Mechanisms of Resistance to Conventional Therapies for Osteosarcoma

Cancers - Tập 13 Số 4 - Trang 683
Louise Marchandet1, Morgane Lallier1, Céline Charrier1, Marc Baud’huin2,1, Benjamin Ory1, François Lamoureux1
1UMR1238, Phy-OS, Sarcomes Osseux et Remodelage des Tissus Calcifiés, INSERM, Université de Nantes, 44035 Nantes, France
2CHU de Nantes, 44035 Nantes, France

Tóm tắt

Osteosarcoma (OS) is the most common primary bone tumor, mainly occurring in children and adolescents. Current standard therapy includes tumor resection associated with multidrug chemotherapy. However, patient survival has not evolved for the past decades. Since the 1970s, the 5-year survival rate is around 75% for patients with localized OS but dramatically drops to 20% for bad responders to chemotherapy or patients with metastases. Resistance is one of the biological processes at the origin of therapeutic failure. Therefore, it is necessary to better understand and decipher molecular mechanisms of resistance to conventional chemotherapy in order to develop new strategies and to adapt treatments for patients, thus improving the survival rate. This review will describe most of the molecular mechanisms involved in OS chemoresistance, such as a decrease in intracellular accumulation of drugs, inactivation of drugs, improved DNA repair, modulations of signaling pathways, resistance linked to autophagy, disruption in genes expression linked to the cell cycle, or even implication of the micro-environment. We will also give an overview of potential therapeutic strategies to circumvent resistance development.

Từ khóa


Tài liệu tham khảo

Lamoureux, 2007, Recent advances in the management of osteosarcoma and forthcoming therapeutic strategies, Expert Rev. Anticancer Ther., 7, 169, 10.1586/14737140.7.2.169

He, 2014, Review of the Molecular Pathogenesis of Osteosarcoma, Asian Pac. J. Cancer Prev., 15, 5967, 10.7314/APJCP.2014.15.15.5967

Marina, 2004, Biology and Therapeutic Advances for Pediatric Osteosarcoma, Oncologist, 9, 422, 10.1634/theoncologist.9-4-422

Sandberg, 2003, Updates on the cytogenetics and molecular genetics of bone and soft tissue tumors: Osteosarcoma and related tumors, Cancer Genet. Cytogenet., 145, 1, 10.1016/S0165-4608(03)00105-5

Klein, 2006, Osteosarcoma: Anatomic and histologic variants, Am. J. Clin. Pathol., 125, 555, 10.1309/UC6KQHLD9LV2KENN

Isakoff, 2015, Osteosarcoma: Current Treatment and a Collaborative Pathway to Success, J. Clin. Oncol., 33, 3029, 10.1200/JCO.2014.59.4895

Rejniak, 2015, Diagnostic assessment of osteosarcoma chemoresistance based on Virtual Clinical Trials, Med. Hypotheses, 85, 348, 10.1016/j.mehy.2015.06.015

ESMO/European Sarcoma Network Working Group (2014). Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann. Oncol., 25, iii113–iii123.

Chen, 2020, Advances in differentiation therapy for osteosarcoma, Drug Discov. Today, 25, 497, 10.1016/j.drudis.2019.08.010

Anderson, 2003, Effectiveness of Radiotherapy for Osteosarcoma that Responds to Chemotherapy, Mayo Clin. Proc., 78, 145, 10.4065/78.2.145

Schwarz, 2009, The Role of Radiotherapy in Oseosarcoma, Cancer Treat. Res., 152, 147, 10.1007/978-1-4419-0284-9_7

Cubedo, 2010, Treatment of Osteosarcoma. A Review, Rev. Esp. Cir. Ortop. Traumatol., 54, 329

Saraf, 2018, Osteosarcoma: Accelerating Progress Makes for a Hopeful Future, Front. Oncol., 8, 4, 10.3389/fonc.2018.00004

Ferrari, 2007, Adjuvant and neoadjuvant combination chemotherapy for osteogenic sarcoma, Curr. Opin. Oncol., 19, 341, 10.1097/CCO.0b013e328122d73f

Mialou, 2005, Metastatic osteosarcoma at diagnosis: Prognostic factors and long-term outcom—The French pediatric experience, Cancer, 104, 1100, 10.1002/cncr.21263

Ottaviani, 2009, Functional, Psychosocial and Professional Outcomes in Long-Term Survivors of Lower-Extremity Osteosarcomas: Amputation Versus Limb Salvage, Cancer Treat. Res., 152, 421, 10.1007/978-1-4419-0284-9_23

Rosen, 1975, The rationale for multiple drug chemotherapy in the treatment of osteogenic sarcoma, Cancer, 35, 936, 10.1002/1097-0142(197503)35:3+<936::AID-CNCR2820350714>3.0.CO;2-B

Goorin, 2003, Presurgical Chemotherapy Compared with Immediate Surgery and Adjuvant Chemotherapy for Nonmetastatic Osteosarcoma: Pediatric Oncology Group Study POG-8651, J. Clin. Oncol., 21, 1574, 10.1200/JCO.2003.08.165

Wittig, 2002, Osteosarcoma: A multidisciplinary approach to diagnosis and treatment, Am. Fam. Physician, 65, 1123

Ando, 2013, Current Therapeutic Strategies and Novel Approaches in Osteosarcoma, Cancers, 5, 591, 10.3390/cancers5020591

Bielack, 2008, Bone Tumors in Adolescents and Young Adults, Curr. Treat. Options Oncol., 9, 67, 10.1007/s11864-008-0057-1

Holohan, 2013, Cancer drug resistance: An evolving paradigm, Nat. Rev. Cancer, 13, 714, 10.1038/nrc3599

Lippert, 2008, Intrinsic and Acquired Drug Resistance in Malignant Tumors. The main reason for therapeutic failure, Arzneimittelforschung, 58, 261

Wang, X. (2020, May 07). Drug Resistance and Combating Drug Resistance in Cancer. Available online: https://cdrjournal.com/article/view/3039.

