nodgoРоссийский журнал детской гематологии и онкологии (РЖДГиО)Russian Journal of Pediatric Hematology and Oncology2311-12672413-5496LTD “Graphica”10.21682/2311-1267-2021-8-1-57-63nodgo-691Research ArticleОБЗОРЫ ЛИТЕРАТУРЫLITERATURE REVIEWSТаргетная терапия в лечении метастатических, рецидивных и рефрактерных форм саркомы Юинга и остеогенной саркомы. Обзор литературыTargeted therapy in metastatic, recurrent and refractory Ewing sarcoma and osteogenic sarcoma. Review of literaturehttps://orcid.org/0000-0001-9540-1162МоргачеваД. А.MorgachevaD. A.

врач-детский онколог отделения химиотерапии онкогематологических заболеваний и трансплантации костного мозга,

197341, Санкт-Петербург, ул. Аккуратова, 2

Pediatric Oncologist, Department of Chemotherapy for Hematologic Diseases and Bone Marrow Transplantation for Children,

2 Akkuratova St., S.-Petersburg, 197341

morgachevadarya483@gmail.comhttps://orcid.org/0000-0001-9445-6866ПановаД. Ю.PanovaD. Yu.

врач-терапевт участковый,

197341, Санкт-Петербург, Коломяжский просп., 20

General Practitioner,

20 Kolomyazhsky Prosp., S.-Petersburg, 197341

dianapanova63@gmail.comhttps://orcid.org/0000-0002-7471-7181БелогуроваМ. Б.BelogurovaM. B.

д.м.н., профессор, ведущий научный сотрудник, 197341, Санкт-Петербург, ул. Аккуратова, 2;

заведующая детским онкологическим отделением, 197758, Санкт-Петербург, пос. Песочный, ул. Ленинградская, 68А

Dr. of Sci. (Med.), Professor, Leading Scientific Collaborator of Research Institute of Hematology, 2 Akkuratova St., S.-Petersburg, 197341;

Head of Children’s Oncology Department, 68А Leningradskaya St., Pesochny, S.-Petersburg, 197758

deton.hospital31@inbox.ruФГБУ «Национальный медицинский исследовательский центр имени В.А. Алмазова» Минздрава РоссииРоссияAlmazov National Medical Research Centre, Ministry of Health of RussiaRussian FederationООО «Современная медицина»РоссияLtd “Modern medicine”Russian FederationФГБУ «Национальный медицинский исследовательский центр имени В.А. Алмазова» Минздрава России; ГБУЗ «Санкт-Петербургский клинический научно-практический центр специализированных видов медицинской помощи (онкологический)»РоссияAlmazov National Medical Research Centre, Ministry of Health of Russia; Saint Petersburg Clinical Scientific and Practical Center of Specialized Medical Assistance (Oncological)Russian Federation202107042021815763Copyright © Моргачева Д.А., Панова Д.Ю., Белогурова М.Б., 20212021Моргачева Д.А., Панова Д.Ю., Белогурова М.Б.Morgacheva D.A., Panova D.Y., Belogurova M.B.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://journal.nodgo.org/jour/article/view/691

Остеогенная саркома (ОС) и саркома Юинга (СЮ) – наиболее часто встречающиеся костные саркомы у детей, подростков и молодых взрослых. Пациенты с метастатическим распространением, рецидивом или рефрактерной формой заболевания имеют неблагоприятный прогноз: 5-летняя общая выживаемость не превышает 20–30 %. В настоящее время проводятся исследования в целях поиска новых мишеней и путей воздействия на эти опухоли. Цель данного обзора – представить актуальные данные из мировой литературы о потенциально эффективных таргетных препаратах для пациентов с метастатическим распространением, рецидивом или рефрактерными формами ОС и СЮ. 

Osteogenic sarcoma (OS) and Ewing sarcoma (ES) are the most common bone sarcomas in children, adolescent and young adults. Patients with metastatic, relapse or refractory disease have unfavorable prognosis: 5-year overall survival does not exceed 20–30 %. Nowadays clinical trials are conducted to find out new targets and ways of influencing these tumors. The aim of this review is to present relevant data from world literature about potential effective targeted drugs for patient with metastases, relapse or refractory OS and ES. 

