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.
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.
This is a preview of subscription content, access via your institution
Open Access articles citing this article.
Artificial intelligence reveals dysregulation of osteosarcoma and cuproptosis-related biomarkers, PDHA1, CDKN2A and neutrophils
Scientific Reports Open Access 26 March 2023
Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment
Bone Research Open Access 27 February 2023
Identification and verification of a BMPs-related gene signature for osteosarcoma prognosis prediction
BMC Cancer Open Access 22 February 2023
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 per month
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$189.00 per year
only $15.75 per issue
Rent or buy this article
Get just this article for as long as you need it
Prices may be subject to local taxes which are calculated during checkout
Mirabello, L., Troisi, R. J. & Savage, S. A. Osteosarcoma incidence and survival rates from 1973 to 2004: data from the Surveillance, Epidemiology, and End Results Program. Cancer 115, 1531–1543 (2009).
Ottaviani, G. & Jaffe, N. The epidemiology of osteosarcoma. Cancer Treat. Res. 152, 3–13 (2009).
Bielack, S. S. et al. Prognostic factors in high-grade osteosarcoma of the extremities or trunk: an analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J. Clin. Oncol. 20, 776–790 (2002).
Isakoff, M. S., Bielack, S. S., Meltzer, P. & Gorlick, R. Osteosarcoma: current treatment and a collaborative pathway to success. J. Clin. Oncol. 33, 3029–3035 (2015).
Meyers, P. A. et al. Osteosarcoma: the addition of muramyl tripeptide to chemotherapy improves overall survival–a report from the Children’s Oncology Group. J. Clin. Oncol. 26, 633–638 (2008).
Marina, N. M. et al. Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial. Lancet Oncol. 17, 1396–1408 (2016).
Ferrari, S. et al. Neoadjuvant chemotherapy with methotrexate, cisplatin, and doxorubicin with or without ifosfamide in nonmetastatic osteosarcoma of the extremity: an Italian sarcoma group trial ISG/OS-1. J. Clin. Oncol. 30, 2112–2118 (2012).
Daw, N. C. et al. Frontline treatment of localized osteosarcoma without methotrexate: results of the St. Jude Children’s Research Hospital OS99 trial. Cancer 117, 2770–2778 (2011).
Gaspar, N. et al. Results of methotrexate-etoposide-ifosfamide based regimen (M-EI) in osteosarcoma patients included in the French OS2006/sarcome-09 study. Eur. J. Cancer 88, 57–66 (2018).
Daw, N. C. et al. Recurrent osteosarcoma with a single pulmonary metastasis: a multi-institutional review. Br. J. Cancer 112, 278–282 (2015).
Buddingh, E. P. et al. Prognostic factors in pulmonary metastasized high-grade osteosarcoma. Pediatr. Blood Cancer 54, 216–221 (2010).
Briccoli, A. et al. High grade osteosarcoma of the extremities metastatic to the lung: long-term results in 323 patients treated combining surgery and chemotherapy, 1985–2005. Surg. Oncol. 19, 193–199 (2010).
Goorin, A. M. et al. Phase II/III trial of etoposide and high-dose ifosfamide in newly diagnosed metastatic osteosarcoma: a pediatric oncology group trial. J. Clin. Oncol. 20, 426–433 (2002).
Berrak, S. G., Pearson, M., Berberoglu, S., Ilhan, I. E. & Jaffe, N. High-dose ifosfamide in relapsed pediatric osteosarcoma: therapeutic effects and renal toxicity. Pediatr. Blood Cancer 44, 215–219 (2005).
Palmerini, E. et al. Gemcitabine and docetaxel in relapsed and unresectable high-grade osteosarcoma and spindle cell sarcoma of bone. BMC Cancer 16, 280 (2016).
Lagmay, J. P. et al. Outcome of patients with recurrent osteosarcoma enrolled in seven phase II trials through Children’s Cancer Group, Pediatric Oncology Group, and Children’s Oncology Group: learning from the past to move forward. J. Clin. Oncol. 34, 3031–3038 (2016).
Arndt, C. A. et al. Inhaled granulocyte-macrophage colony stimulating factor for first pulmonary recurrence of osteosarcoma: effects on disease-free survival and immunomodulation. a report from the Children’s Oncology Group. Clin. Cancer Res. 16, 4024–4030 (2010).
Biegel, J. A., Womer, R. B. & Emanuel, B. S. Complex karyotypes in a series of pediatric osteosarcomas. Cancer Genet. Cytogenet. 38, 89–100 (1989).
Bridge, J. A. et al. Cytogenetic findings in 73 osteosarcoma specimens and a review of the literature. Cancer Genet. Cytogenet. 95, 74–87 (1997).
