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The Future of Chondrosarcoma Research and Treatment

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Chondrosarcoma

Abstract

Chondrosarcomas are the most common cartilaginous malignancies and predominantly affect adults. These tumors display subtype-specific clinical behaviors, with conventional chondrosarcomas having a notably bleak prognosis due to their resistance to available therapies. Recent technologies such as next-generation sequencing (NGS) have captured the genomic complexity of chondrosarcoma biology, including their variations in DNA mutational profiles, epigenetics, and gene expression. While this has dramatically increased the number of candidate therapeutic targets, the precise genetic and epigenetic changes responsible for chondrosarcoma progression and drug resistance remain unknown as their testing has been limited. Systemic chemotherapeutics and recently tested targeted therapies and immunotherapies have failed to show consistent benefit across CS subtypes. Novel therapeutic targets are desperately needed, and future clinical management will likely be informed by an improved understanding of subtype-specific pathways to aid in combination therapy selection. In this chapter, we discuss the future of chondrosarcoma research and summarize ongoing clinical trials evaluating novel approaches to chondrosarcoma treatment.

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References

  1. Jo VY, Fletcher CD. WHO classification of soft tissue tumours: an update based on the 2013 (4th) edition. Pathology. 2014;46(2):95–104.

    Article  CAS  PubMed  Google Scholar 

  2. van Praag Veroniek VM, Rueten-Budde AJ, Ho V, Dijkstra PDS, Study group B, Soft tissue t, et al. Incidence, outcomes and prognostic factors during 25 years of treatment of chondrosarcomas. Surg Oncol. 2018;27(3):402–8.

    Article  PubMed  Google Scholar 

  3. Angelini A, Guerra G, Mavrogenis AF, Pala E, Picci P, Ruggieri P. Clinical outcome of central conventional chondrosarcoma. J Surg Oncol. 2012;106(8):929–37.

    Article  PubMed  Google Scholar 

  4. Fromm J, Klein A, Baur-Melnyk A, Knosel T, Lindner L, Birkenmaier C, et al. Survival and prognostic factors in conventional central chondrosarcoma. BMC Cancer. 2018;18(1):849.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Gelderblom H, Hogendoorn PC, Dijkstra SD, van Rijswijk CS, Krol AD, Taminiau AH, et al. The clinical approach towards chondrosarcoma. Oncologist. 2008;13(3):320–9.

    Article  PubMed  Google Scholar 

  6. Frezza AM, Cesari M, Baumhoer D, Biau D, Bielack S, Campanacci DA, et al. Mesenchymal chondrosarcoma: prognostic factors and outcome in 113 patients. A European Musculoskeletal Oncology Society study. Eur J Cancer. 2015;51(3):374–81.

    Article  PubMed  Google Scholar 

  7. van Maldegem AM, Bovee JV, Gelderblom H. Comprehensive analysis of published studies involving systemic treatment for chondrosarcoma of bone between 2000 and 2013. Clin Sarcoma Res. 2014;4:11.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. van Maldegem A, Conley AP, Rutkowski P, Patel SR, Lugowska I, Desar IME, et al. Outcome of first-line systemic treatment for unresectable conventional, dedifferentiated, mesenchymal, and clear cell chondrosarcoma. Oncologist. 2019;24(1):110–6.

    Article  PubMed  CAS  Google Scholar 

  9. Nooij MA, Whelan J, Bramwell VH, Taminiau AT, Cannon S, Hogendoorn PC, et al. Doxorubicin and cisplatin chemotherapy in high-grade spindle cell sarcomas of the bone, other than osteosarcoma or malignant fibrous histiocytoma: a European Osteosarcoma Intergroup Study. Eur J Cancer. 2005;41(2):225–30.

    Article  CAS  PubMed  Google Scholar 

  10. Xu KM, Switchenko JM, Tian S, Escott CE, Pfister NT, Gillespie TW, et al. More effective systemic therapies are needed for chondrosarcoma: A National Cancer Data Base (NCDB) analysis. J Clin Oncol. 2018;36(15_suppl):e23508-e.

    Article  Google Scholar 

  11. Amary MF, Bacsi K, Maggiani F, Damato S, Halai D, Berisha F, et al. IDH1 and IDH2 mutations are frequent events in central chondrosarcoma and central and periosteal chondromas but not in other mesenchymal tumours. J Pathol. 2011;224(3):334–43.