детиподросткимолодые взрослыеонкологиясаркома Юингаостеогенная саркоматаргетная терапияchildrenadolescentyoung adultsoncologyEwing sarcomaosteogenic sarcomatargeted therapyReferencesRivera-Valentin R.K., Zhu L., Hughes D.P. Bone Sarcomas in Pediatrics: Progress in Our Understanding of Tumor Biology and Implications for Therapy. Paediatr Drugs 2015;17(4):257–71. doi: 10.1007/s40272-015-0134-4.Rivera-Valentin R.K., Zhu L., Hughes D.P. Bone Sarcomas in Pediatrics: Progress in Our Understanding of Tumor Biology and Implications for Therapy. Paediatr Drugs 2015;17(4):257–71. doi: 10.1007/s40272-015-0134-4.Grünewald T.G.P., Cidre-Aranaz F., Surdez, D. Tomazou E.M., de Alava E., Kovar H., Sorensen P.H., Delattre O., Dirksen U. Ewing sarcoma. Nat Rev Dis Primers 2018;4(1):5. doi: 10.1038/s41572-018-0003-x.Grünewald T.G.P., Cidre-Aranaz F., Surdez, D. Tomazou E.M., de Alava E., Kovar H., Sorensen P.H., Delattre O., Dirksen U. Ewing sarcoma. Nat Rev Dis Primers 2018;4(1):5. doi: 10.1038/s41572-018-0003-x.Ferguson J.L., Turner S.P. Bone cancer: Diagnosis and Treatment Principles. Am Fam Physician 2018;98(4):205–13. PMID: 30215968.Ferguson J.L., Turner S.P. Bone cancer: Diagnosis and Treatment Principles. Am Fam Physician 2018;98(4):205–13. PMID: 30215968.American Cancer Society. Survival rates for Ewing tumors. [Electronic resource]: https://www.cancer.org/cancer/ewing-tumor/detection-diagnosis-staging/survival-rates.html (appeal date 09.05.2020).American Cancer Society. Survival rates for Ewing tumors. [Electronic resource]: https://www.cancer.org/cancer/ewing-tumor/detection-diagnosis-staging/survival-rates.html (appeal date 09.05.2020).Leavey P.J., Mascarenhas L., Marina N., Chen Z., Krailo M., Miser J., Brown K., Tarbell N., Bernstein M.L., Granowetter L., Gebhardt M., Grier H.E.; Children Oncology Group. Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence following multimodality therapy: A report from the Childrenʼs Oncology Group. Pediatr Blood Cancer 2008;51(3):334–8. doi: 10.1002/pbc.21618.Leavey P.J., Mascarenhas L., Marina N., Chen Z., Krailo M., Miser J., Brown K., Tarbell N., Bernstein M.L., Granowetter L., Gebhardt M., Grier H.E.; Children Oncology Group. Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence following multimodality therapy: A report from the Childrenʼs Oncology Group. Pediatr Blood Cancer 2008;51(3):334–8. doi: 10.1002/pbc.21618.Yu H., Ge Y., Guo L., Huang L. Potential approaches to the treatment of Ewingʼs sarcoma. Oncotarget 2017;8(3):5523–39. doi: 10.18632/oncotarget.12566.Yu H., Ge Y., Guo L., Huang L. Potential approaches to the treatment of Ewingʼs sarcoma. Oncotarget 2017;8(3):5523–39. doi: 10.18632/oncotarget.12566.Ritter J., Bielack S.S. Osteosarcoma. Ann Oncol 2010;21 Suppl 7:vii320–5. doi: 10.1093/annonc/mdq276.Ritter J., Bielack S.S. Osteosarcoma. Ann Oncol 2010;21 Suppl 7:vii320–5. doi: 10.1093/annonc/mdq276.St. Jude Children’s Research Hospital. Osteosarcoma [Electronic resource]: https://www.stjude.org/disease/osteosarcoma.html (appeal date 10.05.2020).St. Jude Children’s Research Hospital. Osteosarcoma [Electronic resource]: https://www.stjude.org/disease/osteosarcoma.html (appeal date 10.05.2020).American Cancer Society. Survival rates for Ewing tumors. [Electronic resource]: https://www.cancer.org/cancer/osteosarcoma/detection-diagnosis-staging/survival-rates.html (appeal date 10.05.2020).American Cancer Society. Survival rates for Ewing tumors. [Electronic resource]: https://www.cancer.org/cancer/osteosarcoma/detection-diagnosis-staging/survival-rates.html (appeal date 10.05.2020).Shaikh A.B., Li F., Li M., He B., He X., Chen G., Guo B., Li D., Jiang F., Dang L., Zheng S., Liang C., Liu J., Lu C., Liu B., Lu J., Wang L., Lu A., Zhang G. Present Advances and Future Perspectives of Molecular Targeted Therapy for Osteosarcoma. Int J Mol Sci 2016;17(4):506. doi: 10.3390/ijms17040506.Shaikh A.B., Li F., Li M., He B., He X., Chen G., Guo B., Li D., Jiang F., Dang L., Zheng S., Liang C., Liu J., Lu C., Liu B., Lu J., Wang L., Lu A., Zhang G. Present Advances and Future Perspectives of Molecular Targeted Therapy for Osteosarcoma. Int