Chou, 2006, Chemotherapy resistance in osteosarcoma: Current challenges and future directions, Expert Rev. Anticancer Ther., 6, 1075, 10.1586/14737140.6.7.1075

Lewis, 2007, Improvement in Histologic Response But Not Survival in Osteosarcoma Patients Treated With Intensified Chemotherapy: A Randomized Phase III Trial of the European Osteosarcoma Intergroup, J. Natl. Cancer Inst., 99, 112, 10.1093/jnci/djk015

Royen, 2013, Mechanisms of therapy resistance in osteosarcoma: A review, Oncol. Discov., 1, 8, 10.7243/2052-6199-1-8

Fotoohi, 2008, Mechanisms of antifolate resistance and methotrexate efficacy in leukemia cells, Leuk. Lymphoma, 49, 410, 10.1080/10428190701824569

He, 2014, Molecular mechanisms of chemoresistance in osteosarcoma (Review), Oncol. Lett., 7, 1352, 10.3892/ol.2014.1935

Takemura, 1997, Cellular and molecular mechanisms of resistance to antifolate drugs: New analogues and approaches to overcome the resistance, Int. J. Hematol., 66, 459, 10.1016/S0925-5710(97)00058-3

Jensen, 1997, Distinct roles for Sp1 and E2F sites in the growth/cell cycle regulation of the DHFR promoter, J. Cell. Biochem., 67, 24, 10.1002/(SICI)1097-4644(19971001)67:1<24::AID-JCB3>3.0.CO;2-Y

Goldman, 1985, The cellular pharmacology of methotrexate, Pharmacol. Ther., 28, 77, 10.1016/0163-7258(85)90083-X

Bertino, 1996, Resistance Mechanisms to Methotrexate in Tumors, Oncologist, 1, 223, 10.1634/theoncologist.1-4-223

Moscow, 1998, Methotrexate transport and resistance, Leuk. Lymphoma, 30, 215, 10.3109/10428199809057535

Bertino, 1993, Karnofsky memorial lecture. Ode to methotrexate, J. Clin. Oncol., 11, 5, 10.1200/JCO.1993.11.1.5

Wang, 2014, Relationship between RFC gene expression and intracellular drug concentration in methotrexate-resistant osteosarcoma cells, Genet. Mol. Res., 13, 5313, 10.4238/2014.July.24.10

Hattinger, 2003, Genomic imbalances associated with methotrexate resistance in human osteosarcoma cell lines detected by comparative genomic hybridization-based techniques, Eur. J. Cell Biol., 82, 483, 10.1078/0171-9335-00336

Flintoff, 2004, Functional analysis of altered reduced folate carrier sequence changes identified in osteosarcomas, Biochim. Biophys. Acta Mol. Basis Dis., 1690, 110, 10.1016/j.bbadis.2004.05.008

Ifergan, 2003, Reduced folate carrier protein expression in osteosarcoma, Cancer, 98, 1958, 10.1002/cncr.11741

Yang, 2003, Sequence alterations in the reduced folate carrier are observed in osteosarcoma tumor samples, Clin. Cancer Res., 9, 837

Serra, 2004, Analysis of dihydrofolate reductase and reduced folate carrier gene status in relation to methotrexate resistance in osteosarcoma cells, Ann. Oncol., 15, 151, 10.1093/annonc/mdh004

Yang, 2008, Polymorphisms and Methylation of the Reduced Folate Carrier in Osteosarcoma, Clin. Orthop. Relat. Res., 466, 2046, 10.1007/s11999-008-0323-3

Lilienthal, I., and Herold, N. (2020). Targeting Molecular Mechanisms Underlying Treatment Efficacy and Resistance in Osteosarcoma: A Review of Current and Future Strategies. Int. J. Mol. Sci., 21.

Memorial Sloan Kettering Cancer Center (2020, December 15). Phase I Study of High Dose Methotrexate with Simultaneous Trimetrexate and Leucovorin in Patients with Recurrent Osteosarcoma. Report No.: NCT00119301, Available online: https://clinicaltrials.gov/ct2/show/NCT00119301.

Sirotnak, 1984, New folate analogs of the 10-deaza-aminopterin series Basis for structural design and biochemical and pharmacologic properties, Cancer Chemother. Pharmacol., 12, 18

Pro, 2011, Pralatrexate in Patients With Relapsed or Refractory Peripheral T-Cell Lymphoma: Results From the Pivotal PROPEL Study, J. Clin. Oncol., 29, 1182, 10.1200/JCO.2010.29.9024

Alberts, 2004, Efficacy and safety of liposomal anthracyclines in Phase I/II clinical trials, Semin. Oncol., 31, 53, 10.1053/j.seminoncol.2004.08.010

Gorlick, 2009, Novel therapeutic agents for osteosarcoma, Expert Rev. Anticancer Ther., 9, 511, 10.1586/era.09.7

Krishna, 2000, Multidrug resistance (MDR) in cancer. Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs, Eur. J. Pharm. Sci., 11, 265, 10.1016/S0928-0987(00)00114-7

Choi, 2005, ABC transporters as multidrug resistance mechanisms and the development of chemosensitizers for their reversal, Cancer Cell Int., 5, 30, 10.1186/1475-2867-5-30

Chen, 2016, Mammalian drug efflux transporters of the ATP binding cassette (ABC) family in multidrug resistance: A review of the past decade, Cancer Lett., 370, 153, 10.1016/j.canlet.2015.10.010

Amawi, 2019, ABC Transporter-Mediated Multidrug-Resistant Cancer, Adv. Exp. Med. Biol., 1141, 549, 10.1007/978-981-13-7647-4_12

Riordan, 1979, Purification of P-glycoprotein from plasma membrane vesicles of Chinese hamster ovary cell mutants with reduced colchicine permeability, J. Biol. Chem., 254, 12701, 10.1016/S0021-9258(19)86370-6

Li, 2015, Research progress on the multidrug resistance mechanisms of osteosarcoma chemotherapy and reversal, Tumor Biol., 36, 1329, 10.1007/s13277-015-3181-0

Robey, 2018, Revisiting the role of efflux pumps in multidrug-resistant cancer, Nat. Rev. Cancer, 18, 452, 10.1038/s41568-018-0005-8

Schinkel, 2003, Mammalian drug efflux transporters of the ATP binding cassette (ABC) family: An overview, Adv. Drug Deliv. Rev., 55, 3, 10.1016/S0169-409X(02)00169-2

Kartner, 1983, Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines, Science, 221, 1285, 10.1126/science.6137059

