Poly(ADP-ribose) polymerase inhibitors in Ewing sarcoma
نویسندگان
چکیده
PURPOSE OF REVIEW In 2012, two publications revealed a particular sensitivity of Ewing sarcoma cells to the inhibition of poly(ADP-ribose) polymerase (PARP). This review updates the reader on PARP function, the development of PARP inhibitors (PARPi) and the evidence for targeting PARP in Ewing sarcoma. It concludes with a description of ongoing/emerging PARPi clinical trials in patients with Ewing sarcoma. RECENT FINDINGS PARP has a major role in DNA repair, and is a transcription regulator. The oncoprotein in Ewing sarcoma, EWS-FLI1, is proposed to interact with PARP-1, driving PARP-1 expression, which further promotes transcriptional activation by EWS-FLI1. Thus, there are two rationales for PARPi in the treatment of Ewing sarcoma: to disrupt the interaction between EWS-FLI1 and PARP, and for chemo-potentiation or radio-potentiation. The first clinical trial with a single agent PARPi failed to show significant responses, but preclinical evidence for combinations of PARPi with chemotherapy or radiotherapy is very promising. SUMMARY Despite initial excitement for the potential of PARPi as single agent therapy in Ewing sarcoma, the emerging preclinical data now strongly support testing PARPi in combination with chemo/radiotherapy clinically.
منابع مشابه
Sensitizing Ewing sarcoma to chemo- and radiotherapy by inhibition of the DNA-repair enzymes DNA protein kinase (DNA-PK) and poly-ADP-ribose polymerase (PARP) 1/2
Background DNA-PK and PARP inhibitors sensitize cancer cells to chemo- and radiotherapy. ETS transcription factors (EWS-FLI1) have been described as biomarkers for PARP-inhibitor sensitivity. Sensitivity to single agent PARP inhibitors has so far been limited to homologous recombination repair (HRR) deficient tumors, exploiting synthetic lethality. Results In clonogenic assays, single agent r...
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