J Mol Sci 2016;17(4):506. doi: 10.3390/ijms17040506.Brenner J.C., Feng F.Y., Han S., Patel S., Goyal S.V., Bou-Maroun L.M., Liu M., Lonigro R., Prensner J.R., Tomlins S.A., Chinnaiyan A.M. PARP-1 inhibition as a targeted strategy to treat Ewingʼs sarcoma. Cancer Res 2012;72(7):1608–13. doi: 10.1158/0008-5472.CAN-11-3648.Brenner J.C., Feng F.Y., Han S., Patel S., Goyal S.V., Bou-Maroun L.M., Liu M., Lonigro R., Prensner J.R., Tomlins S.A., Chinnaiyan A.M. PARP-1 inhibition as a targeted strategy to treat Ewingʼs sarcoma. Cancer Res 2012;72(7):1608–13. doi: 10.1158/0008-5472.CAN-11-3648.Gourley C., Balmaña J., Ledermann J., Serra V., Dent R., Loibl S., Pujade-Lauraine E., Boulton S.J. Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy. J Clin Oncol 2019;37(25):2257–69. doi: 10.1200/JCO.18.02050.Gourley C., Balmaña J., Ledermann J., Serra V., Dent R., Loibl S., Pujade-Lauraine E., Boulton S.J. Moving From Poly (ADP-Ribose) Polymerase Inhibition to Targeting DNA Repair and DNA Damage Response in Cancer Therapy. J Clin Oncol 2019;37(25):2257–69. doi: 10.1200/JCO.18.02050.Garnett M.J., Edelman E.J., Heidorn S.J., Greenman C.D., Dastur A., Lau K.W., Greninger P., Thompson I.R., Luo X., Soares J., Liu Q., Iorio F., Surdez D., Chen L., Milano R.J., Bignell G.R., Tam A.T., Davies H., Stevenson J.A., Barthorpe S., Lutz S.R., Kogera F., Lawrence K., McLaren-Douglas A., Mitropoulos X., Mironenko T., Thi H., Richardson L., Zhou W., Jewitt F., Zhang T., OʼBrien P., Boisvert J.L., Price S., Hur W., Yang W., Deng X., Butler A., Choi H.G., Chang J.W., Baselga J., Stamenkovic I., Engelman J.A., Sharma S.V., Delattre O., Saez-Rodriguez J., Gray N.S., Settleman J., Futreal P.A., Haber D.A., Stratton M.R., Ramaswamy S., McDermott U., Benes C.H. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 2012;483(7391):570–5. doi: 10.1038/nature11005.Garnett M.J., Edelman E.J., Heidorn S.J., Greenman C.D., Dastur A., Lau K.W., Greninger P., Thompson I.R., Luo X., Soares J., Liu Q., Iorio F., Surdez D., Chen L., Milano R.J., Bignell G.R., Tam A.T., Davies H., Stevenson J.A., Barthorpe S., Lutz S.R., Kogera F., Lawrence K., McLaren-Douglas A., Mitropoulos X., Mironenko T., Thi H., Richardson L., Zhou W., Jewitt F., Zhang T., OʼBrien P., Boisvert J.L., Price S., Hur W., Yang W., Deng X., Butler A., Choi H.G., Chang J.W., Baselga J., Stamenkovic I., Engelman J.A., Sharma S.V., Delattre O., Saez-Rodriguez J., Gray N.S., Settleman J., Futreal P.A., Haber D.A., Stratton M.R., Ramaswamy S., McDermott U., Benes C.H. Systematic identification of genomic markers of drug sensitivity in cancer cells. Nature 2012;483(7391):570–5. doi: 10.1038/nature11005.Choy E., Butrynski J.E., Harmon D.C., Morgan J.A., George S., Wagner A.J., DʼAdamo D., Cote G.M., Flamand Y., Benes C.H., Haber D.A., Baselga J.M., Demetri G.D. Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy. BMC Cancer 2014;14:813. doi: 10.1186/1471-2407-14-813.Choy E., Butrynski J.E., Harmon D.C., Morgan J.A., George S., Wagner A.J., DʼAdamo D., Cote G.M., Flamand Y., Benes C.H., Haber D.A., Baselga J.M., Demetri G.D. Phase II study of olaparib in patients with refractory Ewing sarcoma following failure of standard chemotherapy. BMC Cancer 2014;14:813. doi: 10.1186/1471-2407-14-813.Schafer E.S., Rau R.E., Berg S.L., Liu X., Minard C.G., Bishop A.J.R., Romero J.C., Hicks M.J., Nelson M.D. Jr., Voss S., Reid J.M., Fox E., Weigel B.J., Blaney S.M. Phase 1/2 trial of talazoparib in combination with temozolomide in children and adolescents with refractory/ recurrent solid tumors including Ewing sarcoma: A Childrenʼs Oncology Group Phase 1 Consortium study (ADVL1411). Pediatr Blood Cancer 2020;67(2):e28073. doi: 10.1002/pbc.28073.Schafer E.S., Rau R.E., Berg S.L., Liu X., Minard C.G., Bishop A.J.R., Romero J.C., Hicks M.J., Nelson M.D. Jr., Voss S., Reid J.M., Fox E., Weigel B.J., Blaney S.M. Phase 1/2 trial of talazoparib in combination with temozolomide in children and adolescents with refractory/ recurrent solid tumors including Ewing sarcoma: A Childrenʼs Oncology Group Phase 1 Consortium study (ADVL1411). Pediatr Blood Cancer 