Advancing therapy for osteosarcoma

Despite being the most common primary bone cancer in children and young adults, osteosarcoma is a rare cancer, a fact that has complicated efforts to improve patient outcomes. Moreover, the molecular biology of disease is highly heterogeneous and most of the recurrent genetic alterations occur in tumour-suppressor genes that are challenging therapeutic targets. Herein, Gill and Gorlick discuss the new biological discoveries, technologies, and therapeutic agents and approaches that, through collaborative efforts, are poised to generate advances in the treatment of osteosarcoma after more than four decades of stagnation. Improving the survival of patients with osteosarcoma has long proved challenging, although the treatment of this disease is on the precipice of advancement. The increasing feasibility of molecular profiling together with the creation of both robust model systems and large, well-annotated tissue banks has led to an increased understanding of osteosarcoma biology. The historical invariability of survival outcomes and the limited number of agents known to be active in the treatment of this disease facilitate clinical trials designed to identify efficacious novel therapies using small cohorts of patients. In addition, trial designs will increasingly consider the genetic background of the tumour through biomarker-based patient selection, thereby enriching for clinical activity. Indeed, osteosarcoma cells are known to express a number of surface proteins that might be of therapeutic relevance, including B7-H3, GD2 and HER2, which can be targeted using antibody-drug conjugates and/or adoptive cell therapies. In addition, immune-checkpoint inhibition might augment the latter approach by helping to overcome the immunosuppressive tumour microenvironment. In this Review, we provide a brief overview of current osteosarcoma therapy before focusing on the biological insights from the molecular profiling and preclinical modelling studies that have opened new therapeutic opportunities in this disease.

Automated summary

Osteosarcoma, the most common primary bone cancer in children and young adults, presents challenges in treatment due to its rarity and molecular heterogeneity. Collaborative efforts in biological discoveries, technologies, and therapeutic approaches are expected to advance osteosarcoma treatment and improve patient outcomes. The increasing feasibility of molecular profiling, along with the creation of robust model systems and large tissue banks, has enhanced understanding of osteosarcoma biology.