Scotlandi, 1994, Pre-Treatment of human osteosarcoma cells with N-methylformamide enhances P-glycoprotein expression and resistance to doxorubicin, Int. J. Cancer, 58, 95, 10.1002/ijc.2910580116

Gomes, 2006, Multidrug resistance mediated by ABC transporters in osteosarcoma cell lines: mRNA analysis and functional radiotracer studies, Nucl. Med. Biol., 33, 831, 10.1016/j.nucmedbio.2006.07.011

Oda, 2000, Establishment of new multidrug-resistant human osteosarcoma cell lines, Oncol. Rep., 7, 859

Serra, 2006, 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

Hornicek, 2000, P-Glycoprotein Levels Predict Poor Outcome in Patients With Osteosarcoma, Clin. Orthop. Relat. Res., 373, 11, 10.1097/00003086-200004000-00003

Chan, 1997, P-glycoprotein Expression: Critical Determinant in the Response to Osteosarcoma Chemotherapy, J. Natl. Cancer Inst., 89, 1706, 10.1093/jnci/89.22.1706

Baldini, 1995, Expression of P-Glycoprotein in High-Grade Osteosarcomas in Relation to Clinical Outcome, N. Engl. J. Med., 333, 1380, 10.1056/NEJM199511233332103

Baldini, 1999, P-glycoprotein expression in osteosarcoma: A basis for risk-adapted adjuvant chemotherapy, J. Orthop. Res., 17, 629, 10.1002/jor.1100170502

Serra, 2003, Value of P-Glycoprotein and Clinicopathologic Factors as the Basis for New Treatment Strategies in High-Grade Osteosarcoma of the Extremities, J. Clin. Oncol., 21, 536, 10.1200/JCO.2003.03.144

Caronia, D., Patiño-Garcia, A., Peréz-Martínez, A., Pita, G., Moreno, L.T., Zalacain-Díez, M., Molina, B., Colmenero, I., Sierrasesúmaga, L., and Benítez, J.F. (2011). Effect of ABCB1 and ABCC3 Polymorphisms on Osteosarcoma Survival after Chemotherapy: A Pharmacogenetic Study. PLoS ONE, 6.

Park, 2001, The co-expression of p53 protein and P-glycoprotein is correlated to a poor prognosis in osteosarcoma, Int. Orthop., 24, 307, 10.1007/s002640000196

Serra, 1999, Relationship between P-glycoprotein expression and p53 status in high-grade osteosarcoma, Int. J. Oncol., 14, 301

Jensen, 2008, Immunohistochemical Estimates of Angiogenesis, Proliferative Activity, p53 Expression, and Multiple Drug Resistance Have No Prognostic Impact in Osteosarcoma: A Comparative Clinicopathological Investigation, Sarcoma, 2008, 1, 10.1155/2008/874075

Gorlick, 1999, Expression of HER2/erbB-2 Correlates With Survival in Osteosarcoma, J. Clin. Oncol., 17, 2781, 10.1200/JCO.1999.17.9.2781

Kumta, 2001, Clinical significance of P-glycoprotein immunohistochemistry and doxorubicin binding assay in patients with osteosarcoma, Int. Orthop., 25, 279, 10.1007/s002640100273

Pakos, 2003, The association of P-glycoprotein with response to chemotherapy and clinical outcome in patients with osteosarcoma. A meta-analysis, Cancer, 98, 581, 10.1002/cncr.11546

Zhao, 2014, Association between P-Glycoprotein expression and response to chemotherapy in patients with osteosarcoma: A systematic and meta-analysis, J. Cancer Res. Ther., 10, 206, 10.4103/0973-1482.145874

Schwartz, 2007, Multiple Drug Resistance in Osteogenic Sarcoma: INT0133 from the Children’s Oncology Group, J. Clin. Oncol., 25, 2057, 10.1200/JCO.2006.07.7776

Brambilla, 2011, P-glycoprotein binds to ezrin at amino acid residues 149–242 in the FERM domain and plays a key role in the multidrug resistance of human osteosarcoma, Int. J. Cancer, 130, 2824, 10.1002/ijc.26285

Khanna, 2004, The membrane-cytoskeleton linker ezrin is necessary for osteosarcoma metastasis, Nat. Med., 10, 182, 10.1038/nm982

Yang, 2014, Prevention of multidrug resistance (MDR) in osteosarcoma by NSC23925, Br. J. Cancer, 110, 2896, 10.1038/bjc.2014.254

Lu, 2017, Tetrandrine prevents multidrug resistance in the osteosarcoma cell line, U-2OS, by preventing Pgp overexpression through the inhibition of NF-κB signaling, Int. J. Mol. Med., 39, 993, 10.3892/ijmm.2017.2895

Wu, 2017, Pleiotrophin promotes chemoresistance to doxorubicin in osteosarcoma by upregulating P-glycoprotein, Oncotarget, 8, 63857, 10.18632/oncotarget.19148

Liu, 2016, Targeting ABCB1 (MDR1) in multi-drug resistant osteosarcoma cells using the CRISPR-Cas9 system to reverse drug resistance, Oncotarget, 7, 83502, 10.18632/oncotarget.13148

Fanelli, 2016, Targeting ABCB1 and ABCC1 with their Specific Inhibitor CBT-1® can Overcome Drug Resistance in Osteosarcoma, Curr. Cancer Drug Targets, 16, 261, 10.2174/1568009616666151106120434

Jin, 2000, Ecteinascidin 743, a transcription-targeted chemotherapeutic that inhibits MDR1 activation, Proc. Natl. Acad. Sci. USA, 97, 6775, 10.1073/pnas.97.12.6775

Lee, 2017, DHFR and MDR1 upregulation is associated with chemoresistance in osteosarcoma stem-like cells, Oncol. Lett., 14, 171, 10.3892/ol.2017.6132

Marques da Costa, M.E., Marchais, A., Gomez-Brouchet, A., Job, B., Assoun, N., Daudigeos-Dubus, E., Fromigué, O., Santos, C., Geoerger, B., and Gaspar, N. (2019). In-Vitro and In-Vivo Establishment and Characterization of Bioluminescent Orthotopic Chemotherapy-Resistant Human Osteosarcoma Models in NSG Mice. Cancers, 11.

