{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:48:26Z","timestamp":1785163706268,"version":"3.55.0"},"reference-count":33,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:00:00Z","timestamp":1781049600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100020264","name":"Anne and Don Fizer Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100020264","id-type":"DOI","asserted-by":"crossref"}]},{"name":"Mulva Family Foundation"},{"DOI":"10.13039\/100005984","name":"Dr. Miriam and Sheldon G. Adelson Medical Research Foundation","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100005984","id-type":"DOI","asserted-by":"crossref"}]},{"name":"U.T. MD Anderson Melanoma SPORE","award":["5P50CA221703-05"],"award-info":[{"award-number":["5P50CA221703-05"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background\/Objectives: Uveal melanoma is the most common primary ocular cancer in adults. Patients with metastatic uveal melanoma (mUM) have limited treatment options and poor prognosis. mUM is characterized by high oxidative phosphorylation (OXPHOS), which may be a therapeutic vulnerability for this disease. ONC206 is an imipridone compound that can inhibit OXPHOS indirectly and is currently being evaluated in clinical trials. Thus, we tested the effects of ONC206 on human uveal melanoma cell lines and patient-derived xenografts (PDXs) in vitro and in vivo. Methods: The effects of ONC206 on cell survival, apoptosis, autophagy, oncogenic signaling pathways, and metabolic networks were assessed in vitro using human melanoma cell lines. ONC206 was then tested for safety and anti-tumor activity in vivo using two mUM PDX models. Results: ONC206 treatment produced dose-dependent inhibition of mUM cell growth in vitro, with induction of varying levels of apoptosis and autophagy. ONC206 treatment also downregulated OXPHOS effector proteins and metabolites, thereby impairing mitochondrial OXPHOS. Treatment with ONC206 significantly reduced tumor burden and improved survival in two UM PDX mouse models in vivo. Conclusions: Our findings position ONC206 as a mechanistically distinct agent to target mitochondrial metabolism and to inhibit mUM. As ONC206 is currently being evaluated in multiple clinical studies, our data support further evaluation as a potential new therapeutic strategy for mUM.<\/jats:p>","DOI":"10.3390\/cancers18121895","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T00:48:35Z","timestamp":1781138915000},"page":"1895","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Imipridone ONC206 Inhibits Tumor Growth and Improves Survival in Patient-Derived Xenograft Models of Uveal Melanoma"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4165-7216","authenticated-orcid":false,"given":"Mir Mustafa","family":"Ali","sequence":"first","affiliation":[{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 362, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Md","family":"Alauddin","sequence":"additional","affiliation":[{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 362, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iqbal","family":"Mahmud","sequence":"additional","affiliation":[{"name":"Department of Bioinformatics & Comp Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2615-2179","authenticated-orcid":false,"given":"Aron","family":"Joon","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aalim B.","family":"Momin","sequence":"additional","affiliation":[{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 362, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jacob R.","family":"Cortez","sequence":"additional","affiliation":[{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 362, Houston, TX 77030, USA"},{"name":"Department of Neurosurgery, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2477-5436","authenticated-orcid":false,"given":"Huiqin","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Tan","sequence":"additional","affiliation":[{"name":"Department of Metabolomics Core Facility, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Waikin","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Metabolomics Core Facility, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel William","family":"Anantha","sequence":"additional","affiliation":[{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 362, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Danielle L.","family":"Stolley","sequence":"additional","affiliation":[{"name":"Department of Hematopoietic Biology & Malignancies, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1057-1731","authenticated-orcid":false,"given":"Diana","family":"Shamsutdinova","sequence":"additional","affiliation":[{"name":"Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kurt","family":"Evans","sequence":"additional","affiliation":[{"name":"Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Funda","family":"Merric-Bernstam","sequence":"additional","affiliation":[{"name":"Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meenhard","family":"Herlyn","sequence":"additional","affiliation":[{"name":"Melanoma Research Center, Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monzy","family":"Thomas","sequence":"additional","affiliation":[{"name":"Melanoma