2020;67(2):e28073. doi: 10.1002/pbc.28073.Heisey D.A.R., Lochmann T.L., Floros K.V., Coon C.M., Powell K.M., Jacob S., Calbert M.L., Ghotra M.S., Stein G.T., Maves Y.K., Smith S.C., Benes C.H., Leverson J.D., Souers A.J., Boikos S.A., Faber A.C. The Ewing Family of Tumors Relies on BCL-2 and BCL-XL to Escape PARP Inhibitor Toxicity. Clin Cancer Res 2019;25(5):1664–75. doi: 10.1158/1078-0432.CCR-18-0277.Heisey D.A.R., Lochmann T.L., Floros K.V., Coon C.M., Powell K.M., Jacob S., Calbert M.L., Ghotra M.S., Stein G.T., Maves Y.K., Smith S.C., Benes C.H., Leverson J.D., Souers A.J., Boikos S.A., Faber A.C. The Ewing Family of Tumors Relies on BCL-2 and BCL-XL to Escape PARP Inhibitor Toxicity. Clin Cancer Res 2019;25(5):1664–75. doi: 10.1158/1078-0432.CCR-18-0277.LeRoith D., Roberts C.T. Jr. The insulin-like growth factor system and cancer. Cancer Lett 2003;195(2):127–37. doi: 10.1016/s0304-3835(03)00159-9.LeRoith D., Roberts C.T. Jr. The insulin-like growth factor system and cancer. Cancer Lett 2003;195(2):127–37. doi: 10.1016/s0304-3835(03)00159-9.Scotlandi K., Benini S., Sarti M., Serra M., Lollini P.L., Maurici D., Picci P., Manara M.C., Baldini N. Insulin-like growth factor I receptor-mediated circuit in Ewingʼs sarcoma/peripheral neuroectodermal tumor: a possible therapeutic target. Cancer Res 1996;56(20):4570–4. PMID: 8840962.Scotlandi K., Benini S., Sarti M., Serra M., Lollini P.L., Maurici D., Picci P., Manara M.C., Baldini N. Insulin-like growth factor I receptor-mediated circuit in Ewingʼs sarcoma/peripheral neuroectodermal tumor: a possible therapeutic target. Cancer Res 1996;56(20):4570–4. PMID: 8840962.Van Maldegem A.M., Bovée J.V., Peterse E.F., Hogendoorn P.C., Gelderblom H. Ewing sarcoma: The clinical relevance of the insulinlike growth factor 1 and the poly-ADP-ribose-polymerase pathway. Eur J Cancer 2016;53:171–80. doi: 10.1016/j.ejca.2015.09.009.Van Maldegem A.M., Bovée J.V., Peterse E.F., Hogendoorn P.C., Gelderblom H. Ewing sarcoma: The clinical relevance of the insulinlike growth factor 1 and the poly-ADP-ribose-polymerase pathway. Eur J Cancer 2016;53:171–80. doi: 10.1016/j.ejca.2015.09.009.Olmos D., Postel-Vinay S., Molife L.R., Okuno S.H., Schuetze S.M., Paccagnella M.L., Batzel G.N., Yin D., Pritchard-Jones K., Judson I., Worden F.P., Gualberto A., Scurr M., de Bono J.S., Haluska P. Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study. Lancet Oncol 2010;11(2):129–35. doi: 10.1016/S1470-2045(09)70354-7.Olmos D., Postel-Vinay S., Molife L.R., Okuno S.H., Schuetze S.M., Paccagnella M.L., Batzel G.N., Yin D., Pritchard-Jones K., Judson I., Worden F.P., Gualberto A., Scurr M., de Bono J.S., Haluska P. Safety, pharmacokinetics, and preliminary activity of the anti-IGF-1R antibody figitumumab (CP-751,871) in patients with sarcoma and Ewing's sarcoma: a phase 1 expansion cohort study. Lancet Oncol 2010;11(2):129–35. doi: 10.1016/S1470-2045(09)70354-7.Juergens H., Daw N.C., Geoerger B., Ferrari S., Villarroel M., Aerts I., Whelan J., Dirksen U., Hixon M.L., Yin D., Wang T., Green S., Paccagnella L., Gualberto A. Preliminary efficacy of the anti-insulinlike growth factor type 1 receptor antibody figitumumab in patients with refractory Ewing sarcoma. J Clin Oncol 2011;29(34):4534–40. doi: 10.1200/JCO.2010.33.0670.Juergens H., Daw N.C., Geoerger B., Ferrari S., Villarroel M., Aerts I., Whelan J., Dirksen U., Hixon M.L., Yin D., Wang T., Green S., Paccagnella L., Gualberto A. Preliminary efficacy of the anti-insulinlike growth factor type 1 receptor antibody figitumumab in patients with refractory Ewing sarcoma. J Clin Oncol 2011;29(34):4534–40. doi: 10.1200/JCO.2010.33.0670.Tap W.D., Demetri G., Barnette P., Desai J., Kavan P., Tozer R., Benedetto P.W., Friberg G., Deng H., McCaff ery I., Leitch I., Badola S., Chang S., Zhu M., Tolcher A. Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors. J Clin Oncol 2012;30(15):1849–56. doi: 10.1200/JCO.2011.37.2359.Tap W.D., Demetri G., Barnette P., Desai J., Kavan P., Tozer R., Benedetto P.W., Friberg G., Deng H., McCaff ery I., Leitch I., Badola S., Chang S., Zhu M., Tolcher A. Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic Ewing family tumors or desmoplastic small round cell tumors. J Clin Oncol 2012;30(15):1849–56. doi: 10.1200/JCO.2011.37.2359.Weigel B., Malempati S., Reid J.M., Voss S.D., Cho S.Y., Chen H.X., Krailo M., Villaluna D., Adamson P.C., Blaney S.M. Phase 2 trial of cixutumumab in children, adolescents, and young adults with refractory solid tumors: a report from the Childrenʼs Oncology Group. Pediatr Blood Cancer 2014;61(3):452–6. doi: 10.1002/pbc.24605.Weigel B., Malempati S., Reid J.M., Voss S.D., Cho S.Y., Chen H.X., Krailo M., Villaluna D., Adamson P.C., Blaney S.M. Phase 2 trial of cixutumumab in children, adolescents, and young adults with refractory solid tumors: a report from the Childrenʼs Oncology Group. Pediatr Blood Cancer 2014;61(3):452–6. doi: 10.1002/pbc.24605.Wagner L.M., Fouladi M., Ahmed A., Krailo M.D., Weigel B., DuBois S.G., Doyle L.A., Chen H., Blaney S.M. Phase II study of cixutumumab in combination with temsirolimus in pediatric patients and young adults with recurrent or refractory sarcoma: a report from the Childrenʼs Oncology Group. Pediatr Blood Cancer 2015;62(3):440–4. doi: 10.1002/pbc.25334.Wagner L.M., Fouladi M., Ahmed A., Krailo M.D., Weigel B., DuBois S.G., Doyle L.A., Chen H., Blaney S.M. Phase II study of cixutumumab in combination with temsirolimus in pediatric patients and young adults with recurrent or refractory sarcoma: a report from the Childrenʼs Oncology Group. Pediatr Blood Cancer 2015;62(3):440–4. doi: 10.1002/pbc.25334.Fleuren E.D., Versleijen-Jonkers Y.M., Boerman O.C., van der Graaf W.T. Targeting receptor tyrosine kinases in osteosarcoma and Ewing sarcoma: current hurdles and future perspectives. Biochim Biophys Acta 2014;1845(2):266–76. doi: 10.1016/j.bbcan.2014.02.005.Fleuren E.D., Versleijen-Jonkers Y.M., Boerman O.C., van der Graaf W.T. Targeting receptor tyrosine kinases in osteosarcoma and Ewing sarcoma: current hurdles and future perspectives. Biochim Biophys Acta 2014;1845(2):266–76. doi: 10.1016/j.bbcan.2014.02.005.Zwick E., Bange J., Ullrich A. Receptor tyrosine kinase signalling as a target for cancer intervention strategies. Endocr Relat Cancer 2001;8(3):161–73. doi: 10.1677/erc.0.0080161.Zwick E., Bange J., Ullrich A. Receptor tyrosine kinase signalling as a target for cancer intervention strategies. Endocr Relat Cancer 2001;8(3):161–73. doi: 10.1677/erc.0.0080161.Sulzbacher I., Birner P., Trieb K., Träxler M., Lang S., Chott A. Expression of platelet-derived growth factor-AA is associated with tumor progression in osteosarcoma. Mod Pathol 2003;16:66–71. doi: 10.1097/01.MP.0000043522.76788.0A.Sulzbacher I., Birner P., Trieb K., Träxler M., Lang S., Chott A. Expression of platelet-derived growth factor-AA is associated with tumor progression in osteosarcoma. Mod Pathol 2003;16:66–71. doi: 10.1097/01.MP.0000043522.76788.0A.Bozzi F., Tamborini E., Negri T., Pastore E., Ferrari A., Luksch R., Casanova M., Pierotti M.A., Bellani F.F., Pilotti S. Evidence for activation of KIT, PDGFRα, and PDGFRβ receptors in the Ewing sarcoma family of tumors. Cancer 2007;109:1638–45. doi: 10.1002/cncr.22587.Bozzi F., Tamborini E., Negri T., Pastore E., Ferrari A., Luksch R., Casanova M., Pierotti M.A., Bellani F.F., Pilotti S. Evidence for activation of KIT, PDGFRα, and PDGFRβ receptors in the Ewing sarcoma family of tumors. Cancer 2007;109:1638–45. doi: 10.1002/cncr.22587.Yu X.-W., Wu T.-Y., Yi X., Ren W.-P., Zhou Z.-B., Sun Y.-Q., Zhang C.-Q. Prognostic significance of VEGF expression in osteosarcoma: A meta-analysis. Tumour Biol 2014;35:155–60. doi: 10.1007/s13277-013-1019-1.Yu X.-W., Wu T.-Y., Yi X., Ren W.-P., Zhou Z.-B., Sun Y.-Q., Zhang C.