Unni, K. K. & Dahlin, D. C. Osteosarcoma: pathology and classification. Semin. Roentgenol. 24, 143–152 (1989).
Dahlin, D. C. & Unni, K. K. Osteosarcoma of bone and its important recognizable varieties. Am. J. Surg. Pathol. 1, 61–72 (1977).
Chen, X. et al. Recurrent somatic structural variations contribute to tumorigenesis in pediatric osteosarcoma. Cell Rep. 7, 104–112 (2014).
Wang, L. L. et al. Augmented expression of MYC and/or MYCN protein defines highly aggressive MYC-driven neuroblastoma: a Children’s Oncology Group study. Br. J. Cancer 113, 57–63 (2015).
Slayton, W. B., Schultz, K. R., Silverman, L. B. & Hunger, S. P. How we approach Philadelphia chromosome-positive acute lymphoblastic leukemia in children and young adults. Pediatr. Blood Cancer 67, e28543 (2020).
Glover, J. et al. A summary of the osteosarcoma banking efforts: a report from the Children’s Oncology Group and the QuadW Foundation. Pediatr. Blood Cancer 62, 450–455 (2015).
Glover, J. et al. Osteosarcoma enters a post genomic era with in silico opportunities: generation of the High Dimensional Database for facilitating sarcoma biology research: a report from the Children’s Oncology Group and the QuadW Foundation. PLoS ONE 12, e0181204 (2017).
Strauss, S. J. et al. Report from the 4th European Bone Sarcoma Networking meeting: focus on osteosarcoma. Clin. Sarcoma Res. 8, 17 (2018).
Wu, Z. L. et al. Development of a novel immune-related genes prognostic signature for osteosarcoma. Sci. Rep. 10, 18402 (2020).
Bousquet, M. et al. Whole-exome sequencing in osteosarcoma reveals important heterogeneity of genetic alterations. Ann. Oncol. 27, 738–744 (2016).
Kovac, M. et al. Exome sequencing of osteosarcoma reveals mutation signatures reminiscent of BRCA deficiency. Nat. Commun. 6, 8940 (2015).
Behjati, S. et al. Recurrent mutation of IGF signalling genes and distinct patterns of genomic rearrangement in osteosarcoma. Nat. Commun. 8, 15936 (2017).
Perry, J. A. et al. Complementary genomic approaches highlight the PI3K/mTOR pathway as a common vulnerability in osteosarcoma. Proc. Natl Acad. Sci. USA 111, E5564–E5573 (2014).
Wu, C. C. & Livingston, J. A. Genomics and the immune landscape of osteosarcoma. Adv. Exp. Med. Biol. 1258, 21–36 (2020).
Stephens, P. J. et al. Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144, 27–40 (2011).
Cortés-Ciriano, I. et al. Comprehensive analysis of chromothripsis in 2,658 human cancers using whole-genome sequencing. Nat. Genet. 52, 331–341 (2020).
Lorenz, S. et al. Unscrambling the genomic chaos of osteosarcoma reveals extensive transcript fusion, recurrent rearrangements and frequent novel TP53 aberrations. Oncotarget 7, 5273–5288 (2016).
Wu, C. C. et al. Immuno-genomic landscape of osteosarcoma. Nat. Commun. 11, 1008 (2020).
Lau, C. et al. The Genomic Landscape of Osteosarcoma: a Target Report. 2019 CTOS Annual Meeting (2019).
Sayles, L. C. et al. Genome-informed targeted therapy for osteosarcoma. Cancer Discov. 9, 46–63 (2019).
Northcott, P. A. et al. Medulloblastoma comprises four distinct molecular variants. J. Clin. Oncol. 29, 1408–1414 (2011).
Houghton, P. J. et al. The pediatric preclinical testing program: description of models and early testing results. Pediatr. Blood Cancer 49, 928–940 (2007).
Rokita, J. L. et al. Genomic profiling of childhood tumor patient-derived xenograft models to enable rational clinical trial design. Cell Rep. 29, 1675–1689.e9 (2019).
Kopp, L. M. et al. Phase II trial of the glycoprotein non-metastatic B-targeted antibody-drug conjugate, glembatumumab vedotin (CDX-011), in recurrent osteosarcoma AOST1521: a report from the Children’s Oncology Group. Eur. J. Cancer 121, 177–183 (2019).
Isakoff, M. S. et al. A phase II study of eribulin in recurrent or refractory osteosarcoma: a report from the Children’s Oncology Group. Pediatr. Blood Cancer 66, e27524 (2019).
Gill, J. et al. Dose-response effect of eribulin in preclinical models of osteosarcoma by the pediatric preclinical testing consortium. Pediatr. Blood Cancer 67, e28606 (2020).