    Article  CAS  PubMed  Google Scholar 

  12. Dang L, White DW, Gross S, Bennett BD, Bittinger MA, Driggers EM, et al. Cancer-associated IDH1 mutations produce 2-hydroxyglutarate. Nature. 2009;462(7274):739–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lu C, Venneti S, Akalin A, Fang F, Ward PS, Dematteo RG, et al. Induction of sarcomas by mutant IDH2. Genes Dev. 2013;27(18):1986–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lugowska I, Teterycz P, Mikula M, Kulecka M, Kluska A, Balabas A, et al. IDH1/2 mutations predict shorter survival in chondrosarcoma. J Cancer. 2018;9(6):998–1005.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Tap WD, Villalobos VM, Cote GM, Burris H, Janku F, Mir O, et al. Phase I study of the mutant IDH1 inhibitor ivosidenib: safety and clinical activity in patients with advanced chondrosarcoma. J Clin Oncol. 2020;38(15):1693–701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ayala G, Liu C, Nicosia R, Horowitz S, Lackman R. Microvasculature and VEGF expression in cartilaginous tumors. Hum Pathol. 2000;31(3):341–6.

    Article  CAS  PubMed  Google Scholar 

  17. McGough RL, Aswad BI, Terek RM. Pathologic neovascularization in cartilage tumors. Clin Orthop Relat Res. 2002;397:76–82.

    Article  Google Scholar 

  18. Klenke FM, Abdollahi A, Bertl E, Gebhard MM, Ewerbeck V, Huber PE, et al. Tyrosine kinase inhibitor SU6668 represses chondrosarcoma growth via antiangiogenesis in vivo. BMC Cancer. 2007;7:49.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Jones RL, Katz D, Loggers ET, Davidson D, Rodler ET, Pollack SM. Clinical benefit of antiangiogenic therapy in advanced and metastatic chondrosarcoma. Med Oncol. 2017;34(10):167.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  20. Chow W, Frankel P, Ruel C, Araujo DM, Milhem M, Okuno S, et al. Results of a prospective phase 2 study of pazopanib in patients with surgically unresectable or metastatic chondrosarcoma. Cancer. 2020;126(1):105–11.

    Article  CAS  PubMed  Google Scholar 

  21. Duffaud F, Mir O, Boudou-Rouquette P, Piperno-Neumann S, Penel N, Bompas E, et al. Efficacy and safety of regorafenib in adult patients with metastatic osteosarcoma: a non-comparative, randomised, double-blind, placebo-controlled, phase 2 study. Lancet Oncol. 2019;20(1):120–33.

    Article  CAS  PubMed  Google Scholar 

  22. Dickson MA, Tap WD, Keohan ML, D’Angelo SP, Gounder MM, Antonescu CR, et al. Phase II trial of the CDK4 inhibitor PD0332991 in patients with advanced CDK4-amplified well-differentiated or dedifferentiated liposarcoma. J Clin Oncol. 2013;31(16):2024–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Ouyang Z, Wang S, Zeng M, Li Z, Zhang Q, Wang W, et al. Therapeutic effect of palbociclib in chondrosarcoma: implication of cyclin-dependent kinase 4 as a potential target. Cell Commun Signal. 2019;17(1):17.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Johnston S, Martin M, Di Leo A, Im SA, Awada A, Forrester T, et al. MONARCH 3 final PFS: a randomized study of abemaciclib as initial therapy for advanced breast cancer. NPJ Breast Cancer. 2019;5:5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Grignani G, Palmerini E, Stacchiotti S, Boglione A, Ferraresi V, Frustaci S, et al. A phase 2 trial of imatinib mesylate in patients with recurrent nonresectable chondrosarcomas expressing platelet-derived growth factor receptor-alpha or -beta: an Italian Sarcoma Group study. Cancer. 2011;117(4):826–31.

    Article  CAS  PubMed  Google Scholar 

  26. Schuetze SM, Bolejack V, Choy E, Ganjoo KN, Staddon AP, Chow WA, et al. Phase 2 study of dasatinib in patients with alveolar soft part sarcoma, chondrosarcoma, chordoma, epithelioid sarcoma, or solitary fibrous tumor. Cancer. 2017;123(1):90–7.

    Article  CAS  PubMed  Google Scholar 

  27. van Oosterwijk JG, van Ruler MA, Briaire-de Bruijn IH, Herpers B, Gelderblom H, van de Water B, et al. Src kinases in chondrosarcoma chemoresistance and migration: dasatinib sensitises to doxorubicin in TP53 mutant cells. Br J Cancer. 2013;109(5):1214–22.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Zhang YX, van Oosterwijk JG, Sicinska E, Moss S, Remillard SP, van Wezel T, et al. Functional profiling of receptor tyrosine kinases and downstream signaling in human chondrosarcomas identifies pathways for rational targeted therapy. Clin Cancer Res. 2013;19(14):3796–807.