-Q. Prognostic significance of VEGF expression in osteosarcoma: A meta-analysis. Tumour Biol 2014;35:155–60. doi: 10.1007/s13277-013-1019-1.Bailey K., Cost C., Davis I., Glade-Bender J., Grohar P., Houghton P., Isakoff M., Stewart E., Laack N., Yustein J., Reed D., Janeway K., Gorlick R., Lessnick S., DuBois S., Hingorani P. Emerging novel agents for patients with advanced Ewing sarcoma: a report from the Childrenʼs Oncology Group (COG) New Agents for Ewing Sarcoma Task Force. F1000Res 2019;8:F1000 Faculty Rev-493. doi: 10.12688/f1000research.18139.1.Bailey K., Cost C., Davis I., Glade-Bender J., Grohar P., Houghton P., Isakoff M., Stewart E., Laack N., Yustein J., Reed D., Janeway K., Gorlick R., Lessnick S., DuBois S., Hingorani P. Emerging novel agents for patients with advanced Ewing sarcoma: a report from the Childrenʼs Oncology Group (COG) New Agents for Ewing Sarcoma Task Force. F1000Res 2019;8:F1000 Faculty Rev-493. doi: 10.12688/f1000research.18139.1.Duff aud F., Mir O., Boudou-Rouquette P., Piperno-Neumann S., Penel N., Bompas E., Delcambre C., Kalbacher E., Italiano A., Collard O., Chevreau C., Saada E., Isambert N., Delaye J., Schiffler C., Bouvier C., Vidal V., Chabaud S., Blay J.Y.; French Sarcoma Group. 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. doi: 10.1016/S1470-2045(18)30742-3.Duff aud F., Mir O., Boudou-Rouquette P., Piperno-Neumann S., Penel N., Bompas E., Delcambre C., Kalbacher E., Italiano A., Collard O., Chevreau C., Saada E., Isambert N., Delaye J., Schiffler C., Bouvier C., Vidal V., Chabaud S., Blay J.Y.; French Sarcoma Group. 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. doi: 10.1016/S1470-2045(18)30742-3.Davis L.E., Bolejack V., Ryan C.W., Ganjoo K.N., Loggers E.T., Chawla S., Agulnik M., Livingston M.B., Reed D., Keedy V., Rushing D., Okuno S., Reinke D.K., Riedel R.F., Attia S., Mascarenhas L., Maki R.G. Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma. J Clin Oncol 2019;37(16):1424–31. doi: 10.1200/JCO.18.02374.Davis L.E., Bolejack V., Ryan C.W., Ganjoo K.N., Loggers E.T., Chawla S., Agulnik M., Livingston M.B., Reed D., Keedy V., Rushing D., Okuno S., Reinke D.K., Riedel R.F., Attia S., Mascarenhas L., Maki R.G. Randomized Double-Blind Phase II Study of Regorafenib in Patients With Metastatic Osteosarcoma. J Clin Oncol 2019;37(16):1424–31. doi: 10.1200/JCO.18.02374.Aggerholm-Pedersen N., Rossen P., Rose H., Safwat A. Pazopanib in the Treatment of Bone Sarcomas: Clinical Experience. Transl Oncol 2020;13(2):295–9. doi: 10.1016/j.tranon.2019.12.001.Aggerholm-Pedersen N., Rossen P., Rose H., Safwat A. Pazopanib in the Treatment of Bone Sarcomas: Clinical Experience. Transl Oncol 2020;13(2):295–9. doi: 10.1016/j.tranon.2019.12.001.Italiano A., Mir O., Mathoulin-Pelissier S., Penel N., PipernoNeumann S., Bompas E., Chevreau C., Duff aud F., Entz-Werlé N., Saada E., Ray-Coquard I., Lervat C., Gaspar N., Marec-Berard P., Pacquement H., Wright J., Toulmonde M., Bessede A., Crombe A., Kind M., Bellera C., Blay J.Y. Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2020;21(3):446–55. doi: 10.1016/S1470-2045(19)30825-3.Italiano A., Mir O., Mathoulin-Pelissier S., Penel N., PipernoNeumann S., Bompas E., Chevreau C., Duff aud F., Entz-Werlé N., Saada E., Ray-Coquard I., Lervat C., Gaspar N., Marec-Berard P., Pacquement H., Wright J., Toulmonde M., Bessede A., Crombe A., Kind M., Bellera C., Blay J.Y. Cabozantinib in patients with advanced Ewing sarcoma or osteosarcoma (CABONE): a multicentre, single-arm, phase 2 trial. Lancet Oncol 2020;21(3):446–55. doi: 10.1016/S1470-2045(19)30825-3.Nurmio M., Toppari J., Zaman F., Andersson A.M., Paranko J., Söder O., Jahnukainen K. Inhibition of tyrosine kinases PDGFR and C-Kit by imatinib mesylate interferes with postnatal testicular development in the rat. Int J Androl 2007;30(4):366–76; discussion 376. doi: 10.1111/j.1365-2605.2007.00755.x.Nurmio M., Toppari J., Zaman F., Andersson A.M., Paranko J., Söder O., Jahnukainen K. Inhibition of tyrosine kinases PDGFR and C-Kit by imatinib mesylate interferes with postnatal testicular development in the rat. Int J Androl 2007;30(4):366–76; discussion 376. doi: 10.1111/j.1365-2605.2007.00755.x.McGary E.C., Onn A., Mills L., Heimberger A., Eton O., Thomas G.W., Shtivelband M., Bar-Eli M. Imatinib mesylate inhibits platelet-derived growth factor receptor phosphorylation of melanoma cells but does not aff ect tumorigenicity in vivo. J Invest Dermatol 2004;122(2):400–5. doi: 10.1046/j.0022-202X.2004.22231.x.McGary E.C., Onn A., Mills L., Heimberger A., Eton O., Thomas G.W., Shtivelband M., Bar-Eli