Research Center, Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeqing","family":"Chen","sequence":"additional","affiliation":[{"name":"Melanoma Research Center, Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, PA 19104, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0977-0912","authenticated-orcid":false,"given":"Michael A.","family":"Davies","sequence":"additional","affiliation":[{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 362, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chandrani","family":"Chattopadhyay","sequence":"additional","affiliation":[{"name":"Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd., Unit 362, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2364","DOI":"10.1038\/s41591-022-02015-7","article-title":"Clinical and molecular response to tebentafusp in previously treated patients with metastatic uveal melanoma: A phase 2 trial","volume":"28","author":"Carvajal","year":"2022","journal-title":"Nat. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1170","DOI":"10.1002\/jso.24956","article-title":"Percutaneous hepatic perfusion with melphalan in uveal melanoma: A safe and effective treatment modality in an orphan disease","volume":"117","author":"Karydis","year":"2018","journal-title":"J. Surg. Oncol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5340","DOI":"10.1245\/s10434-024-15293-x","article-title":"Efficacy and Safety of the Melphalan\/Hepatic Delivery System in Patients with Unresectable Metastatic Uveal Melanoma: Results from an Open-Label, Single-Arm, Multicenter Phase 3 Study","volume":"31","author":"Zager","year":"2024","journal-title":"Ann. Surg. Oncol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"vdad040","DOI":"10.1093\/noajnl\/vdad040","article-title":"Pediatric diffuse midline glioma: Understanding the mechanisms and assessing the next generation of personalized therapeutics","volume":"5","author":"Jovanovich","year":"2023","journal-title":"Neuro-Oncol. Adv."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"88","DOI":"10.2174\/1570159X14666160509123229","article-title":"Diffuse Intrinsic Pontine Glioma: New Pathophysiological Insights and Emerging Therapeutic Targets","volume":"15","author":"Johung","year":"2017","journal-title":"Curr. Neuropharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"100899","DOI":"10.1016\/j.neo.2023.100899","article-title":"Therapeutic avenues for targeting treatment challenges of diffuse midline gliomas","volume":"40","author":"Noon","year":"2023","journal-title":"Neoplasia"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1212","DOI":"10.1038\/s41416-023-02361-4","article-title":"Resistance to immune checkpoint therapies by tumour-induced T-cell desertification and exclusion: Key mechanisms, prognostication and new therapeutic opportunities","volume":"129","author":"Wang","year":"2023","journal-title":"Br. J. Cancer"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3344","DOI":"10.1002\/cncr.30258","article-title":"Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies","volume":"122","author":"Algazi","year":"2016","journal-title":"Cancer"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1016\/j.ophtha.2024.09.001","article-title":"Survival in Patients with Uveal Melanoma Is Linked to Genetic Variation at HERC2 Single Nucleotide Polymorphism rs12913832","volume":"132","author":"Gelmi","year":"2025","journal-title":"Ophthalmology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1167\/iovs.65.8.37","article-title":"Protein and mRNA Expression in Uveal Melanoma Cell Lines Are Related to GNA and BAP1 Mutation Status","volume":"65","author":"Gelmi","year":"2024","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"100465","DOI":"10.1016\/j.xhgg.2025.100465","article-title":"Meta-analysis of uveal melanoma genome-wide association studies identifies novel risk loci and population effect size heterogeneity","volume":"6","author":"Mies","year":"2025","journal-title":"Hum. Genet. Genom. Adv."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1097\/CMR.0000000000001089","article-title":"Recent advances in the molecular genetic mechanisms and immune microenvironment of uveal melanoma","volume":"36","author":"Yang","year":"2026","journal-title":"Melanoma Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4187","DOI":"10.1167\/iovs.19-28082","article-title":"Elevated Endogenous SDHA Drives Pathological Metabolism in Highly Metastatic Uveal Melanoma","volume":"60","author":"Chattopadhyay","year":"2019","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1002\/mc.23436","article-title":"Targeting mitochondrial metabolism for metastatic cancer therapy","volume":"61","author":"Passaniti","year":"2022","journal-title":"Mol. Carcinog."