Walkley, C. R. et al. Conditional mouse osteosarcoma, dependent on p53 loss and potentiated by loss of Rb, mimics the human disease. Genes Dev. 22, 1662–1676 (2008).
Berman, S. D. et al. Metastatic osteosarcoma induced by inactivation of Rb and p53 in the osteoblast lineage. Proc. Natl Acad. Sci. USA 105, 11851–11856 (2008).
Jain, M. et al. Sustained loss of a neoplastic phenotype by brief inactivation of MYC. Science 297, 102–104 (2002).
Feng, W. et al. Myc is a prognostic biomarker and potential therapeutic target in osteosarcoma. Ther. Adv. Med. Oncol. 12, 1758835920922055 (2020).
Niu, J. et al. Identification of potential therapeutic targets and immune cell infiltration characteristics in osteosarcoma using bioinformatics strategy. Front. Oncol. 10, 1628 (2020).
Watanabe, A. et al. Osteosarcoma in Sprague-Dawley rats after long-term treatment with teriparatide (human parathyroid hormone (1-34)). J. Toxicol. Sci. 37, 617–629 (2012).
He, Y. et al. cFOS-SOX9 axis reprograms bone marrow-derived mesenchymal stem cells into chondroblastic osteosarcoma. Stem Cell Rep. 8, 1630–1644 (2017).
Zheng, B. et al. PD-1 axis expression in musculoskeletal tumors and antitumor effect of nivolumab in osteosarcoma model of humanized mouse. J. Hematol. Oncol. 11, 16 (2018).
Wagner, F. et al. Humanization of bone and bone marrow in an orthotopic site reveals new potential therapeutic targets in osteosarcoma. Biomaterials 171, 230–246 (2018).
Angstadt, A. Y. et al. Characterization of canine osteosarcoma by array comparative genomic hybridization and RT-qPCR: Signatures of genomic imbalance in canine osteosarcoma parallel the human counterpart. Genes Chromosomes Cancer 50, 859–874 (2011).
Varshney, J., Scott, M. C., Largaespada, D. A. & Subramanian, S. Understanding the osteosarcoma pathobiology: a comparative oncology approach. Vet. Sci. 3, 3 (2016).
Gordon, I., Paoloni, M., Mazcko, C. & Khanna, C. The comparative oncology trials consortium: using spontaneously occurring cancers in dogs to inform the cancer drug development pathway. PLoS Med. 6, e1000161 (2009).
Isakoff, M. S. et al. Rapid protocol enrollment in osteosarcoma: a report from the Children’s Oncology Group. Pediatr. Blood Cancer 63, 370–371 (2016).
Grignani, G. et al. A phase II trial of sorafenib in relapsed and unresectable high-grade osteosarcoma after failure of standard multimodal therapy: an Italian Sarcoma Group study. Ann. Oncol. 23, 508–516 (2012).
Davis, L. E. et al. Randomized double-blind phase II study of regorafenib in patients with metastatic osteosarcoma. J. Clin. Oncol. 37, 1424–1431 (2019).
Smith, M. et al. Abstract LB-353: pediatric preclinical testing program (PPTP) stage 1 evaluation of cabozantinib. Cancer Res. 73 (Suppl. 8), LB-353 (2013).
Italiano, A. et al. Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial. Lancet Oncol. 21, 446–455 (2020).
Gaspar, N. et al. Single-agent expansion cohort of lenvatinib (LEN) and combination dose-finding cohort of LEN+etoposide (ETP)+ifosfamide (IFM) in patients (pts) aged 2 to ≤25 years with relapsed/refractory osteosarcoma (OS). J. Clin. Oncol. 36 (Suppl. 15), 11527 (2018).
Aggerholm-Pedersen, N., Rossen, P., Rose, H. & Safwat, A. Pazopanib in the treatment of bone sarcomas: clinical experience. Transl Oncol. 13, 295–299 (2020).
Grignani, G. et al. Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: a non-randomised phase 2 clinical trial. Lancet Oncol. 16, 98–107 (2015).
Urciuoli, E. et al. Src nuclear localization and its prognostic relevance in human osteosarcoma. J. Cell Physiol. 233, 1658–1670 (2018).
Kolb, E. A. et al. Initial testing of dasatinib by the pediatric preclinical testing program. Pediatr. Blood Cancer 50, 1198–1206 (2008).
Baird, K. et al. Results of a randomized, double-blinded, placebo-controlled, phase 2.5 study of saracatinib (AZD0530), in patients with recurrent osteosarcoma localized to lung. Sarcoma 2020, 7935475 (2020).
