Provocative questions in osteosarcoma basic and translational biology: A report from the Children’s Oncology Group

Roberts RD, Lizardo MM, Reed DR, Hingorani P, Glover J, Allen-Rhoades W, Fan T, Khanna C, Sweet-Cordero EA, Cash T, Bishop MW, Hegde M, Sertil AR, Koelsche C, Mirabello L, Malkin D, Sorensen PH, Meltzer PS, Janeway KA, Gorlick R, Crompton BD. Provocative questions in osteosarcoma basic and translational biology: A report from the Children’s Oncology Group. Cancer. 2019 Oct 15;125(20):3514-3525. doi: 10.1002/cncr.32351. Epub 2019 Jul 29. PMID: 31355930; PMCID: PMC6948723.

Those diagnosed with osteosarcoma today receive the same therapy that others received over the last four decades. Extensive efforts to identify more effective or less toxic regimens have proved disappointing. As we enter a post-genomic era, now recognizing osteosarcoma not as a cancer of mutations but as one defined by p53 loss, chromosomal complexity, copy number alteration, and profound heterogeneity, emerging threads of discovery leave many hopeful that an improving understanding of biology will drive discoveries that improve clinical care. Under the organization of the Bone Tumor Biology Committee of the Children’s Oncology Group, a team of clinicians and scientists sought to define the state-of-the-science and to identify questions that, if answered, have the greatest potential to drive fundamental clinical advances. Having discussed these questions in a series of meetings, each led by invited experts, we distilled these conversations into a series of seven Provocative Questions. These include questions about the molecular events that trigger oncogenesis, the genomic and epigenomic drivers of disease, the biology of lung metastasis, research models that best predict clinical outcomes, and processes for translating findings into clinical trials. Here, we briefly present each Provocative Question, reviewing the current scientific evidence, noting the immediate opportunities, and speculating on the impact that answered questions might have on the field. We do so with an intent to provide a framework around which investigators can build programs and collaborations to tackle the hardest problems and to establish research priorities for those developing policies and providing funding.