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Soft tissue sarcomas: new opportunity of treatment with PARP inhibitors?

  • Monica Mangoni
  • Mariangela Sottili
  • Giulia Salvatore
  • Domenico Campanacci
  • Guido Scoccianti
  • Giovanni Beltrami
  • Camilla Delli Paoli
  • Luca Dominici
  • Virginia Maragna
  • Emanuela Olmetto
  • Icro Meattini
  • Isacco Desideri
  • Pierluigi Bonomo
  • Daniela Greto
  • Lorenzo Livi
RADIOBIOLOGY AND SAFETY

Abstract

Background

Poly(ADP-ribose) polymerases (PARP) are a large family of enzymes involved in several cellular processes, including DNA single-strand break repair via the base-excision repair pathway. PARP inhibitors exert antitumor activity by both catalytic PARP inhibition and PARP–DNA trapping, moreover PARP inhibition represents a potential synthetic lethal approach against cancers with specific DNA-repair defects. Soft tissue sarcoma (STSs) are a heterogeneous group of mesenchymal tumors with locally destructive growth, high risk of recurrence and distant metastasis.

Objectives

The purpuse of this review is to provide an overview of the main preclinical and clinical data on use of PARPi in STSs and of effect and safety of combination of PARPi with irradiation.

Results

Due to numerous genomic alterations in STSs, the DNA damage response pathway can offer an interesting target for biologic therapy. Preclinical and clinical studies showed promising results, with the most robust evidences of PARPi efficacy obtained on Ewing sarcoma bearing EWS–FLI1 or EWS–ERG genomic fusions. The activity of PARP inhibitors resulted potentiated by chemotherapy and radiation. Although mechanisms of synergisms are not completely known, combination of radiation therapy and PARP inhibitors exerts antitumor effect by accumulation of unrepaired DNA damage, arrest in G2/M, activity both on oxic and hypoxic cells, reoxygenation by effect on vessels and promotion of senescence. Early trials have shown a good tolerance profile.

Conclusions

The use of PARP inhibitors in advanced stage STSs, alone or combined in multimodal treatments, is of great interest and warrants further investigations.

Keywords

Poly(ADP-ribose) polymerases (PARP) Soft tissue sarcoma (STSs) DNA damage response pathway Radiation therapy 

Notes

Funding

This study was funded by the Istituto Toscano Tumori.

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical standards

This article does not contain any studies with human participants or animals performed by any of the authors.

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Copyright information

© Italian Society of Medical Radiology 2018

Authors and Affiliations

  • Monica Mangoni
    • 1
    • 3
  • Mariangela Sottili
    • 1
    • 3
  • Giulia Salvatore
    • 1
    • 3
  • Domenico Campanacci
    • 2
    • 3
  • Guido Scoccianti
    • 2
    • 3
  • Giovanni Beltrami
    • 2
    • 3
  • Camilla Delli Paoli
    • 1
  • Luca Dominici
    • 1
  • Virginia Maragna
    • 1
  • Emanuela Olmetto
    • 1
  • Icro Meattini
    • 1
    • 3
  • Isacco Desideri
    • 1
    • 3
  • Pierluigi Bonomo
    • 1
    • 3
  • Daniela Greto
    • 1
    • 3
  • Lorenzo Livi
    • 1
    • 3
  1. 1.Department of Biomedical, Experimental and Clinical Sciences “Mario Serio”, Section of Radiation OncologyUniversity of FlorenceFlorenceItaly
  2. 2.Department of Orthopaedic OncologyAzienda Ospedaliera Universitaria CareggiFlorenceItaly
  3. 3.ITT, Istituto Toscano TumoriFlorenceItaly

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