Monica Mangoni1,2, Mariangela Sottili3,4, Giulia Salvatore3,4, Domenico Campanacci5,4, Guido Scoccianti5,4, Giovanni Beltrami5,4, Camilla Delli Paoli3, Luca Dominici3, Virginia Maragna3, Emanuela Olmetto3, Icro Meattini3,4, Isacco Desideri3,4, Pierluigi Bonomo3,4, Daniela Greto3,4, Lorenzo Livi3,4. 1. Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", Section of Radiation Oncology, University of Florence, Largo Brambilla 3, 50134, Florence, Italy. monica.mangoni@unifi.it. 2. ITT, Istituto Toscano Tumori, Via Taddeo Alderotti 26/N, 50139, Florence, Italy. monica.mangoni@unifi.it. 3. Department of Biomedical, Experimental and Clinical Sciences "Mario Serio", Section of Radiation Oncology, University of Florence, Largo Brambilla 3, 50134, Florence, Italy. 4. ITT, Istituto Toscano Tumori, Via Taddeo Alderotti 26/N, 50139, Florence, Italy. 5. Department of Orthopaedic Oncology, Azienda Ospedaliera Universitaria Careggi, Largo Brambilla 3, 50134, Florence, Italy.
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.
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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