Li, 1995, Lack of functional retinoblastoma protein mediates increased resistance to antimetabolites in human sarcoma cell lines, Proc. Natl. Acad. Sci. USA, 92, 10436, 10.1073/pnas.92.22.10436

Sowers, 2003, mRNA expression levels of E2F transcription factors correlate with dihydrofolate reductase, reduced folate carrier, and thymidylate synthase mRNA expression in osteosarcoma, Mol. Cancer Ther., 2, 535

Hattinger, 2008, Mechanisms of gene amplification and evidence of coamplification in drug-resistant human osteosarcoma cell lines, Genes Chromosom. Cancer, 48, 289, 10.1002/gcc.20640

Song, 2010, Molecular mechanism of chemoresistance by miR-215 in osteosarcoma and colon cancer cells, Mol. Cancer, 9, 96, 10.1186/1476-4598-9-96

Bodley, 1989, DNA topoisomerase II-mediated interaction of doxorubicin and daunorubicin congeners with DNA, Cancer Res., 49, 5969

Minotti, 2004, Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity, Pharmacol. Rev., 56, 185, 10.1124/pr.56.2.6

Rajkumar, 2008, Multiple pathways are involved in drug resistance to doxorubicin in an osteosarcoma cell line, Anti Cancer Drugs, 19, 257, 10.1097/CAD.0b013e3282f435b6

Yang, 2016, Characterization of multidrug-resistant osteosarcoma sublines and the molecular mechanisms of resistance, Mol. Med. Rep., 14, 3269, 10.3892/mmr.2016.5590

Conklin, 2004, Chemotherapy-Associated Oxidative Stress: Impact on Chemotherapeutic Effectiveness, Integr. Cancer Ther., 3, 294, 10.1177/1534735404270335

Townsend, 2003, The importance of glutathione in human disease, Biomed. Pharmacother., 57, 145, 10.1016/S0753-3322(03)00043-X

Siddik, 2003, Cisplatin: Mode of cytotoxic action and molecular basis of resistance, Oncogene, 22, 7265, 10.1038/sj.onc.1206933

Kelland, 2000, Preclinical perspectives on platinum resistance, Drugs, 59, 1, 10.2165/00003495-200059004-00001

Goto, 2001, A novel single-nucleotide polymorphism in the 3′-untranslated region of the human dihydrofolate reductase gene with enhanced expression, Clin. Cancer Res., 7, 1952

Tew, 1996, Glutathione-associated enzymes in the human cell lines of the National Cancer Institute Drug Screening Program, Mol. Pharmacol., 50, 149

Tew, 1994, Glutathione-associated enzymes in anticancer drug resistance, Cancer Res., 54, 4313

Townsend, 2003, The role of glutathione-S-transferase in anti-cancer drug resistance, Oncogene, 22, 7369, 10.1038/sj.onc.1206940

Masanek, 1997, Messenger RNA expression of resistance proteins and related factors in human ovarian carcinoma cell lines resistant to doxorubicin, taxol and cisplatin, Anti Cancer Drugs, 8, 189, 10.1097/00001813-199702000-00010

Ban, 1996, Transfection of glutathione S-transferase (GST)-pi antisense complementary DNA increases the sensitivity of a colon cancer cell line to adriamycin, cisplatin, melphalan, and etoposide, Cancer Res., 56, 3577

Batist, 1986, Overexpression of a novel anionic glutathione transferase in multidrug-resistant human breast cancer cells, J. Biol. Chem., 261, 15544, 10.1016/S0021-9258(18)66748-1

Bai, 1996, Immunohistochemical expression of glutathione S-transferase-Pi can predict chemotherapy response in patients with nonsmall cell lung carcinoma, Cancer, 78, 416, 10.1002/(SICI)1097-0142(19960801)78:3<416::AID-CNCR6>3.0.CO;2-H

Pasello, 2008, Overcoming Glutathione S-Transferase P1–Related Cisplatin Resistance in Osteosarcoma, Cancer Res., 68, 6661, 10.1158/0008-5472.CAN-07-5840

Wei, 2006, Expression of MDR1 and GST-pi in osteosarcoma and soft tissue sarcoma and their correlation with chemotherapy resistance, Zhonghua Zhong Liu Za Zhi Chin. J. Oncol., 28, 445

Huang, 2007, Expression of human glutathione S-transferase P1 mediates the chemosensitivity of osteosarcoma cells, Mol. Cancer Ther., 6, 1610, 10.1158/1535-7163.MCT-06-0580

Komiya, 1998, Role of glutathione in cisplatin resistance in osteosarcoma cell lines, J. Orthop. Res., 16, 15, 10.1002/jor.1100160104

Shoieb, 1998, In vitro reversal of glutathione-S-transferase-mediated resistance in canine osteosarcoma (COS31) cells, In Vivo, 12, 455

Shoieb, 1997, Detection and significance of glutathione-S-transferase pi in osteogenic tumors of dogs, Int. J. Oncol., 10, 635

Bruheim, 2004, Human osteosarcoma xenografts and their sensitivity to chemotherapy, Pathol. Oncol. Res., 10, 133, 10.1007/BF03033741

Uozaki, 1997, Overexpression of resistance-related proteins (metallothioneins, glutathione-S-transferase pi, heat shock protein 27, and lung resistance-related protein) in osteosarcoma. Relationship with poor prognosis, Cancer, 79, 2336, 10.1002/(SICI)1097-0142(19970615)79:12<2336::AID-CNCR7>3.0.CO;2-J

Windsor, 2011, Germline genetic polymorphisms may influence chemotherapy response and disease outcome in osteosarcoma, Cancer, 118, 1856, 10.1002/cncr.26472

Zhang, 2012, Predictive Potential of Glutathione S-Transferase Polymorphisms for Prognosis of Osteosarcoma Patients on Chemotherapy, Asian Pac. J. Cancer Prev., 13, 2705, 10.7314/APJCP.2012.13.6.2705

Yang, 2012, Glutathione S-transferase P1 and DNA polymorphisms influence response to chemotherapy and prognosis of bone tumors, Asian Pac. J. Cancer Prev., 13, 5883, 10.7314/APJCP.2012.13.11.5883

Wang, 2014, The association of glutathione S-transferase polymorphisms in patients with osteosarcoma: Evidence from a meta-analysis, Eur. J. Cancer Care, 24, 417, 10.1111/ecc.12197

