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01.04.2019 | RADIOBIOLOGY AND SAFETY

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

verfasst von: 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

Erschienen in: La radiologia medica | Ausgabe 4/2019

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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.

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Titel: Soft tissue sarcomas: new opportunity of treatment with PARP inhibitors?
verfasst von: 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
Publikationsdatum: 01.04.2019
Verlag: Springer Milan
Erschienen in: La radiologia medica / Ausgabe 4/2019
Print ISSN: 0033-8362
Elektronische ISSN: 1826-6983
DOI: https://doi.org/10.1007/s11547-018-0877-4

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