M. Imatinib mesylate inhibits platelet-derived growth factor receptor phosphorylation of melanoma cells but does not aff ect tumorigenicity in vivo. J Invest Dermatol 2004;122(2):400–5. doi: 10.1046/j.0022-202X.2004.22231.x.Bond M., Bernstein M.L., Pappo A., Schultz K.R., Krailo M., Blaney S.M., Adamson P.C. A phase II study of imatinib mesylate in children with refractory or relapsed solid tumors: A Children’s Oncology Group study. Pediatr. Blood Cancer 2008;50:254–8. doi: 10.1002/pbc.21132.Bond M., Bernstein M.L., Pappo A., Schultz K.R., Krailo M., Blaney S.M., Adamson P.C. A phase II study of imatinib mesylate in children with refractory or relapsed solid tumors: A Children’s Oncology Group study. Pediatr. Blood Cancer 2008;50:254–8. doi: 10.1002/pbc.21132.Grignani G., Palmerini E., Ferraresi V., D’Ambrosio L., Bertulli R., Asaftei S.D., Tamburini A., Pignochino Y., Sangiolo D., Marchesi E. Capozzi F., Biagini R., Gambarotti M., Fagioli F., Casali P.G., Picci P., Ferrari S., Aglietta M.; Italian Sarcoma Group. Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: A non-randomised phase 2 clinical trial. Lancet Oncol 2015;16:98–107. doi: 10.1016/S1470-2045(14)71136-2.Grignani G., Palmerini E., Ferraresi V., D’Ambrosio L., Bertulli R., Asaftei S.D., Tamburini A., Pignochino Y., Sangiolo D., Marchesi E. Capozzi F., Biagini R., Gambarotti M., Fagioli F., Casali P.G., Picci P., Ferrari S., Aglietta M.; Italian Sarcoma Group. Sorafenib and everolimus for patients with unresectable high-grade osteosarcoma progressing after standard treatment: A non-randomised phase 2 clinical trial. Lancet Oncol 2015;16:98–107. doi: 10.1016/S1470-2045(14)71136-2.Oldham S., Hafen E. Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control. Trends Cell Biol 2003;13(2):79–85. doi: 10.1016/s0962-8924(02)00042-9.Oldham S., Hafen E. Insulin/IGF and target of rapamycin signaling: a TOR de force in growth control. Trends Cell Biol 2003;13(2):79–85. doi: 10.1016/s0962-8924(02)00042-9.OʼReilly K.E., Rojo F., She Q.B., Solit D., Mills G.B., Smith D., Lane H., Hofmann F., Hicklin D.J., Ludwig D.L., Baselga J., Rosen N. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66(3):1500–8. doi: 10.1158/0008-5472.CAN-05-2925.OʼReilly K.E., Rojo F., She Q.B., Solit D., Mills G.B., Smith D., Lane H., Hofmann F., Hicklin D.J., Ludwig D.L., Baselga J., Rosen N. mTOR inhibition induces upstream receptor tyrosine kinase signaling and activates Akt. Cancer Res 2006;66(3):1500–8. doi: 10.1158/0008-5472.CAN-05-2925.Kurmasheva R.T., Dudkin L., Billups C., Debelenko L.V., Morton C.L., Houghton P.J. The insulin-like growth factor-1 receptor-targeting antibody, CP-751,871, suppresses tumor-derived VEGF and synergizes with rapamycin in models of childhood sarcoma. Cancer Res 2009;69(19):7662–71. doi: 10.1158/0008-5472.CAN-09-1693.Kurmasheva R.T., Dudkin L., Billups C., Debelenko L.V., Morton C.L., Houghton P.J. The insulin-like growth factor-1 receptor-targeting antibody, CP-751,871, suppresses tumor-derived VEGF and synergizes with rapamycin in models of childhood sarcoma. Cancer Res 2009;69(19):7662–71. doi: 10.1158/0008-5472.CAN-09-1693.Naing A., LoRusso P., Fu S., Hong D.S., Anderson P., Benjamin R.S., Ludwig J., Chen H.X., Doyle L.A., Kurzrock R. Insulin growth factorreceptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewingʼs sarcoma family tumors. Clin Cancer Res 2012;18(9):2625–31. doi: 10.1158/1078-0432.CCR-12-0061.Naing A., LoRusso P., Fu S., Hong D.S., Anderson P., Benjamin R.S., Ludwig J., Chen H.X., Doyle L.A., Kurzrock R. Insulin growth factorreceptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewingʼs sarcoma family tumors. Clin Cancer Res 2012;18(9):2625–31. doi: 10.1158/1078-0432.CCR-12-0061.Schwartz G.K., Tap W.D., Qin L.X., Livingston M.B., Undevia S.D., Chmielowski B., Agulnik M., Schuetze S.M., Reed D.R., Okuno S.H., Ludwig J.A., Keedy V., Rietschel P., Kraft A.S., Adkins D., Van Tine B.A., Brockstein B., Yim V., Bitas C., Abdullah A., Antonescu C.R., Condy M., Dickson M.A., Vasudeva S.D., Ho A.L., Doyle L.A., Chen H.X., Maki R.G. Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial. Lancet Oncol 2013;14(4):371–82. doi: 10.1016/S1470-2045(13)70049-4.Schwartz G.K., Tap W.D., Qin L.X., Livingston M.B., Undevia S.D., Chmielowski B., Agulnik M., Schuetze S.M., Reed D.R., Okuno S.H., Ludwig J.A., Keedy V., Rietschel P., Kraft A.S., Adkins D., Van Tine B.A., Brockstein B., Yim V., Bitas C., Abdullah A., Antonescu C.R., Condy M., Dickson M.A., Vasudeva S.D., Ho A.L., Doyle L.A., Chen H.X., Maki R.G. Cixutumumab and temsirolimus for patients with bone and soft-tissue sarcoma: a multicentre, open-label, phase 2 trial. Lancet Oncol 2013;14(4):371–82. doi: 10.1016/S1470-2045(13)70049-4.Okouneva T., Azarenko O., Wilson L., Littlefield B.A., Jordan M.A. Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase. Mol Cancer Ther 2008;7(7):2003–11. doi: 10.1158/1535-7163.MCT-08-0095.Okouneva T., Azarenko O., Wilson L., Littlefield B.A., Jordan M.A. Inhibition of centromere dynamics by eribulin (E7389) during mitotic metaphase. Mol Cancer Ther 2008;7(7):2003–11. doi: 10.1158/1535-7163.MCT-08-0095.Kolb E.A., Gorlick R., Reynolds C.P., Kang M.H., Carol H., Lock R., Keir S.T., Maris J.M., Billups C.A., Desjardins C., Kurmasheva R.T., Houghton P.J., Smith M.A. Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program. Pediatr Blood Cancer 2013;60(8):1325–32. doi: 10.1002/pbc.24517.Kolb E.A., Gorlick R., Reynolds C.P., Kang M.H., Carol H., Lock R., Keir S.T., Maris J.M., Billups C.A., Desjardins C., Kurmasheva R.T., Houghton P.J., Smith M.A. Initial testing (stage 1) of eribulin, a novel tubulin binding agent, by the pediatric preclinical testing program. Pediatr Blood Cancer 2013;60(8):1325–32. doi: 10.1002/pbc.24517.Schafer E.S., Rau R.E., Berg S., Liu X., Minard C.G., DʼAdamo D., Scott R., Reyderman L., Martinez G., Devarajan S., Reid J.M., Fox E., Weigel B.J., Blaney S.M. A phase 1 study of eribulin mesylate (E7389), a novel microtubule-targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors: A Childrenʼs Oncology Group Phase 1 Consortium study (ADVL1314). Pediatr Blood Cancer 2018;65(8):e27066. doi: 10.1002/pbc.27066.Schafer E.S., Rau R.E., Berg S., Liu X., Minard C.G., DʼAdamo D., Scott R., Reyderman L., Martinez G., Devarajan S., Reid J.M., Fox E., Weigel B.J., Blaney S.M. A phase 1 study of eribulin mesylate (E7389), a novel microtubule-targeting chemotherapeutic agent, in children with refractory or recurrent solid tumors: A Childrenʼs Oncology Group Phase 1 Consortium study (ADVL1314). Pediatr Blood Cancer 2018;65(8):e27066. doi: 10.1002/pbc.27066.Schettini F., De Santo I., Rea C.G., De Placido P., Formisano L., Giuliano M., Arpino G., De Laurentiis M., Puglisi F., De Placido S., Del Mastro L. CDK 4/6 Inhibitors as Single Agent in Advanced Solid Tumors. Front Oncol 2018;8:608. doi: 10.3389/fonc.2018.00608.Schettini F., De Santo I., Rea C.G., De Placido P., Formisano L., Giuliano M., Arpino G., De Laurentiis M., Puglisi F., De Placido S., Del Mastro L. CDK 4/6 Inhibitors as Single Agent in Advanced Solid Tumors. Front Oncol 2018;8:608. doi: 10.3389/fonc.2018.00608.Kennedy A.L., Vallurupalli M., Chen L., Crompton B., Cowley G., Vazquez F., Weir B.A., Tsherniak A., Parasuraman S., Kim S., Alexe G., Stegmaier K. Functional, chemical genomic, and superenhancer screening identify sensitivity to cyclin D1/CDK4 pathway inhibition in Ewing sarcoma. Oncotarget 2015;6(30):30178–93. doi: 10.18632/oncotarget.4903.Kennedy A.L., Vallurupalli M., Chen L., Crompton B., Cowley G., Vazquez F., Weir B.A., Tsherniak A., Parasuraman S., Kim S., Alexe G., Stegmaier K. Functional, chemical genomic, and superenhancer screening identify sensitivity to cyclin D1/CDK4 pathway inhibition in Ewing sarcoma. Oncotarget 2015;6(30):30178–93. doi: 10.18632/oncotarget.4903.Serrano M., Hannon G.J., Beach D. A new regulatory motif in cellcycle control causing specific inhibition of cyclin D/CDK4. Nature 1993;366(6456):704–7. doi: 10.1038/366704a0.Serrano M., Hannon G.J., Beach D. A new regulatory motif in cellcycle control causing specific inhibition of cyclin D/CDK4. Nature 1993;366(6456):704–7. doi: 10.1038/366704a0.

The authors declare that there are no conflicts of interest present.