{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T04:22:23Z","timestamp":1772252543681,"version":"3.50.1"},"reference-count":50,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T00:00:00Z","timestamp":1605052800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: Osteosarcoma is a rare but aggressive bone cancer that occurs primarily in children. Like other rare cancers, treatment advances for osteosarcoma have stagnated, with little improvement in survival for the past several decades. Developing new treatments has been hampered by extensive genomic heterogeneity and limited access to patient samples to study the biology of this complex disease. Methods: To overcome these barriers, we combined the power of comparative oncology with patient-derived models of cancer and high-throughput chemical screens in a cross-species drug discovery pipeline. Results: Coupling in vitro high-throughput drug screens on low-passage and established cell lines with in vivo validation in patient-derived xenografts we identify the proteasome and CRM1 nuclear export pathways as therapeutic sensitivities in osteosarcoma, with dual inhibition of these pathways inducing synergistic cytotoxicity. Conclusions: These collective efforts provide an experimental framework and set of new tools for osteosarcoma and other rare cancers to identify and study new therapeutic vulnerabilities.<\/jats:p>","DOI":"10.3390\/cancers12113335","type":"journal-article","created":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T19:08:28Z","timestamp":1605121708000},"page":"3335","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["A Comparative Oncology Drug Discovery Pipeline to Identify and Validate New Treatments for Osteosarcoma"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1510-9343","authenticated-orcid":false,"given":"Jason A.","family":"Somarelli","sequence":"first","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"},{"name":"Duke Cancer Institute, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gabrielle","family":"Rupprecht","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1821-0156","authenticated-orcid":false,"given":"Erdem","family":"Altunel","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1769-5307","authenticated-orcid":false,"given":"Etienne M.","family":"Flamant","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sneha","family":"Rao","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7453-0045","authenticated-orcid":false,"given":"Dharshan","family":"Sivaraj","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0704-1529","authenticated-orcid":false,"given":"Alexander L.","family":"Lazarides","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah M.","family":"Hoskinson","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1466-8899","authenticated-orcid":false,"given":"Maya U.","family":"Sheth","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Serene","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"So Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics and Microbiology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kathryn E.","family":"Ware","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anika","family":"Agarwal","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1322-4858","authenticated-orcid":false,"given":"Mark M.","family":"Cullen","sequence":"additional","affiliation":[{"name":"Department of Orthopaedics, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Laura E.","family":"Selmic","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0273-6284","authenticated-orcid":false,"given":"Jeffrey I.","family":"Everitt","sequence":"additional","affiliation":[{"name":"Duke Cancer Institute, Durham, NC 27710, USA"},{"name":"Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3957-061X","authenticated-orcid":false,"given":"Shannon J.","family":"McCall","sequence":"additional","affiliation":[{"name":"Duke Cancer Institute, Durham, NC 27710, USA"},{"name":"Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cindy","family":"Eward","sequence":"additional","affiliation":[{"name":"Surgery Service, Triangle Veterinary Referral Hospital, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"William C.","family":"Eward","sequence":"additional","affiliation":[{"name":"Duke Cancer Institute, Durham, NC 27710, USA"},{"name":"Department of Orthopaedics, Duke University Medical Center, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David S.","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA"},{"name":"Duke Cancer Institute, Durham, NC 27710, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,11,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1002\/ijc.24320","article-title":"International osteosarcoma incidence patterns in children and adolescents, middle ages and elderly persons","volume":"125","author":"Mirabello","year":"2009","journal-title":"Int. J. Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"167","DOI":"10.18632\/oncoscience.21","article-title":"Theranostic profiling for actionable aberrations in advanced high risk osteosarcoma with aggressive biology reveals high molecular diversity: The human fingerprint hypothesis","volume":"1","author":"Anderson","year":"2014","journal-title":"Oncoscience"},{"key":"ref_3","first-page":"547","article-title":"Osteosarcoma: A Meta-Analysis and Review of the Literature","volume":"44","author":"Friebele","year":"2015","journal-title":"Am. J. Orthop."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.3892\/ol.2014.1935","article-title":"Molecular mechanisms of chemoresistance in osteosarcoma (Review)","volume":"7","author":"He","year":"2014","journal-title":"Oncol. Lett."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1200\/EDBK_100015","article-title":"Predicting and Preventing Anthracycline-Related Cardiotoxicity","volume":"38","author":"Armenian","year":"2018","journal-title":"Am. Soc. Clin. Oncol. Educ. Book"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1007\/978-3-319-04843-7_13","article-title":"Using Canine Osteosarcoma as a Model to Assess Efficacy of Novel Therapies: Can Old Dogs Teach Us New Tricks?","volume":"Volume 804","author":"Rodriguez","year":"2014","journal-title":"Current Advances in Osteosarcoma"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"20140231","DOI":"10.1098\/rstb.2014.0231","article-title":"Comparative oncology: What dogs and other species can teach us about humans with cancer","volume":"370","author":"Schiffman","year":"2015","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Paoloni, M., Davis, S., Lana, S., Withrow, S., Sangiorgi, L., Picci, P., Hewitt, S.M., Triche, T., Meltzer, P., and Khanna, C. (2009). Canine tumor cross-species genomics uncovers targets linked to osteosarcoma progression. BMC Genomics, 10.","DOI":"10.1186\/1471-2164-10-625"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"R132","DOI":"10.1186\/gb-2013-14-12-r132","article-title":"Genome-wide analyses implicate 33 loci in heritable dog osteosarcoma, including regulatory variants near CDKN2A\/B","volume":"14","author":"Karlsson","year":"2013","journal-title":"Genome Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1002\/gcc.20908","article-title":"Characterization of canine osteosarcoma by array comparative genomic hybridization and RT-qPCR: Signatures of genomic imbalance in canine osteosarcoma parallel the human counterpart","volume":"50","author":"Angstadt","year":"2011","journal-title":"Genes Chromosomes Cancer"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"572","DOI":"10.1016\/j.cancergen.2012.09.005","article-title":"A genome-wide approach to comparative oncology: High-resolution oligonucleotide aCGH of canine and human osteosarcoma pinpoints shared microaberrations","volume":"205","author":"Angstadt","year":"2012","journal-title":"Cancer Genet."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1038\/nature04338","article-title":"Genome sequence, comparative analysis and haplotype structure of the domestic dog","volume":"438","author":"Wade","year":"2005","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1093\/molbev\/msz254","article-title":"Improving Cancer Drug Discovery by Studying Cancer across the Tree of Life","volume":"37","author":"Somarelli","year":"2020","journal-title":"Mol. Biol. Evol."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Makielski, K.M., Mills, L.J., Sarver, A.L., Henson, M.S., Spector, L.G., Naik, S., and Modiano, J.F. (2019). Risk Factors for Development of Canine and Human Osteosarcoma: A Comparative Review. Vet. Sci., 6.","DOI":"10.3390\/vetsci6020048"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"933","DOI":"10.1016\/j.cell.2015.03.053","article-title":"Prospective derivation of a living organoid biobank of colorectal cancer patients","volume":"161","author":"Francies","year":"2015","journal-title":"Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1038\/nature11003","article-title":"The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity","volume":"483","author":"Barretina","year":"2012","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1126\/science.aao2774","article-title":"Patient-derived organoids model treatment response of metastatic gastrointestinal cancers","volume":"359","author":"Vlachogiannis","year":"2018","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Koga, Y., and Ochiai, A. (2019). Systematic Review of Patient-Derived Xenograft Models for Preclinical Studies of Anti-Cancer Drugs in Solid Tumors. Cells, 8.","DOI":"10.3390\/cells8050418"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1038\/nm.3954","article-title":"High-throughput screening using patient-derived tumor xenografts to predict clinical trial drug response","volume":"21","author":"Gao","year":"2015","journal-title":"Nat. Med."