Background: Advanced and unresectable bone and soft tissue sarcomas (BSTS) still represent an unmet medical need. We demonstrated that the alkylating agent trabectedin and the PARP1-inhibitor olaparib display antitumor activity in BSTS preclinical models. Moreover, in a phase Ib clinical trial (NCT02398058), feasibility, tolerability and encouraging results have been observed and the treatment combination is currently under study in a phase II trial (NCT03838744). Methods: Differential expression of genes involved in DNA Damage Response and Repair was evaluated by Nanostring® technology, extracting RNA from pre-treatment tumor samples of 16 responder (≥6-month progression free survival) and 16 non-responder patients. Data validation was performed by quantitative real-time PCR, RNA in situ hybridization, and immunohistochemistry. The correlation between the identified candidate genes and both progression-free survival and overall survival was investigated in the publicly available dataset "Sarcoma (TCGA, The Cancer Genome Atlas)". Results: Differential RNA expression analysis revealed an 8-gene signature (CDKN2A, PIK3R1, SLFN11, ATM, APEX2, BLM, XRCC2, MAD2L2) defining patients with better outcome upon trabectedin+olaparib treatment. In responder vs. non-responder patients, a significant differential expression of these genes was further confirmed by RNA in situ hybridization and by qRT-PCR and immunohistochemistry in selected experiments. Correlation between survival outcomes and genetic alterations in the identified genes was shown in the TCGA sarcoma dataset. Conclusions: This work identified an 8-gene expression signature to improve prediction of response to trabectedin+olaparib combination in BSTS. The predictive role of these potential biomarkers warrants further investigation.

DNA damage response and repair genes in advanced bone and soft tissue sarcomas: An 8-gene signature as a candidate predictive biomarker of response to trabectedin and olaparib combination

Alessandra Merlini
Co-first
;
Maria Laura Centomo
Co-first
;
Giulio Ferrero;Giulia Chiabotto;Enrico Berrino;Giorgia Giordano;Silvia Brusco;Elena Maldi;Federica Capozzi;Claudio Isella;Giovanni Crisafulli;Massimo Aglietta;Dario Sangiolo;Lorenzo D’Ambrosio;Alberto Bardelli;Ymera Pignochino
Co-last
;
2022-01-01

Abstract

Background: Advanced and unresectable bone and soft tissue sarcomas (BSTS) still represent an unmet medical need. We demonstrated that the alkylating agent trabectedin and the PARP1-inhibitor olaparib display antitumor activity in BSTS preclinical models. Moreover, in a phase Ib clinical trial (NCT02398058), feasibility, tolerability and encouraging results have been observed and the treatment combination is currently under study in a phase II trial (NCT03838744). Methods: Differential expression of genes involved in DNA Damage Response and Repair was evaluated by Nanostring® technology, extracting RNA from pre-treatment tumor samples of 16 responder (≥6-month progression free survival) and 16 non-responder patients. Data validation was performed by quantitative real-time PCR, RNA in situ hybridization, and immunohistochemistry. The correlation between the identified candidate genes and both progression-free survival and overall survival was investigated in the publicly available dataset "Sarcoma (TCGA, The Cancer Genome Atlas)". Results: Differential RNA expression analysis revealed an 8-gene signature (CDKN2A, PIK3R1, SLFN11, ATM, APEX2, BLM, XRCC2, MAD2L2) defining patients with better outcome upon trabectedin+olaparib treatment. In responder vs. non-responder patients, a significant differential expression of these genes was further confirmed by RNA in situ hybridization and by qRT-PCR and immunohistochemistry in selected experiments. Correlation between survival outcomes and genetic alterations in the identified genes was shown in the TCGA sarcoma dataset. Conclusions: This work identified an 8-gene expression signature to improve prediction of response to trabectedin+olaparib combination in BSTS. The predictive role of these potential biomarkers warrants further investigation.
2022
Aug 30
12
844250
844263
DNA damage response and repair genes; bone and soft tissue sarcomas; olaparib; predictive biomarkers; trabectedin.
Alessandra Merlini, Maria Laura Centomo, Giulio Ferrero, Giulia Chiabotto, Umberto Miglio,Enrico Berrino, Giorgia Giordano, Silvia Brusco, Alberto Pisacane, Elena Maldi, Ivana Sarotto,Federica Capozzi, Cristina Lano, Claudio Isella, Giovanni Crisafulli, Massimo Aglietta,Angelo Paolo Dei Tos, Marta Sbaraglia,Dario Sangiolo, Lorenzo D’Ambrosio, Alberto Bardelli, Ymera Pignochino, Giovanni Grignani
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2318/1875243
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