A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcomaResearch in context
Verónica Rey,
Juan Tornín,
Juan Jose Alba-Linares,
Cristina Robledo,
Dzohara Murillo,
Aida Rodríguez,
Borja Gallego,
Carmen Huergo,
Cristina Viera,
Alejandro Braña,
Aurora Astudillo,
Dominique Heymann,
Karoly Szuhai,
Judith V.M.G. Bovée,
Agustín F. Fernández,
Mario F. Fraga,
Javier Alonso,
René Rodríguez
Affiliations
Verónica Rey
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain; CIBER en oncología (CIBERONC), 28029, Madrid, Spain
Juan Tornín
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain
Juan Jose Alba-Linares
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain; Cancer Epigenetics and Nanomedicine Laboratory, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), El Entrego, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain
Cristina Robledo
Unidad de Tumores Sólidos Infantiles, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), 28220, Madrid, Spain
Dzohara Murillo
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain
Aida Rodríguez
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain
Borja Gallego
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain
Carmen Huergo
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain; CIBER en oncología (CIBERONC), 28029, Madrid, Spain
Cristina Viera
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain
Alejandro Braña
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain; Department of Traumatology, University Hospital of Asturias (HUCA), Oviedo, Spain
Aurora Astudillo
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain; Department of Pathology, University Hospital of Asturias (HUCA), Oviedo, Spain
Dominique Heymann
Nantes Université, CNRS, US2B, UMR 6286, 44000, Nantes, France; Institut de Cancérologie de l'Ouest, Tumor Heterogeneity and Precision Medicine Lab. Université de Nantes, 44805, Saint-Herblain, France; Department of Oncology and Metabolism, Medical School, University of Sheffield, Sheffield, UK
Karoly Szuhai
Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands
Judith V.M.G. Bovée
Department of Pathology, Leiden University Medical Center, Leiden, Netherlands
Agustín F. Fernández
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain; Cancer Epigenetics and Nanomedicine Laboratory, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), El Entrego, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain
Mario F. Fraga
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain; Cancer Epigenetics and Nanomedicine Laboratory, Nanomaterials and Nanotechnology Research Center (CINN-CSIC), El Entrego, Spain; Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain
Javier Alonso
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Instituto de Salud Carlos III, 28029, Madrid, Spain; Unidad de Tumores Sólidos Infantiles, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III (ISCIII), 28220, Madrid, Spain
René Rodríguez
Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Hospital Universitario Central de Asturias, Avenida de Roma, s/n, 33011, Oviedo, Spain; Instituto Universitario de Oncología del Principado de Asturias, 33011, Oviedo, Spain; CIBER en oncología (CIBERONC), 28029, Madrid, Spain; Corresponding author. Sarcomas and Experimental Therapeutics Lab., Instituto de Investigación Sanitaria del Principado de Asturias (ISPA), Av. de Roma s/n, 33011, Oviedo, Spain.
Summary: Background: Sarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. Among sarcomas, the clinical management of chondrosarcomas remains a complex challenge, as high-grade tumours do not respond to current therapies. Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are among the most common mutations detected in chondrosarcomas and may represent a therapeutic opportunity. The presence of mutated IDH (mIDH) enzymes results in the accumulation of the oncometabolite 2-HG leading to molecular alterations that contribute to drive tumour growth. Methods: We developed a personalized medicine strategy based on the targeted NGS/Sanger sequencing of sarcoma samples (n = 6) and the use of matched patient-derived cell lines as a drug-testing platform. The anti-tumour potential of IDH mutations found in two chondrosarcoma cases was analysed in vitro, in vivo and molecularly (transcriptomic and DNA methylation analyses). Findings: We treated several chondrosarcoma models with specific mIDH1/2 inhibitors. Among these treatments, only the mIDH2 inhibitor enasidenib was able to decrease 2-HG levels and efficiently reduce the viability of mIDH2 chondrosarcoma cells. Importantly, oral administration of enasidenib in xenografted mice resulted in a complete abrogation of tumour growth. Enasidenib induced a profound remodelling of the transcriptomic landscape not associated to changes in the 5 mC methylation levels and its anti-tumour effects were associated with the repression of proliferative pathways such as those controlled by E2F factors. Interpretation: Overall, this work provides preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas. Funding: Supported by the Spanish Research Agency/FEDER (grants PID2022-142020OB-I00; PID2019-106666RB-I00), the ISC III/FEDER (PI20CIII/00020; DTS18CIII/00005; CB16/12/00390; CB06/07/1009; CB19/07/00057); the GEIS group (GEIS-62); and the PCTI (Asturias)/FEDER (IDI/2021/000027).