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Lu, M., Zessin, A.S., Glover, W., and Hsu, D.S. (2017). Activation of the mTOR Pathway by Oxaliplatin in the Treatment of Colorectal Cancer Liver Metastasis. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0169439"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"117","DOI":"10.3389\/fonc.2020.00117","article-title":"From the Clinic to the Bench and Back Again in One Dog Year: How a Cross-Species Pipeline to Identify New Treatments for Sarcoma Illuminates the Path Forward in Precision Medicine","volume":"10","author":"Rao","year":"2020","journal-title":"Front. Oncol."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Somarelli, J.A., Roghani, R.S., Moghaddam, A.S., Thomas, B.C., Rupprecht, G., Ware, K.E., Altunel, E., Mantyh, J.B., Kim, S.Y., and McCall, S.J. (2020). A Precision Medicine Drug Discovery Pipeline Identifies Combined CDK2 and 9 Inhibition as a Novel Therapeutic Strategy in Colorectal Cancer. Mol. Cancer Ther.","DOI":"10.1158\/1535-7163.MCT-20-0454"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Altunel, E., Roghani, R.S., Chen, K.Y., Kim, S.Y., McCall, S., Ware, K.E., Shen, X., Somarelli, J.A., and Hsu, D.S. (2020). Development of a precision medicine pipeline to identify personalized treatments for colorectal cancer. BMC Cancer, 20.","DOI":"10.1186\/s12885-020-07090-y"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1038\/s41416-019-0616-1","article-title":"Patient-derived organoids as a potential model to predict response to PD-1\/PD-L1 checkpoint inhibitors","volume":"121","author":"Scognamiglio","year":"2019","journal-title":"Br. J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1972","DOI":"10.1016\/j.cell.2018.11.021","article-title":"Organoid Modeling of the Tumor Immune Microenvironment","volume":"175","author":"Neal","year":"2018","journal-title":"Cell"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"462","DOI":"10.1158\/2159-8290.CD-16-1154","article-title":"Personalized In Vitro and In Vivo Cancer Models to Guide Precision Medicine","volume":"7","author":"Pauli","year":"2017","journal-title":"Cancer Discov."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"78896","DOI":"10.18632\/oncotarget.12969","article-title":"XPO1 inhibitor combination therapy with bortezomib or carfilzomib induces nuclear localization of IkappaBalpha and overcomes acquired proteasome inhibitor resistance in human multiple myeloma","volume":"7","author":"Turner","year":"2016","journal-title":"Oncotarget"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1158\/1535-7163.MCT-16-0553","article-title":"Nuclear Export of Ubiquitinated Proteins Determines the Sensitivity of Colorectal Cancer to Proteasome Inhibitor","volume":"16","author":"Wu","year":"2017","journal-title":"Mol. Cancer Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"78883","DOI":"10.18632\/oncotarget.12428","article-title":"Selinexor, a Selective Inhibitor of Nuclear Export (SINE) compound, acts through NF-kappaB deactivation and combines with proteasome inhibitors to synergistically induce tumor cell death","volume":"7","author":"Kashyap","year":"2016","journal-title":"Oncotarget"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"635","DOI":"10.1007\/s10555-017-9697-6","article-title":"Proteasome-associated deubiquitinases and cancer","volume":"36","author":"Mofers","year":"2017","journal-title":"Cancer Metastasis Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"16010","DOI":"10.1038\/sigtrans.2016.10","article-title":"Inhibiting cancer cell hallmark features through nuclear export inhibition","volume":"1","author":"Sun","year":"2016","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"(2019). XPO1 Inhibitor Approved for Multiple Myeloma. Cancer Discov., 9, 1150\u20131151.","DOI":"10.1158\/2159-8290.CD-NB2019-085"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2955","DOI":"10.1158\/1078-0432.CCR-06-0170","article-title":"United States Food and Drug Administration Approval Summary: Bortezomib for the Treatment of Progressive Multiple Myeloma after One Prior Therapy","volume":"12","author":"Kane","year":"2006","journal-title":"Clin. Cancer Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"325","DOI":"10.1016\/j.molcel.2011.08.025","article-title":"Systematic and Quantitative Assessment of the Ubiquitin-Modified Proteome","volume":"44","author":"Kim","year":"2011","journal-title":"Mol. Cell"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4907","DOI":"10.1182\/blood-2005-08-3531","article-title":"Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells","volume":"107","author":"Obeng","year":"2006","journal-title":"Blood"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1041","DOI":"10.1016\/S0092-8674(00)80370-0","article-title":"Exportin 1 (Crm1p) Is an Essential Nuclear Export Factor","volume":"90","author":"Stade","year":"1997","journal-title":"Cell"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1452","DOI":"10.1158\/2159-8290.CD-19-0298","article-title":"Altered Nuclear Export Signal Recognition as a Driver of Oncogenesis","volume":"9","author":"Taylor","year":"2019","journal-title":"Cancer Discov."