Kubo, T. et al. Platelet-derived growth factor receptor as a prognostic marker and a therapeutic target for imatinib mesylate therapy in osteosarcoma. Cancer 112, 2119–2129 (2008).
Chugh, R. et al. Phase II multicenter trial of imatinib in 10 histologic subtypes of sarcoma using a bayesian hierarchical statistical model. J. Clin. Oncol. 27, 3148–3153 (2009).
Kolb, E. A. et al. Preclinical evaluation of the combination of AZD1775 and irinotecan against selected pediatric solid tumors: a pediatric preclinical testing consortium report. Pediatr. Blood Cancer 67, e28098 (2020).
Kreahling, J. M. et al. Wee1 inhibition by MK-1775 leads to tumor inhibition and enhances efficacy of gemcitabine in human sarcomas. PLoS ONE 8, e57523 (2013).
PosthumaDeBoer, J. et al. WEE1 inhibition sensitizes osteosarcoma to radiotherapy. BMC Cancer 11, 156 (2011).
Zhou, Y. et al. Expression and therapeutic implications of cyclin-dependent kinase 4 (CDK4) in osteosarcoma. Biochim. Biophys. Acta Mol. Basis Dis. 1864, 1573–1582 (2018).
Higuchi, T. et al. Sorafenib and palbociclib combination regresses a cisplatinum-resistant osteosarcoma in a PDOX mouse model. Anticancer Res. 39, 4079 (2019).
Tavanti, E. et al. Preclinical validation of Aurora kinases-targeting drugs in osteosarcoma. Br. J. Cancer 109, 2607–2618 (2013).
Maris, J. M. et al. Initial testing of the aurora kinase A inhibitor MLN8237 by the pediatric preclinical testing program (PPTP). Pediatr. Blood Cancer 55, 26–34 (2010).
Zhao, Z. et al. Aurora B kinase as a novel molecular target for inhibition the growth of osteosarcoma. Mol. Carcinog. 58, 1056–1067 (2019).
Mossé, Y. P. et al. A phase II study of alisertib in children with recurrent/refractory solid tumors or leukemia: Children’s Oncology Group Phase I and Pilot Consortium (ADVL0921). Clin. Cancer Res. 25, 3229 (2019).
Fu, W. et al. The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells. Mol. Cancer Ther. 10, 1018–1027 (2011).
Gorlick, R. et al. Initial testing (stage 1) of the cyclin dependent kinase inhibitor SCH 727965 (dinaciclib) by the pediatric preclinical testing program. Pediatr. Blood Cancer 59, 1266–1274 (2012).
Li, X. et al. Inhibition of ATR-Chk1 signaling blocks DNA double-strand-break repair and induces cytoplasmic vacuolization in metastatic osteosarcoma. Ther. Adv. Med. Oncol. 12, 1758835920956900 (2020).
Kleinerman, E. S., Murray, J. L., Snyder, J. S., Cunningham, J. E. & Fidler, I. J. Activation of tumoricidal properties in monocytes from cancer patients following intravenous administration of liposomes containing muramyl tripeptide phosphatidylethanolamine. Cancer Res. 49, 4665–4670 (1989).
Gordon, N. et al. Fas expression in lung metastasis from osteosarcoma patients. J. Pediatr. Hematol. Oncol. 27, 611–615 (2005).
Gordon, N. & Kleinerman, E. S. The role of Fas/FasL in the metastatic potential of osteosarcoma and targeting this pathway for the treatment of osteosarcoma lung metastases. Cancer Treat. Res. 152, 497–508 (2009).
Koshkina, N. V., Rao-Bindal, K. & Kleinerman, E. S. Effect of the histone deacetylase inhibitor SNDX-275 on Fas signaling in osteosarcoma cells and the feasibility of its topical application for the treatment of osteosarcoma lung metastases. Cancer 117, 3457–3467 (2011).
Gross, A. C. et al. IL-6 and CXCL8 mediate osteosarcoma-lung interactions critical to metastasis. JCI Insight 3, e99791 (2018).
Liu, J. F. et al. CXCL13/CXCR5 interaction facilitates VCAM-1-dependent migration in human osteosarcoma. Int. J. Mol. Sci. 21, 6095 (2020).
Morrow, J. J. et al. Positively selected enhancer elements endow osteosarcoma cells with metastatic competence. Nat. Med. 24, 176–185 (2018).
Murgai, M. et al. KLF4-dependent perivascular cell plasticity mediates pre-metastatic niche formation and metastasis. Nat. Med. 23, 1176–1190 (2017).
Charan, M. et al. Tumor secreted ANGPTL2 facilitates recruitment of neutrophils to the lung to promote lung pre-metastatic niche formation and targeting ANGPTL2 signaling affects metastatic disease. Oncotarget 11, 510–522 (2020).
