1. Predictive Value of MRP-1 in Localized High-Risk Soft Tissue Sarcomas: A Translational Research Associated to ISG-STS 1001 Randomized Phase III Trialmm
- Author
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Jean-Yves Blay, Domenico Franco Merlo, Claudia Valverde, Antonella Brunello, Paola Collini, Salvatore Lorenzo Renne, Cleofé Romagosa, Antonio Lopez-Pousa, Joaquín Dopazo, Silvia Stacchiotti, Piero Picci, Angelo Paolo Dei Tos, Marco Gambarotti, Marta Barisella, Rafael Ramos, Paolo G. Casali, Antonio Gutierrez, Valérie Velasco, J. Martin-Broto, Silvia Bagué, David S. Moura, Nadia Hindi, Vittorio Quagliuolo, Giovanni Grignani, Maria Lopez-Alvarez, Alessandro Gronchi, Jean-Michel Coindre, Daniel Lopez-Lopez, Emanuela Palmerini, Luca Braglia, European Commission, Cancer Research UK, Associazione Italiana per la Ricerca sul Cancro, and Fundación Científica Asociación Española Contra el Cáncer
- Subjects
Oncology ,Male ,Cancer Research ,medicine.medical_specialty ,medicine.medical_treatment ,Translational Research, Biomedical ,stomatognathic system ,Predictive Value of Tests ,Internal medicine ,medicine ,Humans ,Doxorubicin ,Palifosfamide ,Chemotherapy ,Ifosfamide ,Tissue microarray ,business.industry ,Sarcoma ,medicine.disease ,Prognosis ,Nilotinib ,Selumetinib ,Female ,Multidrug Resistance-Associated Proteins ,business ,medicine.drug - Abstract
MRP-1 is implicated in multidrug resistance and was described as prognostic in high-risk patients with soft-tissue sarcoma (STS) in a previous study. The current research aimed to validate MRP-1 prognostic/predictive value in localized sarcomas treated with anthracyclines plus ifosfamide within the ISG-1001 phase III study. In addition, the inhibitory activity on MRP-1 was investigated in preclinical studies to identify new combinations able to increase the efficacy of standard chemotherapy in STS. MRP-1 expression was assessed by IHC in tissue microarrays from patients with STS and tested for correlation with disease-free survival (DFS) and overall survival (OS). In vitro studies tested the efficacy of MRP-1 inhibitors (nilotinib, ripretinib, selumetinib, and avapritinib) in sarcoma cell lines. The effect of combinations of the most active MRP-1 inhibitors and chemotherapy was measured on the basis of apoptosis. MRP-1 was evaluable in 231 of 264 cases who entered the study. MRP-1 expression (strong intensity) was independently associated with worse DFS [HR, 1.78; 95% confidence interval (CI), 1.11–2.83; P = 0.016], in the multivariate analysis, with a trend for a worse OS (HR, 1.78; 95% CI, 0.97–3.25; P = 0.062). In vitro studies showed that the addition of MRP-1 inhibitors (nilotinib or avapritinib) to doxorubicin plus palifosfamide, significantly increased cell death in SK-UT-1 and CP0024 cell lines. MRP-1 is an adverse predictive factor in localized high-risk patients with STS treated with neoadjuvant anthracyclines plus ifosfamide followed by surgery. In vitro findings support the clinical assessment of the combination of chemotherapy and MRP-1 inhibitors as a promising strategy to overcome the drug ceiling effect for chemotherapy., The study was partially funded through a European Union grant (EUROSARC FP7 278472). The authors would like to thank Patricio Ledesma Figueroa for Data Management. J. Martin-Broto, D.S. Moura and N. Hindi would like to thank the International Accelerator Award funded by Cancer Research UK [C56167/A29363], Associazione Italiana per la Ricerca sul Cancro [AIRC - 24297] and Fundacion Científica – Asociacion Espanola Contra el Cancer [Foundation AECC - GEACC19007MA]. D.S. Moura was supported by a Sara Borrell grant (CD20/00155) funded by the Instituto de Salud Carlos III. C. Romagosa was supported by a grant from the “Programa d'impuls del talent i de l'ocupabilitat del PERIS 2016–2020.” J-Y. Blay would like to express gratitude for the support from NetSARC (INCA and DGOS) EURACAN (EC 739521) and LYRICAN (INCA-DGOS-INSERM 12563). The ISH1001 study was supported by Eurosarc (FP7–278742).
- Published
- 2021