{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T18:09:26Z","timestamp":1776276566071,"version":"3.50.1"},"reference-count":49,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,3,27]],"date-time":"2020-03-27T00:00:00Z","timestamp":1585267200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2015M3A9B6027818"],"award-info":[{"award-number":["2015M3A9B6027818"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2015K1A1A2028365"],"award-info":[{"award-number":["2015K1A1A2028365"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2016K2A9A1A03904900"],"award-info":[{"award-number":["2016K2A9A1A03904900"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003725","name":"National Research Foundation of Korea","doi-asserted-by":"publisher","award":["2018M3A9C4076477"],"award-info":[{"award-number":["2018M3A9C4076477"]}],"id":[{"id":"10.13039\/501100003725","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Although natural products are an important source of drugs and drug leads, identification and validation of their target proteins have proven difficult. Here, we report the development of a systematic strategy for target identification and validation employing drug affinity responsive target stability (DARTS) and mass spectrometry imaging (MSI) without modifying or labeling natural compounds. Through a validation step using curcumin, which targets aminopeptidase N (APN), we successfully standardized the systematic strategy. Using label-free voacangine, an antiangiogenic alkaloid molecule as the model natural compound, DARTS analysis revealed vascular endothelial growth factor receptor 2 (VEGFR2) as a target protein. Voacangine inhibits VEGFR2 kinase activity and its downstream signaling by binding to the kinase domain of VEGFR2, as was revealed by docking simulation. Through cell culture assays, voacangine was found to inhibit the growth of glioblastoma cells expressing high levels of VEGFR2. Specific localization of voacangine to tumor compartments in a glioblastoma xenograft mouse was revealed by MSI analysis. The overlap of histological images with the MSI signals for voacangine was intense in the tumor regions and showed colocalization of voacangine and VEGFR2 in the tumor tissues by immunofluorescence analysis of VEGFR2. The strategy employing DARTS and MSI to identify and validate the targets of a natural compound as demonstrated for voacangine in this study is expected to streamline the general approach of drug discovery and validation using other biomolecules including natural products.<\/jats:p>","DOI":"10.3390\/biom10040508","type":"journal-article","created":{"date-parts":[[2020,4,1]],"date-time":"2020-04-01T05:52:30Z","timestamp":1585720350000},"page":"508","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Identification and Validation of VEGFR2 Kinase as a Target of Voacangine by a Systematic Combination of DARTS and MSI"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4447-9864","authenticated-orcid":false,"given":"Yonghyo","family":"Kim","sequence":"first","affiliation":[{"name":"Chemical Genomics Global Research Lab., Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea"},{"name":"Clinical Protein Science &amp; Imaging, Department of Biomedical Engineering, Lund University, BMC D13, SE-221 84 Lund, Sweden"},{"name":"Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Barngatan 4, SE-221 85 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yutaka","family":"Sugihara","sequence":"additional","affiliation":[{"name":"Clinical Protein Science &amp; Imaging, Department of Biomedical Engineering, Lund University, BMC D13, SE-221 84 Lund, Sweden"},{"name":"Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Barngatan 4, SE-221 85 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tae Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Chemical Genomics Global Research Lab., Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sung Min","family":"Cho","sequence":"additional","affiliation":[{"name":"Chemical Genomics Global Research Lab., Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jin Young","family":"Kim","sequence":"additional","affiliation":[{"name":"Biomedical Omics Group, Korea Basic Science Institute, Ochang, Chungbuk 28119, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0855-6516","authenticated-orcid":false,"given":"Ju Yeon","family":"Lee","sequence":"additional","affiliation":[{"name":"Biomedical Omics Group, Korea Basic Science Institute, Ochang, Chungbuk 28119, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jong Shin","family":"Yoo","sequence":"additional","affiliation":[{"name":"Biomedical Omics Group, Korea Basic Science Institute, Ochang, Chungbuk 28119, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Doona","family":"Song","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gyoonhee","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Melinda","family":"Rezeli","sequence":"additional","affiliation":[{"name":"Clinical Protein Science &amp; Imaging, Department of Biomedical Engineering, Lund University, BMC D13, SE-221 84 