A portion of bone cancers may respond to existing insulin-like growth factor 1 receptor inhibitors because they carry mutations in IGF signaling genes, a study recently published in Nature Communications suggests. The sarcoma team at the Norwegian Radium Hospital at Oslo University Hospital was represented in this study by Bodil Bjerkehagen, the sarcoma reference pathologist, Olga Zaikova, on behalf of the orthopedists, and Ola Myklebost, PI in the ICGC Bone Cancer Project. This study is a side branch from their previous participation in the European Network of Excellence on Bone Tumours, and is carried out by the International Cancer Genomics Consortium at the Sanger Centre in Hinxton outside Cambridge.
Summary of findings and OUH contributions, by Ola Myklebost:
Good tissue biopsies from the rare osteosarcomas are hard to come by, and the Radium Hospital contribution was possible only because our surgeons have collected open biopsies for many years. 25 of our samples had sufficient size and quality to be whole genome sequenced, together with 12 samples from the UK, and 75 samples had their exomes determined.
Osteosarcomas have extremely scrambled and highly variable genomes, and it has been a challenge to understand what causes this. We have previously described the high number of fusion genes and trans-spliced transcripts in cell lines, but in this study we have investigated patient samples. Because we also have the blood samples this is of course a much better study. However, although some of the processes involved in scrambling the genome now is better described, and the mutated genes are identified, we still are far from understanding the underlying biology. One striking feature was however that many growth factor receptor genes were amplified, and in particular components of the IGF pathway was mutated. We have previously observed the affection of IGF-related genes in sarcomas, and have also tested targeting of the IGFR inhibitor in cell lines, but this study identified additional related aberrations.
One feature that was not obvious from the genome data is that many osteosarcoma cell lines are sensitive to PARP inhibitors, apparently due to aberrations in the homologous recombination repair pathways. It has been claimed that this is because osteosarcomas are “BRCA-like”, i.e. resembling breast and ovarian cancers with mutations in the BRCA genes. However, judging from our genome data, this is not the case. Our local group is now taking another angle to possible treatment by characterising the sensitivity of our panel of cell lines to PARP inhibition, and investigating correlation with the many possible mechanistic biomarkers. We are in discussion with the European Bone Sarcoma Network on the possibility for a clinical trial. For this we would prefer to have some solid preclinical data on predictive biomarkers, but since they do not so far seem to be very accurate, we may propose to use a trial to find better markers. A problem of course is that the cell lines have many more aberrations than the typical patient tumour, and biomarkers identified in vitro may not be valid in patients.
The Nature Communications article:
Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma.
Behjati S, Tarpey PS, Haase K, Ye H, Young MD, Alexandrov LB, Farndon SJ, Collord G, Wedge DC, Martincorena I, Cooke SL, Davies H, Mifsud W, Lidgren M, Martin S, Latimer C, Maddison M, Butler AP, Teague JW, Pillay N, Shlien A, McDermott U, Futreal PA, Baumhoer D, Zaikova O, Bjerkehagen B, Myklebost O, Amary MF, Tirabosco R, Van Loo P, Stratton MR, Flanagan AM, Campbell PJ.
Nat Commun. 2017 Jun 23;8:15936. doi: 10.1038/ncomms15936.
Article from GenomeWeb covering the findings:
Subset of Bone Cancers Have Mutations Affecting IGF Signaling, Suggesting Possible Treatment (PDF format)