Coley, W. B. The treatment of inoperable sarcoma by bacterial toxins (the mixed toxins of the Streptococcus erysipelas and the Bacillus prodigiosus). Proc. R. Soc. Med. 3, 1–48 (1910).
Jeys, L. M., Grimer, R. J., Carter, S. R., Tillman, R. M. & Abudu, A. Post operative infection and increased survival in osteosarcoma patients: are they associated? Ann. Surg. Oncol. 14, 2887–2895 (2007).
Chen, Y. U., Xu, S. F., Xu, M. & Yu, X. C. Postoperative infection and survival in osteosarcoma patients: reconsideration of immunotherapy for osteosarcoma. Mol. Clin. Oncol. 3, 495–500 (2015).
Koirala, P. et al. Immune infiltration and PD-L1 expression in the tumor microenvironment are prognostic in osteosarcoma. Sci. Rep. 6, 30093 (2016).
Koirala, P. et al. HHLA2, a member of the B7 family, is expressed in human osteosarcoma and is associated with metastases and worse survival. Sci. Rep. 6, 31154 (2016).
Wolf-Dennen, K., Gordon, N. & Kleinerman, E. S. Exosomal communication by metastatic osteosarcoma cells modulates alveolar macrophages to an M2 tumor-promoting phenotype and inhibits tumoricidal functions. Oncoimmunology 9, 1747677 (2020).
Corre, I., Verrecchia, F., Crenn, V., Redini, F. & Trichet, V. The osteosarcoma microenvironment: a complex but targetable ecosystem. Cells 9, 976 (2020).
Kleinerman, E. S., Erickson, K. L., Schroit, A. J., Fogler, W. E. & Fidler, I. J. Activation of tumoricidal properties in human blood monocytes by liposomes containing lipophilic muramyl tripeptide. Cancer Res. 43, 2010–2014 (1983).
Gisch, N., Buske, B., Heine, H., Lindner, B. & Zähringer, U. Synthesis of biotinylated muramyl tripeptides with NOD2-stimulating activity. Bioorg. Med. Chem. Lett. 21, 3362–3366 (2011).
Anderson, P. M. et al. Mifamurtide in metastatic and recurrent osteosarcoma: a patient access study with pharmacokinetic, pharmacodynamic, and safety assessments. Pediatr. Blood Cancer 61, 238–244 (2014).
Bielack, S. S. et al. Methotrexate, doxorubicin, and cisplatin (MAP) plus maintenance pegylated interferon Alfa-2b versus MAP alone in patients with resectable high-grade osteosarcoma and good histologic response to preoperative MAP: first results of the EURAMOS-1 good response randomized controlled trial. J. Clin. Oncol. 33, 2279–2287 (2015).
Sikic, B. I. et al. First-in-human, first-in-class phase I trial of the anti-CD47 antibody Hu5F9-G4 in patients with advanced cancers. J. Clin. Oncol. 37, 946–953 (2019).
Xu, J. F. et al. CD47 blockade inhibits tumor progression human osteosarcoma in xenograft models. Oncotarget 6, 23662–23670 (2015).
Theruvath, J. et al. Abstract PR07: GD2 is a macrophage checkpoint molecule and combined GD2/CD47 blockade results in synergistic effects and tumor clearance in xenograft models of neuroblastoma and osteosarcoma. Cancer Res. 80 (Suppl. 14), PR07 (2020).
Harjunpaa, H., Llort Asens, M., Guenther, C. & Fagerholm, S. C. Cell adhesion molecules and their roles and regulation in the immune and tumor microenvironment. Front. Immunol. 10, 1078 (2019).
Huang, A. Y.-C. Targeting VCAM1-a4b1 signaling to ameliorate pulmonary osteosarcoma metastasis. NIH https://grantome.com/grant/NIH/R21-CA218790-01 (2017).
Fritzsching, B. et al. CD8+/FOXP3+-ratio in osteosarcoma microenvironment separates survivors from non-survivors: a multicenter validated retrospective study. Oncoimmunology 4, e990800 (2015).
Geukes Foppen, M. H., Donia, M., Svane, I. M. & Haanen, J. B. Tumor-infiltrating lymphocytes for the treatment of metastatic cancer. Mol. Oncol. 9, 1918–1935 (2015).
Guma, S. R. et al. Natural killer cell therapy and aerosol interleukin-2 for the treatment of osteosarcoma lung metastasis. Pediatr. Blood Cancer 61, 618–626 (2014).
Kiany, S., Huang, G. & Kleinerman, E. S. Effect of entinostat on NK cell-mediated cytotoxicity against osteosarcoma cells and osteosarcoma lung metastasis. Oncoimmunology 6, e1333214 (2017).
