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  • Review Article
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Advancing therapy for osteosarcoma

Nature Reviews Clinical Oncology volume 18, pages 609–624 (2021)Cite this article

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Abstract

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.

Key points

  • Osteosarcoma is the most common primary malignant tumour of bone, with a peak incidence in adolescents and young adults coinciding with the pubertal growth spurt.

  • Limited progress has been made in improving the survival outcomes in patients with osteosarcoma over the past four decades.

  • Improved molecular characterization has revealed subcategories of osteosarcoma that might enable a precision medicine approach with agents targeting key alterations in a particular pathway.

  • Tumour-suppressor genes are commonly altered in this disease, particularly TP53 (>90%) and RB1 (30%). Molecular targets include receptor tyrosine kinases, CDK4/6, Aurora kinase B and DNA damage response pathways.

  • Immune-based targeted therapies, including monoclonal antibodies, antibody–drug conjugates and chimeric antigen receptor T cells targeting cell-surface proteins commonly overexpressed in osteosarcoma, are in active clinical development.

  • Owing to advances in biological understanding, the development of robust preclinical models, the feasibility of rapid clinical testing and novel treatment concepts, long-awaited improvements in the outcomes of patients with osteosarcoma are anticipated in the near future.

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Fig. 1: EFS with chemotherapy regimens comprising two, three or four drugs in patients with osteosarcoma.
Fig. 2: Molecular categories of osteosarcoma and responses to the corresponding molecularly targeted treatments in PPTC PDX models.
Fig. 3: Comparisons of the activity of ADCs and drugs similar to the ADC payloads in PDX models of osteosarcoma.
Fig. 4: Targeting the surfaceome of osteosarcoma.

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Acknowledgements

The work of R.G. is supported by The University of Texas MD Anderson Cancer Center as the H. Grant Taylor, M.D., W.W. Sutow, M.D. and Margaret P. Sullivan, M.D. Distinguished Chair in Pediatrics. J.G. and R.G. both acknowledge support from The Foster Foundation, Swim Across America, the Osteosarcoma Institute, the QuadW Foundation and the Barbara Epstein Foundation.

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    Jonathan Gill & Richard Gorlick

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Related links

Bone Cancer Research Trust: https://www.bcrt.org.uk/

Children’s Oncology Group (COG): https://childrensoncologygroup.org/index.php/childrens-oncology-group

Count Me In: https://www.broadinstitute.org/count-me-in

EuroBoNeT: https://cordis.europa.eu/project/id/18814

ITCC P4: https://www.itccp4.eu

National Cancer Institute (NCI) Therapeutically Applicable Research to Generate Effective Treatments (TARGET) Osteosarcoma project: https://ocg.cancer.gov/programs/target/projects/osteosarcoma

NCI Paediatric Preclinical Testing Consortium: http://www.ncipptc.org/

Osteosarcoma Project: http://www.osproject.org

QuadW Foundation: http://www.quadw.org/

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Gill, J., Gorlick, R. Advancing therapy for osteosarcoma. Nat Rev Clin Oncol 18, 609–624 (2021). https://doi.org/10.1038/s41571-021-00519-8

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