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

Abstract

Patients who are diagnosed with osteosarcoma (OS) today receive the same therapy that patients have received over the last 4 decades. Extensive efforts to identify more effective or less toxic regimens have proved disappointing. As we enter a postgenomic era in which we now recognize OS 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, review the current scientific evidence, note the immediate opportunities, and speculate 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. Cancer 2019;125:3514-3525.

Identification of 9-Gene Epithelial–Mesenchymal Transition Related Signature of Osteosarcoma by Integrating Multi Cohorts

“…Osteosarcoma is the most common malignant tumor in children and adolescents, 1 and at present, is treated mainly by surgery, radiotherapy, and chemotherapy. 2 Unfortunately, these established treatments have not significantly improved the survival rate of local and metastatic osteosarcoma.…”

Development and characterization of the novel human osteosarcoma cell line COS-33 with sustained activation of the mTOR pathway

“…However, the clinical and survival outcomes for patients with OS have not improved over the last four decades. This is in part due to the rarity of the disease and the high genetic heterogeneity at diagnosis, which together challenge us to better understand OS biology in order to make discoveries that can improve clinical care [7]. One way to overcome the difficulty in assessing OS patient samples is to establish new cell lines and to thoroughly characterize the existing models.…”

Increased DEF6 expression is correlated with metastasis and poor prognosis in human osteosarcoma

“…Due to the clinical importance of metastasis, a major cause of therapeutic failure in patients with OS (7), early prediction and inhibition of OS metastasis is an appealing curative approach. However, a robust biomarker for predicting metastasis and prognosis in patients with OS does not exist (37). Accumulating evidence suggests that in various types of cancer, such as ovarian carcinoma and colorectal cancer, DEF6 is associated with disease progression and poor prognosis (12,(17)(18)(19)(20).…”