Tullius B. P., Setty B. A., Lee D. A. in Current Advances in Osteosarcoma: Clinical Perspectives: Past, Present and Future (eds Kleinerman E. S. & Gorlick R.) 141–154 (Springer International Publishing, 2020).
Habib, S., Tariq, S. M. & Tariq, M. Chimeric antigen receptor-natural killer cells: the future of cancer immunotherapy. Ochsner J. 19, 186–187 (2019).
Wang, L. et al. B7-H3 is overexpressed in patients suffering osteosarcoma and associated with tumor aggressiveness and metastasis. PLoS ONE 8, e70689 (2013).
McEachron, T. A., Triche, T. J., Sorenson, L., Parham, D. M. & Carpten, J. D. Profiling targetable immune checkpoints in osteosarcoma. Oncoimmunology 7, e1475873 (2018).
Le Cesne, A. et al. Programmed cell death 1 (PD-1) targeting in patients with advanced osteosarcomas: results from the PEMBROSARC study. Eur. J. Cancer 119, 151–157 (2019).
Tawbi, H. A. et al. Pembrolizumab in advanced soft-tissue sarcoma and bone sarcoma (SARC028): a multicentre, two-cohort, single-arm, open-label, phase 2 trial. Lancet Oncol. 18, 1493–1501 (2017).
Davis, K. L. et al. Nivolumab in children and young adults with relapsed or refractory solid tumours or lymphoma (ADVL1412): a multicentre, open-label, single-arm, phase 1-2 trial. Lancet Oncol. 21, 541–550 (2020).
Gröbner, S. N. et al. The landscape of genomic alterations across childhood cancers. Nature 555, 321–327 (2018).
Dhupkar, P., Gordon, N., Stewart, J. & Kleinerman, E. S. Anti-PD-1 therapy redirects macrophages from an M2 to an M1 phenotype inducing regression of OS lung metastases. Cancer Med. 7, 2654–2664 (2018).
Hong, Y. K. et al. Epigenetic modulation enhances immunotherapy for hepatocellular carcinoma. Cell Immunol. 336, 66–74 (2019).
Lhuillier, C. et al. Radiotherapy-exposed CD8+ and CD4+ neoantigens enhance tumor control. J. Clin. Invest. 131, e138740 (2021).
Zhang, B. CD73: a novel target for cancer immunotherapy. Cancer Res. 70, 6407–6411 (2010).
Roth, M. et al. Targeting glycoprotein NMB with antibody-drug conjugate, glembatumumab vedotin, for the treatment of osteosarcoma. Pediatr. Blood Cancer 63, 32–38 (2016).
Kolb, E. A. et al. Initial testing (stage 1) of glembatumumab vedotin (CDX-011) by the pediatric preclinical testing program. Pediatr. Blood Cancer 61, 1816–1821 (2014).
Cui, J. C. et al. Expression and clinical implications of leucine-rich repeat containing 15 (LRRC15) in osteosarcoma. J. Orthop. Res. 38, 2362–2372 (2020).
Hingorani, P. et al. ABBV-085, antibody-drug conjugate targeting LRRC15, is effective in osteosarcoma: a report by the Pediatric Preclinical Testing Consortium. Mol. Cancer Ther. 20, 535–540 (2021).
Gill J. H. P. et al. Evaluation of ABBV-085, an antibody-drug conjugate targeting LRRC15, in osteosarcoma by the Pediatric Preclinical Testing Consortium. Connective Tissue Oncology Society Meeting (Poster). 137 (2019).
Demetri, G. D. et al. First-in-human phase 1 study of ABBV-085, an antibody-drug conjugate (ADC) targeting LRRC15, in sarcomas and other advanced solid tumors. J. Clin. Oncol. 37, 3004–3004 (2019).
Gorlick, R. et al. Expression of HER2/erbB-2 correlates with survival in osteosarcoma. J. Clin. Oncol. 17, 2781–2788 (1999).
Gorlick, S. et al. HER-2 expression is not prognostic in osteosarcoma; a Children’s Oncology Group prospective biology study. Pediatr. Blood Cancer 61, 1558–1564 (2014).
Gill J., Geller D., & Gorlick, R. in Current Advances in Osteosarcoma (ed. Kleinerman, M. D. E. S.) 161–177 (Springer International Publishing, 2014).
Ebb, D. et al. Phase II trial of trastuzumab in combination with cytotoxic chemotherapy for treatment of metastatic osteosarcoma with human epidermal growth factor receptor 2 overexpression: a report from the Children’s Oncology Group. J. Clin. Oncol. 30, 2545–2551 (2012).