Liu, 2014, Predictive potential of ABCB1, ABCC3, and GSTP1 gene polymorphisms on osteosarcoma survival after chemotherapy, Tumor Biol., 35, 9897, 10.1007/s13277-014-1917-x

Petrilli, 2010, Glutathione S-transferase polymorphisms in osteosarcoma patients, Pharmacogenet. Genom., 20, 507, 10.1097/FPC.0b013e32833caa45

Yin, 2000, Glutathione S-transferase p elicits protection against H2O2-induced cell death via coordinated regulation of stress kinases, Cancer Res., 60, 4053

Adler, 1999, Regulation of JNK signaling by GSTp, EMBO J., 18, 1321, 10.1093/emboj/18.5.1321

Lu, 2004, Dual effects of glutathione-S-transferase pi on As2O3 action in prostate cancer cells: Enhancement of growth inhibition and inhibition of apoptosis, Oncogene, 23, 3945, 10.1038/sj.onc.1207500

Pasello, 2011, Targeting glutathione-S transferase enzymes in musculoskeletal sarcomas: A promising therapeutic strategy, Anal. Cell. Pathol., 34, 131, 10.1155/2011/414985

Sau, 2012, Targeting GSTP1-1 induces JNK activation and leads to apoptosis in cisplatin-sensitive and -resistant human osteosarcoma cell lines, Mol. BioSyst., 8, 994, 10.1039/C1MB05295K

Chatterjee, 2017, Mechanisms of DNA damage, repair, and mutagenesis, Environ. Mol. Mutagen., 58, 235, 10.1002/em.22087

Fanelli, 2020, Cisplatin Resistance in Osteosarcoma: In vitro Validation of Candidate DNA Repair-Related Therapeutic Targets and Drugs for Tailored Treatments, Front. Oncol., 10, 331, 10.3389/fonc.2020.00331

Fishel, 2007, The DNA base excision repair protein Ape1/Ref-1 as a therapeutic and chemopreventive target, Mol. Asp. Med., 28, 375, 10.1016/j.mam.2007.04.005

Wang, 2004, Human apurinic endonuclease 1 (APE1) expression and prognostic significance in osteosarcoma: Enhanced sensitivity of osteosarcoma to DNA damaging agents using silencing RNA APE1 expression inhibition, Mol. Cancer Ther., 3, 679, 10.1158/1535-7163.679.3.6

Yang, 2010, APEX1 Gene Amplification and Its Protein Overexpression in Osteosarcoma: Correlation with Recurrence, Metastasis, and Survival, Technol. Cancer Res. Treat., 9, 161, 10.1177/153303461000900205

Yang, 2005, Alterations in the expression of the apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1) in human melanoma and identification of the therapeutic potential of resveratrol as an APE/Ref-1 inhibitor, Mol. Cancer Ther., 4, 1923, 10.1158/1535-7163.MCT-05-0229

Luo, 2004, Inhibition of the human apurinic/apyrimidinic endonuclease (APE1) repair activity and sensitization of breast cancer cells to DNA alkylating agents with lucanthone, Anticancer Res., 24, 2127

Madhusudan, 2005, Isolation of a small molecule inhibitor of DNA base excision repair, Nucleic Acids Res., 33, 4711, 10.1093/nar/gki781

Seiple, 2007, Potent Inhibition of Human Apurinic/Apyrimidinic Endonuclease 1 by Arylstibonic Acids, Mol. Pharmacol., 73, 669, 10.1124/mol.107.042622

Dai, 2016, miR-513a-5p regulates radiosensitivity of osteosarcoma by targeting human apurinic/apyrimidinic endonuclease, Oncotarget, 9, 25414, 10.18632/oncotarget.11003

Liang, 2019, MicroRNA-765 sensitizes osteosarcoma cells to cisplatin via downregulating APE1 expression, OncoTargets Ther., 12, 7203, 10.2147/OTT.S194800

Wang, 2007, Vector-based Ape1 small interfering RNA enhances the sensitivity of human osteosarcoma cells to endostatin in vivo, Cancer Sci., 98, 1993, 10.1111/j.1349-7006.2007.00616.x

Park, 2018, The PARP inhibitor olaparib potentiates the effect of the DNA damaging agent doxorubicin in osteosarcoma, J. Exp. Clin. Cancer Res., 37, 107, 10.1186/s13046-018-0772-9

National Cancer Institute (NCI) (2020, December 20). NCI-COG Pediatric MATCH (Molecular Analysis for Therapy Choice)-Phase 2 Subprotocol of Olaparib in Patients With Tumors Harboring Defects in DNA Damage Repair Genes. Report No.: NCT03233204, Available online: https://clinicaltrials.gov/ct2/show/NCT03233204.

Janeway, K. (2020, December 20). Phase II Trial of Olaparib in Combination with Ceralasertib in Patients With Recurrent Osteosarcoma. Report No.: NCT04417062, Available online: https://clinicaltrials.gov/ct2/show/NCT04417062.

2013, Nucleotide Excision Repair in Eukaryotes, Cold Spring Harb. Perspect. Biol., 5, a012609

Hattinger, 2015, Excision repair cross-complementation group 1 protein expression predicts survival in patients with high-grade, non-metastatic osteosarcoma treated with neoadjuvant chemotherapy, Histopathology, 67, 338, 10.1111/his.12653

Nathrath, 2002, Expression of genes of potential importance in the response to chemotherapy in osteosarcoma patients, Klin. Padiatr., 214, 230, 10.1055/s-2002-33189

Li, 2007, Expressions of ERCC2 and ERCC4 genes in osteosarcoma and peripheral blood lymphocytes and their clinical significance, Beijing Da Xue Xue Bao, 39, 467

Caronia, 2009, Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients, Pharmacogenom. J., 9, 347, 10.1038/tpj.2009.19

Hao, 2012, Association of four ERCC1 and ERCC2 SNPs with survival of bone tumour patients, Asian Pac. J. Cancer Prev., 13, 3821, 10.7314/APJCP.2012.13.8.3821

Liu, 2017, Meta-analysis showing that ERCC1 polymorphism is predictive of osteosarcoma prognosis, Oncotarget, 8, 62769, 10.18632/oncotarget.19370

