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; 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

doi:10.3389/fonc.2022.844250

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

Front Oncol. 2022 Aug 30:12:844250. doi: 10.3389/fonc.2022.844250. eCollection 2022.

Authors

Alessandra Merlini^{1

2}, Maria Laura Centomo^{1

2}, Giulio Ferrero^{3

4}, Giulia Chiabotto⁵, Umberto Miglio¹, Enrico Berrino^{1

5}, Giorgia Giordano^{1

2}, Silvia Brusco^{1

2}, Alberto Pisacane¹, Elena Maldi¹, Ivana Sarotto¹, Federica Capozzi¹, Cristina Lano^{1

2}, Claudio Isella^{1

2}, Giovanni Crisafulli^{1

2}, Massimo Aglietta^{1

2}, Angelo Paolo Dei Tos^{6

7}, Marta Sbaraglia⁶, Dario Sangiolo^{1

2}, Lorenzo D'Ambrosio^{1

2

8}, Alberto Bardelli^{1

2}, Ymera Pignochino^{1

3}, Giovanni Grignani¹

Affiliations

¹ Candiolo Cancer Institute, FPO-IRCCS, Turin, Italy.
² Department of Oncology, University of Torino, Turin, Italy.
³ Department of Clinical and Biological Sciences, University of Torino, Turin, Italy.
⁴ Department of Computer Science, University of Torino, Turin, Italy.
⁵ Department of Medical Sciences, University of Torino, Turin, Italy.
⁶ Department of Pathology, Azienda Ospedale-Università Padova, Padua, Italy.
⁷ Department of Medicine (DIMED), University of Padua School of Medicine, Padua, Italy.
⁸ Medical Oncology, AOU San Luigi Gonzaga, Orbassano (TO), Italy.

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.

Keywords: DNA damage response and repair genes; bone and soft tissue sarcomas; olaparib; predictive biomarkers; trabectedin.

Copyright © 2022 Merlini, Centomo, Ferrero, Chiabotto, Miglio, Berrino, Giordano, Brusco, Pisacane, Maldi, Sarotto, Capozzi, Lano, Isella, Crisafulli, Aglietta, Dei Tos, Sbaraglia, Sangiolo, D’Ambrosio, Bardelli, Pignochino and Grignani.

Associated data

ClinicalTrials.gov/NCT03838744