fusing part of the FOXO1 gene with either the PAX3 or the PAX7 genes.

In this study, 58 percent of patients with intermediate or high-risk embryonal subtype tumours had mutations in genes, including NRAS, KRAS and HRAS, that make up the RAS pathway. The pathway helps to regulate cell division and is often deregulated in cancer cells. No RAS pathway mutations were found in alveolar rhabdomyosarcoma.

RAS pathway mutations were not the only changes that distinguished the normal and embryonal tumour genomes. “Based on mutations we found in the genome, there is evidence of high levels of oxidative stress in the tumours,” Dyer said.

When researchers screened a library of more than 200 drugs and related compounds for activity against embryonal subtype tumour cells from three patients, the most promising results involved drugs that increased oxidative stress in tumour cells. The drugs killed cancer cells and also enhanced the effectiveness of chemotherapy. Drugs that targeted the RAS pathway showed little activity against the tumour cells.

“This suggests that altering the ability of tumour cells to handle that stress or increasing the stress just a bit is enough to push the cell over the edge and it dies,” Dyer said. “This gives us novel and exciting new therapeutic options to pursue based on results from drug screenings of primary tumour samples from patients.”

Publication: Targeting Oxidative Stress in Embryonal Rhabdomyosarcoma. 

Xiang Chen, Elizabeth Stewart, Anang A. Shelat, Chunxu Qu, Armita Bahrami, Mark Hatley, Gang Wu, Cori Bradley, Justina McEvoy, Alberto Pappo, Sheri Spunt, Marcus B. Valentine, Virginia Valentine, Fred Krafcik, Walter H. Lang, Monika Wierdl, Lyudmila Tsurkan, Viktor Tolleman, Sara M. Federico, Chris Morton, Charles Lu, Li Ding, John Easton, Michael Rusch, Panduka Nagahawatte, Jianmin Wang, Matthew Parker, Lei Wei, Erin Hedlund, David Finkelstein, Michael Edmonson, Sheila Shurtleff, Kristy Boggs, Heather Mulder, Donald Yergeau, Steve Skapek, Douglas S. Hawkins, Nilsa Ramirez, Philip M. Potter, John A. Sandoval, Andrew M. Davidoff, Elaine R. Mardis, Richard K. Wilson, Jinghui Zhang, James R. Downing, Michael A. Dyer. 

Cancer Cell (December 09, 2013): http://www.cell.com/cancer-cell/abstract/S1535-6108

Cancer Drugs

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