Obiedat, 2018, The effect of ERCC1 and ERCC2 gene polymorphysims on response to cisplatin based therapy in osteosarcoma patients, BMC Med. Genet., 19, 1, 10.1186/s12881-018-0627-4

DeChant, 2003, Identification of drug-regulated genes in osteosarcoma cells, Int. J. Cancer, 105, 636, 10.1002/ijc.11135

Liebermann, 1995, Molecular controls of growth arrest and apoptosis: p53-dependent and independent pathways, Oncogene, 11, 199

Muller, 2013, p53 mutations in cancer, Nat. Cell Biol., 15, 2, 10.1038/ncb2641

Overholtzer, 2003, The presence of p53 mutations in human osteosarcomas correlates with high levels of genomic instability, Proc. Natl. Acad. Sci. USA, 100, 11547, 10.1073/pnas.1934852100

Wong, 2007, p53-R273H gains new function in induction of drug resistance through down-regulation of procaspase-3, Mol. Cancer Ther., 6, 1054, 10.1158/1535-7163.MCT-06-0336

Sato, 2000, Enhancement of drug-induced apoptosis by antisense oligodeoxynucleotides targeted against Mdm2 and p21WAF1/CIP1, Anticancer Res., 20, 837

Asada, 2000, De novo deletions of p53 gene and wild-type p53 correlate with acquired cisplatin-resistance in human osteosarcoma OST cell line, Anticancer Res., 19, 5131

Tsuchiya, 2000, Sensitization and caffeine potentiation of cisplatin cytotoxicity resulting from introduction of wild-type p53 gene in human osteosarcoma, Anticancer Res., 20, 235

Fan, 1999, Modulation of Cisplatinum Cytotoxicity by p53: Effect of p53-Mediated Apoptosis and DNA Repair, Mol. Pharmacol., 56, 966, 10.1124/mol.56.5.966

Song, 2009, Mechanism of chemoresistance mediated by miR-140 in human osteosarcoma and colon cancer cells, Oncogene, 28, 4065, 10.1038/onc.2009.274

Goto, 1998, Association of Loss of Heterozygosity at the p53 Locus with Chemoresistance in Osteosarcomas, Jpn. J. Cancer Res., 89, 539, 10.1111/j.1349-7006.1998.tb03295.x

Ferrari, 2004, Evaluation of P-glycoprotein, HER-2/ErbB-2, p53, and Bcl-2 in primary tumor and metachronous lung metastases in patients with high-grade osteosarcoma, Cancer, 100, 1936, 10.1002/cncr.20151

Rossner, 2008, Mutations in p53, p53 protein overexpression and breast cancer survival, J. Cell. Mol. Med., 13, 3847, 10.1111/j.1582-4934.2008.00553.x

Pakos, 2004, Prognostic significance of TP53 tumor suppressor gene expression and mutations in human osteosarcoma: A meta-analysis, Clin. Cancer Res., 10, 6208, 10.1158/1078-0432.CCR-04-0246

Wunder, 2005, TP53 Mutations and Outcome in Osteosarcoma: A Prospective, Multicenter Study, J. Clin. Oncol., 23, 1483, 10.1200/JCO.2005.04.074

Hata, 2015, The BCL-2 family: Key mediators of the apoptotic response to targeted anti-cancer therapeutics, Cancer Discov., 5, 475, 10.1158/2159-8290.CD-15-0011

Reed, 1997, Double identity for proteins of the Bcl-2 family, Nat. Cell Biol., 387, 773

Zhao, 2009, Enhanced chemosensitivity of drug-resistant osteosarcoma cells by lentivirus-mediated Bcl-2 silencing, Biochem. Biophys. Res. Commun., 390, 642, 10.1016/j.bbrc.2009.10.020

Eliseev, 2008, Runx2-mediated activation of the Bax gene increases osteosarcoma cell sensitivity to apoptosis, Oncogene, 27, 3605, 10.1038/sj.onc.1211020

2003, Antisense to apoptosis inhibitors facilitates chemotherapy and TRAIL-induced death signaling, Ann. N. Y. Acad. Sci., 1002, 90, 10.1196/annals.1281.019

Zhang, 2000, Role of BAX in the Apoptotic Response to Anticancer Agents, Science, 290, 989, 10.1126/science.290.5493.989

Wu, 2012, Expressions of p53, c-MYC, BCL-2 and apoptotic index in human osteosarcoma and their correlations with prognosis of patients, Cancer Epidemiol., 36, 212, 10.1016/j.canep.2011.08.002

Nedelcu, 2007, Livin and Bcl-2 expression in high-grade osteosarcoma, J. Cancer Res. Clin. Oncol., 134, 237, 10.1007/s00432-007-0276-z

Konstadoulakis, 2008, Prognostic value of bax, bcl-2, and p53 staining in primary osteosarcoma, J. Surg. Oncol., 97, 259, 10.1002/jso.20913

Patatsos, 2018, Pre-clinical evaluation of proteasome inhibitors for canine and human osteosarcoma, Vet. Comp. Oncol., 16, 544, 10.1111/vco.12413

Lemmon, 2010, Cell Signaling by Receptor Tyrosine Kinases, Cell, 141, 1117, 10.1016/j.cell.2010.06.011

Pignochino, 2009, Sorafenib blocks tumour growth, angiogenesis and metastatic potential in preclinical models of osteosarcoma through a mechanism potentially involving the inhibition of ERK1/2, MCL-1 and ezrin pathways, Mol. Cancer, 8, 118, 10.1186/1476-4598-8-118

Hughes, 2004, Cell Surface Expression of Epidermal Growth Factor Receptor and Her-2 with Nuclear Expression of Her-4 in Primary Osteosarcoma, Cancer Res., 64, 2047, 10.1158/0008-5472.CAN-03-3096

Zhou, 2011, VEGF and EMMPRIN expression correlates with survival of patients with osteosarcoma, Surg. Oncol., 20, 13, 10.1016/j.suronc.2009.09.002

Wu, 2019, Transferrin receptor-1 and VEGF are prognostic factors for osteosarcoma, J. Orthop. Surg. Res., 14, 1, 10.1186/s13018-019-1301-z

Ebb, 2012, 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, 10.1200/JCO.2011.37.4546

Maris, 2008, Initial testing of the VEGFR inhibitor AZD2171 by the pediatric preclinical testing program, Pediatr. Blood Cancer, 50, 581, 10.1002/pbc.21232

