Researchers report in Nature Communications (“Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma”) that a genetic sequencing study has revealed that some patients with osteosarcoma could be helped by an existing drug.

The team, from the Wellcome Trust Sanger Institute, University College London Cancer Institute, and the Royal National Orthopedic Hospital NHS Trust, that 10% of patients with a genetic mutation in particular growth-factor-signaling genes may benefit from IGF1R inhibitors.

The results, the scientists say, suggest a re-trial of IGF1R inhibitors for the subset of patients with osteosarcoma who are likely to respond based on their genetic profile.

The current treatment for osteosarcoma is chemotherapy followed by surgery, where the bone tumors are removed. There has not been a new treatment for osteosarcoma in almost 40 years.

In the study, investigators analyzed the genome of 112 childhood and adult tumors—double the number of tumors studied previously. In 10% of cases, the team discovered cancer-causing mutations in insulin-like growth factor (IGF) signaling genes. IGF signaling plays a major role in bone growth and development during puberty. Researchers believe that IGF signaling is also implicated in the uncontrolled bone growth that is characteristic of osteosarcoma.

IGF signaling genes are the target of IGF1R inhibitors. Past clinical trials of IGF1R inhibitors as a treatment for osteosarcoma yielded mixed results, although occasionally patients responded to therapy. IGF1R inhibitors have not been further tested in osteosarcoma, as it had been unclear which patients would benefit from the treatment.

“Osteosarcoma is difficult to treat,” notes Sam Behjati, Ph.D., first author from the Wellcome Trust Sanger Institute and University of Cambridge. “Despite extensive research over the past 40 years, no new treatment options have been found. In this study, we reveal a clear biological target for osteosarcoma that can be reached with existing drugs.”

In the study, scientists looked for mutations in the tumors to understand the mechanism of osteosarcoma development. The genetic information revealed a specific process for rearranging the chromosomes that results in several cancer-driving mutations at once.

“In a whole-genome study of osteosarcoma, structural variants were identified as a major source of driver mutation. Some of these variants occurred in the context of chromothripsis, the shattering of chromosomes resulting in copy number oscillations,” wrote the researchers. “Using whole-exome sequencing combined with copy number arrays, Kovac et al. described genomic alterations in osteosarcoma indicative of compromised homology-directed DNA repair.”

“We have unpicked the mechanism behind osteosarcoma for the first time,” adds Adrienne Flanagan, Ph.D., senior author from the Royal National Orthopedic Hospital NHS Trust and University College London Cancer Institute. “We discovered a new process—chromothripsis amplification—in which the chromosome is shattered, multiplied, and rejigged to generate multiple cancer-driving mutations at the same time. We believe this is why we see very similar osteosarcoma tumors in children and adults, which are not the result of aging.” 

“Currently, there are no new osteosarcoma treatments on the horizon,” says Peter Campbell, M.D., Ph.D., lead author from the Wellcome Trust Sanger Institute. “Genomic sequencing has provided the evidence needed to revisit clinical trials of IGF1R inhibitors for the subset of patients that responded in the past. The mutations of patients' tumors may enable clinicians to predict who will, and will not respond to these drugs, resulting in more efficient clinical trials.”








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