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Theodoropoulos, N., Lancman, G., and Chari, A. (2020). Targeting Nuclear Export Proteins in Multiple Myeloma Therapy. Target. Oncol., 1\u201312.","DOI":"10.1007\/s11523-020-00758-2"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"103504","DOI":"10.1016\/j.jprot.2019.103504","article-title":"XPO1 is a critical player for bortezomib resistance in multiple myeloma: A quantitative proteomic approach","volume":"209","author":"Chanukuppa","year":"2019","journal-title":"J. Proteomics"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1186\/1476-4598-9-176","article-title":"Bone marrow stromal cells from multiple myeloma patients uniquely induce bortezomib resistant NF-kappaB activity in myeloma cells","volume":"9","author":"Markovina","year":"2010","journal-title":"Mol. Cancer"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4094","DOI":"10.1200\/JCO.2016.67.5066","article-title":"Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination With Fludarabine and Cytarabine, in Pediatric Relapsed or Refractory Acute Leukemia","volume":"34","author":"Alexander","year":"2016","journal-title":"J. Clin. Oncol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"e28062","DOI":"10.1002\/pbc.28062","article-title":"Treatment of children with relapsed and refractory acute lymphoblastic leukemia with mitoxantrone, vincristine, pegaspargase, dexamethasone, and bortezomib","volume":"67","author":"August","year":"2020","journal-title":"Pediatr. Blood Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1093\/annonc\/mdu526","article-title":"EURAMOS-1, an international randomised study for osteosarcoma: Results from pre-randomisation treatment","volume":"26","author":"Whelan","year":"2015","journal-title":"Ann. Oncol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1016\/S1470-2045(16)30214-5","article-title":"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","volume":"17","author":"Marina","year":"2016","journal-title":"Lancet Oncol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2112","DOI":"10.1200\/JCO.2011.38.4420","article-title":"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","volume":"30","author":"Ferrari","year":"2012","journal-title":"J. Clin. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"33","DOI":"10.4103\/0971-5851.203513","article-title":"Pediatric Osteosarcoma: An Updated Review","volume":"38","author":"Taran","year":"2017","journal-title":"Indian J. Med. Paediatr. Oncol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1002\/cncr.25446","article-title":"Twenty years of follow-up of survivors of childhood osteosarcoma","volume":"117","author":"Nagarajan","year":"2011","journal-title":"Cancer"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4107","DOI":"10.1158\/1078-0432.CCR-19-3637","article-title":"Patient-Derived Organoids from Multiple Colorectal Cancer Liver Metastases Reveal Moderate Intra-patient Pharmacotranscriptomic Heterogeneity","volume":"26","author":"Bruun","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"eaay2574","DOI":"10.1126\/scitranslmed.aay2574","article-title":"Patient-derived organoids can predict response to chemotherapy in metastatic colorectal cancer patients","volume":"11","author":"Ooft","year":"2019","journal-title":"Sci. Transl. Med."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Xu, S., Ware, K.E., Ding, Y., Kim, S.Y., Sheth, M.U., Rao, S.R., Chan, W., Armstrong, A.J., Eward, W.C., and Jolly, M.K. (2019). An Integrative Systems Biology and Experimental Approach Identifies Convergence of Epithelial Plasticity, Metabolism, and Autophagy to Promote Chemoresistance. J. Clin. Med., 8.","DOI":"10.3390\/jcm8020205"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/11\/3335\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:32:06Z","timestamp":1760178726000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/11\/3335"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,11]]},"references-count":50,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2020,11]]}},"alternative-id":["cancers12113335"],"URL":"https:\/\/doi.org\/10.3390\/cancers12113335","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2020.10.19.346387","asserted-by":"object"}]},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,11]]}}}