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"542","DOI":"10.1093\/neuonc\/noaa283","article-title":"Mechanisms of imipridones in targeting mitochondrial metabolism in cancer cells","volume":"23","author":"Bonner","year":"2021","journal-title":"Neuro-Oncology"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1542","DOI":"10.1200\/JCO.23.01134","article-title":"ONC201 (Dordaviprone) in Recurrent H3 K27M-Mutant Diffuse Midline Glioma","volume":"42","author":"Gardner","year":"2024","journal-title":"J. Clin. Oncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1846","DOI":"10.1038\/s41416-024-02866-6","article-title":"Imipridones inhibit tumor growth and improve survival in an orthotopic liver metastasis mouse model of human uveal melanoma","volume":"131","author":"Chattopadhyay","year":"2024","journal-title":"Br. J. Cancer"},{"key":"ref_18","first-page":"607","article-title":"Characterization of three cell lines derived from fine needle biopsy of choroidal melanoma with metastatic outcome","volume":"17","author":"Burgess","year":"2011","journal-title":"Mol. Vis."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1476-4598-11-22","article-title":"Antitumor effects of the investigational selective MEK inhibitor TAK733 against cutaneous and uveal melanoma cell lines","volume":"11","author":"Atefi","year":"2012","journal-title":"Mol. Cancer"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1111\/pcmr.12304","article-title":"Biology of advanced uveal melanoma and next steps for clinical therapeutics","volume":"28","author":"Luke","year":"2015","journal-title":"Pigment. Cell Melanoma Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1002\/ijc.2910620208","article-title":"Establishment and characterization of an uveal-melanoma cell line","volume":"62","author":"Blom","year":"1995","journal-title":"Int. J. Cancer"},{"key":"ref_22","first-page":"T5","article-title":"Uveal Melanoma Cell Lines: Where do they come from? (An American Ophthalmological Society Thesis)","volume":"114","author":"Jager","year":"2016","journal-title":"Trans. Am. Ophthalmol. Soc."},{"key":"ref_23","first-page":"3198","article-title":"Studies of tumor-infiltrating lymphocytes from a human choroidal melanoma","volume":"32","author":"Ksander","year":"1991","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1002\/(SICI)1097-0215(19971114)73:4<470::AID-IJC3>3.0.CO;2-X","article-title":"Melanomas that develop within the eye inhibit lymphocyte proliferation","volume":"73","author":"Verbik","year":"1997","journal-title":"Int. J. Cancer"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/j.tips.2011.11.002","article-title":"Targeting Src family kinases in anti-cancer therapies: Turning promise into triumph","volume":"33","author":"Zhang","year":"2012","journal-title":"Trends Pharmacol. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Hsu, P.C., Yang, C.T., Jablons, D.M., and You, L. (2020). The Crosstalk between Src and Hippo\/YAP Signaling Pathways in Non-Small Cell Lung Cancer (NSCLC). Cancers, 12.","DOI":"10.3390\/cancers12061361"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2302","DOI":"10.1074\/jbc.RA118.004364","article-title":"SRC tyrosine kinase activates the YAP\/TAZ axis and thereby drives tumor growth and metastasis","volume":"294","author":"Lamar","year":"2019","journal-title":"J. Biol. Chem."},{"key":"ref_28","first-page":"135","article-title":"Multiple roles and therapeutic implications of Akt signaling in cancer","volume":"2","author":"Calvo","year":"2009","journal-title":"OncoTargets Ther."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1438","DOI":"10.1093\/neuonc\/noac041","article-title":"Imipridones affect tumor bioenergetics and promote cell lineage differentiation in diffuse midline gliomas","volume":"24","author":"Przystal","year":"2022","journal-title":"Neuro-Oncology"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2202104","DOI":"10.1080\/15384047.2023.2202104","article-title":"A novel dopamine receptor D2 antagonist (ONC206) potentiates the effects of olaparib in endometrial cancer","volume":"24","author":"Paraghamian","year":"2023","journal-title":"Cancer Biol. Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"101015","DOI":"10.1016\/j.neo.2024.101015","article-title":"ONC206 targeting ClpP induces mitochondrial dysfunction and protective autophagy in hepatocellular carcinoma cells","volume":"55","author":"Cao","year":"2024","journal-title":"Neoplasia"},{"key":"ref_32","first-page":"521","article-title":"ONC206 has anti-tumorigenic effects in human ovarian cancer cells and in a transgenic mouse model of high-grade serous ovarian cancer","volume":"12","author":"Tucker","year":"2022","journal-title":"Am. J. Cancer Res."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Lim, B., Peterson, C.B., Davis, A., Cho, E., Pearson, T., Liu, H., Hwang, M., Ueno, N.T., and Lee, J. (2021). ONC201 and an MEK Inhibitor Trametinib Synergistically Inhibit the Growth of Triple-Negative Breast Cancer Cells. Biomedicines, 9.","DOI":"10.3390\/biomedicines9101410"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/12\/1895\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T04:21:08Z","timestamp":1781324468000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/18\/12\/1895"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,10]]},"references-count":33,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["cancers18121895"],"URL":"https:\/\/doi.org\/10.3390\/cancers18121895","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,10]]}}}