MacEwen, 2004, IGF-1 receptor contributes to the malignant phenotype in human and canine osteosarcoma, J. Cell. Biochem., 92, 77, 10.1002/jcb.20046

Hassan, 2011, Cell surface receptor expression patterns in osteosarcoma, Cancer, 118, 740, 10.1002/cncr.26339

Wang, 2011, Increased expression of insulin-like growth factor-1 receptor is correlated with tumor metastasis and prognosis in patients with osteosarcoma, J. Surg. Oncol., 105, 235, 10.1002/jso.22077

Luk, 2011, IGF1R-Targeted Therapy and Its Enhancement of Doxorubicin Chemosensitivity in Human Osteosarcoma Cell Lines, Cancer Investig., 29, 521, 10.3109/07357907.2011.606252

Rettew, 2012, Multiple receptor tyrosine kinases promote the in vitro phenotype of metastatic human osteosarcoma cell lines, Oncogenesis, 1, e34, 10.1038/oncsis.2012.34

Anderson, 2016, A phase II study of clinical activity of SCH 717454 (robatumumab) in patients with relapsed osteosarcoma and Ewing sarcoma, Pediatr. Blood Cancer, 63, 1761, 10.1002/pbc.26087

Chitnis, 2008, The Type 1 Insulin-Like Growth Factor Receptor Pathway, Clin. Cancer Res., 14, 6364, 10.1158/1078-0432.CCR-07-4879

Analysis of Aberrant Signal Transduction Pathways in Osteosarcoma Cell Lines (2020, November 08). Cancer Research. Available online: https://cancerres.aacrjournals.org/content/65/9_Supplement/1075.2.

Adamopoulos, 2016, Deciphering signaling networks in osteosarcoma pathobiology, Exp. Biol. Med., 241, 1296, 10.1177/1535370216648806

Kuijjer, M.L., van den Akker, B.E., Hilhorst, R., Mommersteeg, M., Buddingh, E.P., Serra, M., Buerger, H., Hogendoorn, P.C., and Cleton-Jansen, A.-M. (2014). Kinome and mRNA expression profiling of high-grade osteosarcoma cell lines implies Akt signaling as possible target for therapy. BMC Med. Genom., 7.

2009, Targeting the mTOR Signaling Network for Cancer Therapy, J. Clin. Oncol., 27, 2278, 10.1200/JCO.2008.20.0766

Gordon, 2008, Evaluation of the mammalian target of rapamycin pathway and the effect of rapamycin on target expression and cellular proliferation in osteosarcoma cells from dogs, Am. J. Vet. Res., 69, 1079, 10.2460/ajvr.69.8.1079

Gazitt, 1992, Targeted therapy of human osteosarcoma with 17AAG or rapamycin: Characterization of induced apoptosis and inhibition of mTOR and Akt/MAPK/Wnt pathways, Int. J. Oncol., 34, 551

Wan, 2005, Rapamycin Inhibits Ezrin-Mediated Metastatic Behavior in a Murine Model of Osteosarcoma, Cancer Res., 65, 2406, 10.1158/0008-5472.CAN-04-3135

Houghton, 2011, Initial testing (stage 1) of the mTOR kinase inhibitor AZD8055 by the pediatric preclinical testing program, Pediatr. Blood Cancer, 58, 191, 10.1002/pbc.22935

Chandhanayingyong, 2012, MAPK/ERK Signaling in Osteosarcomas, Ewing Sarcomas and Chondrosarcomas: Therapeutic Implications and Future Directions, Sarcoma, 2012, e404810, 10.1155/2012/404810

Cai, 2014, Wnt Pathway in Osteosarcoma, from Oncogenic to Therapeutic, J. Cell. Biochem., 115, 625, 10.1002/jcb.24708

Vijayakumar, 2011, High-Frequency Canonical Wnt Activation in Multiple Sarcoma Subtypes Drives Proliferation through a TCF/β-Catenin Target Gene, CDC25A, Cancer Cell, 19, 601, 10.1016/j.ccr.2011.03.010

Leow, 2009, Antitumor activity of natural compounds, curcumin and PKF118-310, as Wnt/β-catenin antagonists against human osteosarcoma cells, Investig. New Drugs, 28, 766, 10.1007/s10637-009-9311-z

Guo, 2008, Dominant Negative LRP5 Decreases Tumorigenicity and Metastasis of Osteosarcoma in an Animal Model, Clin. Orthop. Relat. Res., 466, 2039, 10.1007/s11999-008-0344-y

Kansara, 2009, Wnt inhibitory factor 1 is epigenetically silenced in human osteosarcoma, and targeted disruption accelerates osteosarcomagenesis in mice, J. Clin. Investig., 119, 837, 10.1172/JCI37175

Kansara, 2014, Translational biology of osteosarcoma, Nat. Rev. Cancer, 14, 722, 10.1038/nrc3838

Danieau, G., Morice, S., Redini, F., Verrecchia, F., and Le Royer, B.B. (2019). New Insights about the Wnt/β-Catenin Signaling Pathway in Primary Bone Tumors and Their Microenvironment: A Promising Target to Develop Therapeutic Strategies?. Int. J. Mol. Sci., 20.

Marion, 2012, Targeted inhibition of T-cell factor activity promotes syndecan-2 expression and sensitization to doxorubicin in osteosarcoma cells and bone tumors in mice, J. Bone Miner. Res., 27, 2118, 10.1002/jbmr.1650

Jiang, 2015, TRIM37 promoted the growth and migration of the pancreatic cancer cells, Tumor Biol., 37, 2629, 10.1007/s13277-015-4078-7

Tao, 2017, TRIM37 promotes tumor cell proliferation and drug resistance in pediatric osteosarcoma, Oncol. Lett., 14, 6365

Fang, 2018, Targeting the Wnt/β-catenin pathway in human osteosarcoma cells, Oncotarget, 9, 36780, 10.18632/oncotarget.26377

Krishnamurthy, 2018, Targeting the Wnt/beta-catenin pathway in cancer: Update on effectors and inhibitors, Cancer Treat. Rev., 62, 50, 10.1016/j.ctrv.2017.11.002