Ahmed, N. et al. Human epidermal growth factor receptor 2 (HER2)-specific chimeric antigen receptor-modified T cells for the immunotherapy of HER2-positive sarcoma. J. Clin. Oncol. 33, 1688–1696 (2015).
Navai S. et al. Administration of HER2-CAR T cells after lymphodepletion safely improves T cell expansion and induces clinical responses in patients with advanced sarcomas (AACR Annual Meeting, 2019).
Modi, S. et al. Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase Ib study. J. Clin. Oncol. 38, 1887–1896 (2020).
Hingorani, P. et al. Abstract LB-217: preclinical evaluation of trastuzumab deruxtecan (T-DXd; DS-8201a), a HER2 antibody-drug conjugate, in pediatric solid tumors by the Pediatric Preclinical Testing Consortium (PPTC). Cancer Res. 80 (Suppl. 16), LB-217 (2020).
Roth, M. et al. Ganglioside GD2 as a therapeutic target for antibody-mediated therapy in patients with osteosarcoma. Cancer 120, 548–554 (2014).
Poon, V. I. et al. Ganglioside GD2 expression is maintained upon recurrence in patients with osteosarcoma. Clin. Sarcoma Res. 5, 4 (2015).
Keyel, M. E. & Reynolds, C. P. Spotlight on dinutuximab in the treatment of high-risk neuroblastoma: development and place in therapy. Biologics 13, 1–12 (2019).
Hingorani, P. et al. Phase II study of antidisialoganglioside antibody, dinutuximab, in combination with GM-CSF in patients with recurrent osteosarcoma (AOST1421): a report from the Children’s Oncology Group. J. Clin. Oncol. 38 (Suppl. 15), 10508 (2020).
Picarda, E., Ohaegbulam, K. C. & Zang, X. Molecular pathways: targeting B7-H3 (CD276) for human cancer immunotherapy. Clin. Cancer Res. 22, 3425–3431 (2016).
Onda, M., Wang, Q. C., Guo, H. F., Cheung, N. K. & Pastan, I. In vitro and in vivo cytotoxic activities of recombinant immunotoxin 8H9(Fv)-PE38 against breast cancer, osteosarcoma, and neuroblastoma. Cancer Res. 64, 1419–1424 (2004).
Kurmasheva, R. et al. Abstract C003: initial testing of m276-PBD CD276 antibody-drug conjugate in preclinical models of pediatric cancers by the Pediatric Preclinical Testing Consortium (PPTC). Mol. Cancer Ther. 18 (Suppl. 12), C003 (2019).
Seaman, S. et al. Eradication of tumors through simultaneous ablation of CD276/B7-H3-positive tumor cells and tumor vasculature. Cancer Cell 31, 501–515.e8 (2017).
Scribner, J. A. et al. Preclinical development of MGC018, a duocarmycin-based antibody-drug conjugate targeting B7-H3 for solid cancer. Mol. Cancer Ther. https://doi.org/10.1158/1535-7163.Mct-20-0116 (2020).
Powderly, J. D. et al. Preliminary dose escalation results from a phase I/II, first-in-human study of MGC018 (anti-B7-H3 antibody-drug conjugate) in patients with advanced solid tumors. J. Clin. Oncol. 38 (Suppl. 15), 3071–3071 (2020).
Majzner, R. G. et al. CAR T cells targeting B7-H3, a pan-cancer antigen, demonstrate potent preclinical activity against pediatric solid tumors and brain tumors. Clin. Cancer Res. 25, 2560–2574 (2019).
Hassan, S. E. et al. Cell surface receptor expression patterns in osteosarcoma. Cancer 118, 740–749 (2012).
Sevelda, F. et al. EGFR is not a major driver for osteosarcoma cell growth in vitro but contributes to starvation and chemotherapy resistance. J. Exp. Clin. Cancer Res. 34, 134 (2015).
Huang, Z. et al. Clinicopathological and prognostic values of ErbB receptor family amplification in primary osteosarcoma. Scand. J. Clin. Lab. Invest. 79, 601–612 (2019).
O’Rourke, D. M. et al. A single dose of peripherally infused EGFRvIII-directed CAR T cells mediates antigen loss and induces adaptive resistance in patients with recurrent glioblastoma. Sci. Transl Med. https://doi.org/10.1126/scitranslmed.aaa0984 (2017).
Schultz, L. Chimeric antigen receptor T cell therapy for pediatric B-ALL: narrowing the gap between early and long-term outcomes. Front. Immunol. 11, 1985 (2020).
Zhou, Y. et al. Single-cell RNA landscape of intratumoral heterogeneity and immunosuppressive microenvironment in advanced osteosarcoma. Nat. Commun. 11, 6322 (2020).