    Article  CAS  PubMed  Google Scholar 

  29. Perez J, Decouvelaere AV, Pointecouteau T, Pissaloux D, Michot JP, Besse A, et al. Inhibition of chondrosarcoma growth by mTOR inhibitor in an in vivo syngeneic rat model. PLoS One. 2012;7(6):e32458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Bernstein-Molho R, Kollender Y, Issakov J, Bickels J, Dadia S, Flusser G, et al. Clinical activity of mTOR inhibition in combination with cyclophosphamide in the treatment of recurrent unresectable chondrosarcomas. Cancer Chemother Pharmacol. 2012;70(6):855–60.

    Article  CAS  PubMed  Google Scholar 

  31. David E, Blanchard F, Heymann MF, De Pinieux G, Gouin F, Redini F, et al. The bone niche of chondrosarcoma: a sanctuary for drug resistance, tumour growth and also a source of new therapeutic targets. Sarcoma. 2011;2011:932451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Otero JE, Stevens JW, Malandra AE, Fredericks DC, Odgren PR, Buckwalter JA, et al. Osteoclast inhibition impairs chondrosarcoma growth and bone destruction. J Orthop Res. 2014;32(12):1562–71.

    Article  CAS  PubMed  Google Scholar 

  33. Lu C, Ward PS, Kapoor GS, Rohle D, Turcan S, Abdel-Wahab O, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483(7390):474–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Bui C, Ouzzine M, Talhaoui I, Sharp S, Prydz K, Coughtrie MW, et al. Epigenetics: methylation-associated repression of heparan sulfate 3-O-sulfotransferase gene expression contributes to the invasive phenotype of H-EMC-SS chondrosarcoma cells. FASEB J. 2010;24(2):436–50.

    Article  CAS  PubMed  Google Scholar 

  35. Hamm CA, Xie H, Costa FF, Vanin EF, Seftor EA, Sredni ST, et al. Global demethylation of rat chondrosarcoma cells after treatment with 5-aza-2'-deoxycytidine results in increased tumorigenicity. PLoS One. 2009;4(12):e8340.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Monga V, Dodd R, Scherer A, Gutierrez WR, Tanas M, Mott SL, et al. Phase Ib study of decitabine in combination with gemcitabine in treatment of advanced soft tissue and bone sarcomas. J Clin Oncol. 2020;38(15_suppl):11550.

    Article  Google Scholar 

  37. Sakimura R, Tanaka K, Yamamoto S, Matsunobu T, Li X, Hanada M, et al. The effects of histone deacetylase inhibitors on the induction of differentiation in chondrosarcoma cells. Clin Cancer Res. 2007;13(1):275–82.

    Article  CAS  PubMed  Google Scholar 

  38. Sheikh T, Patwardhan P, Schwartz GK. Abstract 5066: Combination treatment with SAHA and 5-Azacytidine (Decitabine) induces apoptosis and suppresses tumor growth in preclinical models of chondrosarcoma. Cancer Res. 2017;77(13 Supplement):5066.

    Google Scholar 

  39. Thanindratarn P, Dean DC, Nelson SD, Hornicek FJ, Duan Z. Advances in immune checkpoint inhibitors for bone sarcoma therapy. J Bone Oncol. 2019;15:100221.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Kostine M, Cleven AH, de Miranda NF, Italiano A, Cleton-Jansen AM, Bovee JV. Analysis of PD-L1, T-cell infiltrate and HLA expression in chondrosarcoma indicates potential for response to immunotherapy specifically in the dedifferentiated subtype. Mod Pathol. 2016;29(9):1028–37.

    Article  CAS  PubMed  Google Scholar 

  41. Tawbi HA, Burgess M, Bolejack V, Van Tine BA, Schuetze SM, Hu J, 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. 2017;18(11):1493–501.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Paoluzzi L, Cacavio A, Ghesani M, Karambelkar A, Rapkiewicz A, Weber J, et al. Response to anti-PD1 therapy with nivolumab in metastatic sarcomas. Clin Sarcoma Res. 2016;6:24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Wagner MJ, Ricciotti RW, Mantilla J, Loggers ET, Pollack SM, Cranmer LD. Response to PD1 inhibition in conventional chondrosarcoma. J Immunother Cancer. 2018;6(1):94.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgment

This work was supported, in part, by the Department of Orthopaedic Surgery at UCLA.

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Correspondence to Zhenfeng Duan .

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Thanindratarn, P., Dean, D.C., Hornicek, F.J., Duan, Z. (2021). The Future of Chondrosarcoma Research and Treatment. In: Hornicek, F.J. (eds) Chondrosarcoma. Springer, Cham. https://doi.org/10.1007/978-3-030-74572-1_13

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  • DOI: https://doi.org/10.1007/978-3-030-74572-1_13

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