Harb, 2019, Recent Development of Wnt Signaling Pathway Inhibitors for Cancer Therapeutics, Curr. Oncol. Rep., 21, 12, 10.1007/s11912-019-0763-9

Degenhardt, 2006, Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis, Cancer Cell, 10, 51, 10.1016/j.ccr.2006.06.001

Maiuri, 2007, Kroemer GSelf-eating and self-killing: Crosstalk between autophagy and apoptosis, Nat. Rev. Mol. Cell Biol., 8, 741, 10.1038/nrm2239

Kim, 2013, Cytoprotective role of autophagy during paclitaxel-induced apoptosis in Saos-2 osteosarcoma cells, Int. J. Oncol., 42, 1985, 10.3892/ijo.2013.1884

Zhang, 2009, Expression of Beclin1 in osteosarcoma and the effects of down-regulation of autophagy on the chemotherapeutic sensitivity, J. Huazhong Univ. Sci. Technol. Med. Sci., 29, 737, 10.1007/s11596-009-0613-3

Coupienne, 2011, RIP3 expression induces a death profile change in U2OS osteosarcoma cells after 5-ALA-PDT, Lasers Surg. Med., 43, 557, 10.1002/lsm.21088

Tang, 2010, HMGB1 release and redox regulates autophagy and apoptosis in cancer cells, Oncogene, 29, 5299, 10.1038/onc.2010.261

Huang, 2012, Targeting HMGB1-mediated autophagy as a novel therapeutic strategy for osteosarcoma, Autophagy, 8, 275, 10.4161/auto.8.2.18940

Huang, 2012, HMGB1 Promotes Drug Resistance in Osteosarcoma, Cancer Res., 72, 230, 10.1158/0008-5472.CAN-11-2001

Yang, 2014, High-mobility group nucleosome-binding domain 5 increases drug resistance in osteosarcoma through upregulating autophagy, Tumor Biol. J. Int. Soc. Oncodev. Biol. Med., 35, 6357, 10.1007/s13277-014-1833-0

Xiao, 2018, HSP90AA1-mediated autophagy promotes drug resistance in osteosarcoma, J. Exp. Clin. Cancer Res., 37, 201, 10.1186/s13046-018-0880-6

Amaravadi, 2007, Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma, J. Clin. Investig., 117, 326, 10.1172/JCI28833

Carew, 2009, Autophagy inhibition enhances vorinostat-induced apoptosis via ubiquitinated protein accumulation, J. Cell. Mol. Med., 14, 2448, 10.1111/j.1582-4934.2009.00832.x

Shen, 2013, Chloroquine blocks the autophagic process in cisplatin-resistant osteosarcoma cells by regulating the expression of p62/SQSTM1, Int. J. Mol. Med., 32, 448, 10.3892/ijmm.2013.1399

Liu, 2017, Effect of rapamycin and chloroquine on osteosarcoma, Zhonghua Yi Xue Za Zhi, 97, 1510

Senthebane, D.A., Rowe, A., Thomford, N.E., Shipanga, H., Munro, D., Al Mazeedi, M.A.M., Almazyadi, H.A.M., Kallmeyer, K., Dandara, C., and Pepper, M.S. (2017). The Role of Tumor Microenvironment in Chemoresistance: To Survive, Keep Your Enemies Closer. Int. J. Mol. Sci., 18.

Vinogradov, 2012, Cancer stem cells and drug resistance: The potential of nanomedicine, Nanomedicine, 7, 597, 10.2217/nnm.12.22

Liu, 2011, Cancer stem cells in osteosarcoma: Recent progress and perspective, Acta Oncol., 50, 1142, 10.3109/0284186X.2011.584553

Zhang, 2013, Transforming Growth Factor β1 Signal is Crucial for Dedifferentiation of Cancer Cells to Cancer Stem Cells in Osteosarcoma, Stem Cells, 31, 433, 10.1002/stem.1298

Gibbs, 2005, Stem-Like Cells in Bone Sarcomas: Implications for Tumorigenesis, Neoplasia, 7, 967, 10.1593/neo.05394

Tirino, V., Desiderio, V., d’Aquino, R., De Francesco, F., Pirozzi, G., Graziano, A., Galderisi, U., Cavaliere, C., de Rosa, A., and Papaccio, G. (2008). Detection and characterization of CD133+ cancer stem cells in human solid tumours. PLoS ONE, 3.

Santulli, 2009, Identification and expansion of human osteosarcoma-cancer-stem cells by long-term 3-aminobenzamide treatment, J. Cell. Physiol., 219, 301, 10.1002/jcp.21667

Martins-Neves, S.R., Lopes, Á.O., do Carmo, A., Paiva, A.A., Simões, P.C., Abrunhosa, A.J., and Gomes, C.M.F. (2012). Therapeutic implications of an enriched cancer stem-like cell population in a human osteosarcoma cell line. BMC Cancer, 12.

Fujii, 2009, Sphere-forming stem-like cell populations with drug resistance in human sarcoma cell lines, Int. J. Oncol., 34, 1381

Honoki, 2010, Possible involvement of stem-like populations with elevated ALDH1 in sarcomas for chemotherapeutic drug resistance, Oncol. Rep., 24, 501, 10.3892/or_00000885

Chan, 2013, Pharmacological Inactivation of Skp2 SCF Ubiquitin Ligase Restricts Cancer Stem Cell Traits and Cancer Progression, Cell, 154, 556, 10.1016/j.cell.2013.06.048

Ding, 2018, S-phase kinase-associated protein 2 is involved in epithelial-mesenchymal transition in methotrexate-resistant osteosarcoma cells, Int. J. Oncol., 52, 1841

Cheng, 2016, Nitidine chloride suppresses epithelial-to-mesenchymal transition in osteosarcoma cell migration and invasion through Akt/GSK-3β/Snail signaling pathway, Oncol. Rep., 36, 1023, 10.3892/or.2016.4846

Kolb, 2003, Phase II study of ecteinascidin 743 in heavily pretreated patients with recurrent osteosarcoma, Cancer, 98, 832, 10.1002/cncr.11563

Ratti, 2017, Trabectedin Overrides Osteosarcoma Differentiative Block and Reprograms the Tumor Immune Environment Enabling Effective Combination with Immune Checkpoint Inhibitors, Clin. Cancer Res., 23, 5149, 10.1158/1078-0432.CCR-16-3186