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte","family":"Welinder","sequence":"additional","affiliation":[{"name":"Clinical Protein Science &amp; Imaging, Department of Biomedical Engineering, Lund University, BMC D13, SE-221 84 Lund, Sweden"},{"name":"Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Barngatan 4, SE-221 85 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Roger","family":"Appelqvist","sequence":"additional","affiliation":[{"name":"Clinical Protein Science &amp; Imaging, Department of Biomedical Engineering, Lund University, BMC D13, SE-221 84 Lund, Sweden"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gy\u00f6rgy","family":"Marko-Varga","sequence":"additional","affiliation":[{"name":"Chemical Genomics Global Research Lab., Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea"},{"name":"Clinical Protein Science &amp; Imaging, Department of Biomedical Engineering, Lund University, BMC D13, SE-221 84 Lund, Sweden"},{"name":"Department of Surgery, Tokyo Medical University, 6-7-1 Nishishinjiku, Shinjuku-ku, Tokyo 160-0023, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6919-833X","authenticated-orcid":false,"given":"Ho Jeong","family":"Kwon","sequence":"additional","affiliation":[{"name":"Chemical Genomics Global Research Lab., Department of Biotechnology, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea"},{"name":"Department of Internal Medicine, College of Medicine, Yonsei University, Seoul 03722, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2020,3,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1126\/science.287.5460.1964","article-title":"Target-oriented and diversity-oriented organic synthesis in drug discovery","volume":"287","author":"Schreiber","year":"2000","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1038\/nchembio.1199","article-title":"Target identification and mechanism of action in chemical biology and drug discovery","volume":"9","author":"Schenone","year":"2013","journal-title":"Nat. Chem. Biol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1969","DOI":"10.1126\/science.287.5460.1969","article-title":"Mechanism-based target identification and drug discovery in cancer research","volume":"287","author":"Gibbs","year":"2000","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1960","DOI":"10.1126\/science.287.5460.1960","article-title":"Drug discovery: A historical perspective","volume":"287","author":"Drews","year":"2000","journal-title":"Science"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"612","DOI":"10.1039\/C5NP00101C","article-title":"Target identification of natural products and bioactive compounds using affinity-based probes","volume":"33","author":"Pan","year":"2016","journal-title":"Nat. Prod. Rep."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2744","DOI":"10.1002\/anie.201208749","article-title":"Target identification for small bioactive molecules: Finding the needle in the haystack","volume":"52","author":"Ziegler","year":"2013","journal-title":"Angew. Chemie-Int. Ed."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"616","DOI":"10.1038\/nchembio.216","article-title":"Target profiling of small molecules by chemical proteomics","volume":"5","author":"Rix","year":"2009","journal-title":"Nat. Chem. Biol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1039\/C5NP00107B","article-title":"Advances in identification and validation of protein targets of natural products without chemical modification","volume":"33","author":"Chang","year":"2016","journal-title":"Nat. Prod. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.cbpa.2007.07.011","article-title":"Affinity selection-mass spectrometry screening techniques for small molecule drug discovery","volume":"11","author":"Annis","year":"2007","journal-title":"Curr. Opin. Chem. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.chembiol.2012.01.002","article-title":"Mass spectrometry-based proteomics in preclinical drug discovery","volume":"19","author":"Schirle","year":"2012","journal-title":"Chem. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"84","DOI":"10.1126\/science.1233606","article-title":"Monitoring drug target engagement in cells and tissues using the cellular thermal shift assay","volume":"341","author":"Molina","year":"2013","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"163","DOI":"10.1002\/9780470559277.ch110180","article-title":"Target Identification using drug affinity responsive target stability (DARTS)","volume":"3","author":"Lomenick","year":"2011","journal-title":"Curr. Protoc. Chem. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"21984","DOI":"10.1073\/pnas.0910040106","article-title":"Target identification using drug affinity responsive target stability (DARTS)","volume":"106","author":"Lomenick","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"4175","DOI":"10.1021\/ac702610a","article-title":"Thermodynamic analysis of protein stability and ligand binding using a chemical modification- and mass spectrometry-based strategy","volume":"80","author":"West","year":"2008","journal-title":"Anal. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/978-1-4939-2269-7_22","article-title":"Drug affinity responsive target stability (DARTS) for small-molecule target identification","volume":"1263","author":"Pai","year":"2015","journal-title":"Methods Mol. Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"101","DOI":"10.1038\/nmeth1145","article-title":"Imaging mass spectrometry of proteins and peptides: 3D volume reconstruction","volume":"5","author":"Andersson","year":"2008","journal-title":"Nat. Methods"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1038\/86573","article-title":"Imaging mass spectrometry: A new technology for the analysis of protein expression in mammalian tissues","volume":"7","author":"Stoeckli","year":"2001","journal-title":"Nat. Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"869","DOI":"10.2217\/bmm.15.64","article-title":"Drug localizations in tissue by mass spectrometry imaging","volume":"9","year":"2015","journal-title":"Biomark. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"982","DOI":"10.1016\/j.jprot.2011.03.019","article-title":"Drug localization in different lung cancer phenotypes by MALDI mass spectrometry imaging","volume":"74","author":"Fehniger","year":"2011","journal-title":"J. Proteom."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1016\/j.tibtech.2010.12.002","article-title":"MALDI imaging mass spectrometry of human tissue: Method challenges and clinical perspectives","volume":"29","author":"Seeley","year":"2011","journal-title":"Trends Biotechnol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1038\/nmeth1094","article-title":"MALDI imaging mass spectrometry: Molecular snapshots of biochemical systems","volume":"4","author":"Cornett","year":"2007","journal-title":"Nat. Methods"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Kim, Y.H., Fujimura, Y., Hagihara, T., Sasaki, M., Yukihira, D., Nagao, T., Miura, D., Yamaguchi, S., Saito, K., and Tanaka, H. (2013). In situ label-free imaging for visualizing the biotransformation of a bioactive polyphenol. Sci. Rep., 3.","DOI":"10.1038\/srep02805"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.copbio.2018.08.003","article-title":"Advanced MALDI mass spectrometry imaging in pharmaceutical research and drug development","volume":"55","author":"Schulz","year":"2019","journal-title":"Curr. Opin. Biotechnol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"695","DOI":"10.1016\/S1074-5521(03)00169-8","article-title":"Irreversible inhibition of CD13\/aminopeptidase N by the antiangiogenic agent curcumin","volume":"10","author":"Shim","year":"2003","journal-title":"Chem. Biol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.bbrc.2011.11.109","article-title":"A natural small molecule voacangine inhibits angiogenesis both in vitro and in vivo","volume":"417","author":"Kim","year":"2012","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_26","first-page":"327","article-title":"In vivo antitumor activity of SU11248, a novel tyrosine kinase inhibitor targeting vascular endothelial growth factor and platelet-derived growth factor receptors: Determination of a pharmacokinetic\/pharmacodynamic relationship","volume":"9","author":"Mendel","year":"2003","journal-title":"Clin. Cancer Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1116","DOI":"10.1021\/jm0204183","article-title":"Discovery of 5-[5-fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2, 4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosin","volume":"46","author":"Sun","year":"2003","journal-title":"J. Med. Chem."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1158\/1535-7163.MCT-05-0333","article-title":"SU14813: A novel multiple receptor tyrosine kinase inhibitor with potent antiangiogenic and antitumor activity","volume":"5","author":"Patyna","year":"2006","journal-title":"Mol. Cancer Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"513","DOI":"10.1158\/1535-7163.MCT-14-0208","article-title":"Sunitinib dose escalation overcomes transient resistance in clear cell renal cell carcinoma and is associated with epigenetic modifications","volume":"14","author":"Adelaiye","year":"2015","journal-title":"Mol. Cancer Ther."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1002\/path.1124","article-title":"Vascularization of cutaneous melanoma involves vessel co-option and has clinical significance","volume":"197","author":"Paku","year":"2002","journal-title":"J. Pathol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1148","DOI":"10.1111\/bph.12990","article-title":"Localization of sunitinib, its metabolites and its target receptors in tumour-bearing mice: A MALDI-MS imaging study","volume":"172","author":"Torok","year":"2015","journal-title":"Br. J. Pharmacol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"359","DOI":"10.1038\/nrm1911","article-title":"VEGF receptor signalling-In control of vascular function","volume":"7","author":"Olsson","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Bankhead, P., Loughrey, M.B., Fern\u00e1ndez, J.A., Dombrowski, Y., McArt, D.G., Dunne, P.D., McQuaid, S., Gray, R.T., Murray, L.J., and Coleman, H.G. (2017). QuPath: Open source software for digital pathology image analysis. Sci. Rep., 7.","DOI":"10.1038\/s41598-017-17204-5"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"536","DOI":"10.1016\/S0093-7754(01)90021-1","article-title":"Angiogenesis-dependent diseases","volume":"28","author":"Folkman","year":"2001","journal-title":"Semin. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1757","DOI":"10.1056\/NEJM199512283332608","article-title":"Clinical applications of research on angiogenesis","volume":"333","author":"Flier","year":"1995","journal-title":"N. Engl. J. Med."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"569","DOI":"10.1038\/nrclinonc.2009.130","article-title":"An overview of small-molecule inhibitors of VEGFR signaling","volume":"6","author":"Ivy","year":"2009","journal-title":"Nat. Rev. Clin. Oncol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"592","DOI":"10.4161\/cbt.9.8.11103","article-title":"ZD6474, a dual tyrosine kinase inhibitor of EGFR and VEGFR-2, inhibits MAPK\/ERK and AKT\/PI3-K and induces apoptosis in breast cancer cells","volume":"9","author":"Sarkar","year":"2010","journal-title":"Cancer Biol. Ther."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1038\/359845a0","article-title":"Vascular endothelial growth factor is a potential tumour angiogenesis factor in human gliomas in vivo","volume":"359","author":"Plate","year":"1992","journal-title":"Nature"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2280","DOI":"10.1158\/1535-7163.MCT-07-0181","article-title":"Pharmacodynamic and pharmacokinetic study of chronic low-dose metronomic cyclophosphamide therapy in mice","volume":"6","author":"Emmenegger","year":"2007","journal-title":"Mol. Cancer Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1593\/neo.09166","article-title":"In vivo antitumor and antimetastatic activity of Sunitinib in preclinical Neuroblastoma mouse model","volume":"11","author":"Zhang","year":"2009","journal-title":"Neoplasia"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2003","DOI":"10.1016\/j.cellsig.2007.05.013","article-title":"Vascular endothelial growth factor receptor-2: Structure, function, intracellular signalling and therapeutic inhibition","volume":"19","author":"Holmes","year":"2007","journal-title":"Cell. Signal."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1789","DOI":"10.1158\/1535-7163.MCT-08-0124","article-title":"Thymoquinone inhibits tumor angiogenesis and tumor growth through suppressing AKT and extracellular signal-regulated kinase signaling pathways","volume":"7","author":"Yi","year":"2008","journal-title":"Mol. Cancer Ther."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1111\/j.1750-3639.2005.tb00115.x","article-title":"Angiogenesis in Gliomas: Biology and Molecular Pathophysiology","volume":"15","author":"Fischer","year":"2006","journal-title":"Brain Pathol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2148","DOI":"10.1158\/1078-0432.CCR-08-1332","article-title":"Sunitinib mediates reversal of myeloid-derived suppressor cell accumulation in renal cell carcinoma patients","volume":"15","author":"Ko","year":"2009","journal-title":"Clin. Cancer Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1126\/science.1104819","article-title":"Normalization of tumor vasculature: An emerging concept in antiangiogenic therapy","volume":"307","author":"Jain","year":"2005","journal-title":"Science"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1634\/theoncologist.12-1-107","article-title":"Food and Drug Administration Drug Approval Summary: Sunitinib Malate for the Treatment of Gastrointestinal Stromal Tumor and Advanced Renal Cell Carcinoma","volume":"12","author":"Rock","year":"2007","journal-title":"Oncologist"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"694","DOI":"10.6004\/jnccn.2013.0204","article-title":"Clinical treatment decisions for advanced renal cell cancer","volume":"11","author":"Choueiri","year":"2013","journal-title":"JNCCN J. Natl. Compr. Cancer Netw."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1571","DOI":"10.1586\/era.12.81","article-title":"Primary resistance to tyrosine kinase inhibitors in patients with advanced renal cell carcinoma: State-of-the-science","volume":"12","author":"Porta","year":"2012","journal-title":"Expert Rev. Anticancer Ther."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1549","DOI":"10.1093\/annonc\/mdr533","article-title":"Primary anti-vascular endothelial growth factor (VEGF)-refractory metastatic renal cell carcinoma: Clinical characteristics, risk factors, and subsequent therapy","volume":"23","author":"Heng","year":"2012","journal-title":"Ann. Oncol."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/4\/508\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:12:22Z","timestamp":1760173942000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/10\/4\/508"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,3,27]]},"references-count":49,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2020,4]]}},"alternative-id":["biom10040508"],"URL":"https:\/\/doi.org\/10.3390\/biom10040508","relation":{"has-preprint":[{"id-type":"doi","id":"10.20944\/preprints202002.0009.v1","asserted-by":"object"}]},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,3,27]]}}}