Moriarity, B. S. et al. A Sleeping Beauty forward genetic screen identifies new genes and pathways driving osteosarcoma development and metastasis. Nat. Genet. 47, 615–624 (2015).
Parra, E. R., Francisco-Cruz, A. & Wistuba, I. I. State-of-the-art of profiling immune contexture in the era of multiplexed staining and digital analysis to study paraffin tumor tissues. Cancers 11, 247 (2019).
Anninga, J. K. et al. Chemotherapeutic adjuvant treatment for osteosarcoma: where do we stand? Eur. J. Cancer 47, 2431–2445 (2011).
Fuchs, N. et al. Long-term results of the co-operative German-Austrian-Swiss osteosarcoma study group’s protocol COSS-86 of intensive multidrug chemotherapy and surgery for osteosarcoma of the limbs. Ann. Oncol. 9, 893–899 (1998).
Bacci, G. et al. Neoadjuvant chemotherapy for osteosarcoma of the extremity: long-term results of the Rizzoli’s 4th protocol. Eur. J. Cancer 37, 2030–2039 (2001).
Goorin, A. M. et al. Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. J. Clin. Oncol. 21, 1574–1580 (2003).
Chou, A. J. et al. Addition of muramyl tripeptide to chemotherapy for patients with newly diagnosed metastatic osteosarcoma: a report from the Children’s Oncology Group. Cancer 115, 5339–5348 (2009).
Serra, M. et al. May P-glycoprotein status be used to stratify high-grade osteosarcoma patients? Results from the Italian/Scandinavian Sarcoma Group 1 treatment protocol. Int. J. Oncol. 29, 1459–1468 (2006).
Whelan, J. S. et al. Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials. Ann. Oncol. 23, 1607–1616 (2012).
Link, M. P. et al. The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N. Engl. J. Med. 314, 1600–1606 (1986).
Marec-Berard, P. et al. Methotrexate-etoposide-ifosfamide compared with doxorubicin-cisplatin-ifosfamide chemotherapy in osteosarcoma treatment, patients aged 18–25 years. J. Adolesc. Young Adult Oncol. 9, 172–182 (2020).
Winkler, K. et al. Neoadjuvant chemotherapy for osteogenic sarcoma: results of a Cooperative German/Austrian study. J. Clin. Oncol. 2, 617–624 (1984).
Winkler, K. et al. Neoadjuvant chemotherapy of osteosarcoma: results of a randomized cooperative trial (COSS-82) with salvage chemotherapy based on histological tumor response. J. Clin. Oncol. 6, 329–337 (1988).
Bramwell, V. H. et al. A randomized comparison of two short intensive chemotherapy regimens in children and young adults with osteosarcoma: results in patients with metastases: a Study of the European Osteosarcoma Intergroup. Sarcoma 1, 155–160 (1997).
Le Deley, M. C. et al. SFOP OS94: a randomised trial comparing preoperative high-dose methotrexate plus doxorubicin to high-dose methotrexate plus etoposide and ifosfamide in osteosarcoma patients. Eur. J. Cancer 43, 752–761 (2007).
Ferrari, S. et al. Nonmetastatic osteosarcoma of the extremity: results of a neoadjuvant chemotherapy protocol (IOR/OS-3) with high-dose methotrexate, intraarterial or intravenous cisplatin, doxorubicin, and salvage chemotherapy based on histologic tumor response. Tumori 85, 458–464 (1999).
Smeland, S. et al. Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII: prognostic factors for outcome and the role of replacement salvage chemotherapy for poor histological responders. Eur. J. Cancer 39, 488–494 (2003).
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.
The authors declare no competing interests.
Peer review information
Nature Reviews Clinical Oncology thanks Bruno Fuchs, Dominique Heymann, Massimo Serra and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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
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/
Rights and permissions
About this article
Cite this article
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
This article is cited by
Identification and verification of a BMPs-related gene signature for osteosarcoma prognosis prediction
BMC Cancer (2023)
Artificial intelligence reveals dysregulation of osteosarcoma and cuproptosis-related biomarkers, PDHA1, CDKN2A and neutrophils
Scientific Reports (2023)
Managing the immune microenvironment of osteosarcoma: the outlook for osteosarcoma treatment
Bone Research (2023)
Nuclear receptor modulators inhibit osteosarcoma cell proliferation and tumour growth by regulating the mTOR signaling pathway
Cell Death & Disease (2023)
T2-weighted MRI radiomics in high-grade intramedullary osteosarcoma: predictive accuracy in assessing histologic response to chemotherapy, overall survival, and disease-free survival
Skeletal Radiology (2023)