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Activity of trabectedin and the PARP inhibitor rucaparib in soft-tissue sarcomas
Audrey Laroche1,2, Vanessa Chaire1,2, François Le Loarer2,3
1INSERM ACTION U1218, Institut Bergonié, 229 cours de l'Argonne, 33076, Bordeaux cedex, France.
Background:
Trabectedin has recently been approved in the USA and in Europe for advanced soft-tissue sarcoma patients who have been treated with anthracycline-based chemotherapy without success. The mechanism of action of trabectedin depends on the status of both the nucleotide excision repair (NER) and homologous recombination (HR) DNA repair pathways. Trabectedin results in DNA double-strand breaks. We hypothesized that PARP-1 inhibition is able to perpetuate trabectedin-induced DNA damage.
Methods:
We explored the effects of combining a PARP inhibitor (rucaparib) and trabectedin in a large panel of soft-tissue sarcoma (STS) cell lines and in a mouse model of dedifferentiated liposarcoma.
Results:
The combination of rucaparib and trabectedin in vitro was synergistic, inhibited cell proliferation, induced apoptosis, and accumulated in the G2/M phase of the cell cycle with higher efficacy than either single agent alone. The combination also resulted in enhanced γH2AX intranuclear accumulation as a result of DNA damage induction. In vivo, the combination of trabectedin and rucaparib significantly enhanced progression-free survival with an increased percentage of tumor necrosis.
Conclusion:
The combination of PARP inhibitor and trabectedin is beneficial in pre-clinical models of soft-tissue sarcoma and deserves further exploration in the clinical setting.
Insights
Combining trabectedin with PARP inhibitor rucaparib shows synergistic effects in soft-tissue sarcoma models. This combination enhances DNA damage and improves progression-free survival, warranting clinical investigation.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Trabectedin is approved for advanced soft-tissue sarcoma (STS) post-anthracycline chemotherapy.
- Trabectedin's efficacy is linked to DNA repair pathways (NER, HR) and induces DNA double-strand breaks.
- PARP-1 inhibition may potentiate trabectedin-induced DNA damage.
Purpose of the Study:
- To investigate the synergistic potential of combining trabectedin with a PARP inhibitor (rucaparib).
- To evaluate the combination's efficacy in preclinical models of soft-tissue sarcoma.
Main Methods:
- Tested trabectedin and rucaparib combination in STS cell lines and a liposarcoma mouse model.
- Assessed synergistic effects, cell proliferation, apoptosis, cell cycle, and DNA damage markers (γH2AX).
- Evaluated in vivo efficacy by measuring progression-free survival and tumor necrosis.
Main Results:
- In vitro, the combination demonstrated synergistic activity, inhibiting proliferation, inducing apoptosis, and causing G2/M cell cycle arrest.
- Enhanced γH2AX accumulation indicated increased DNA damage induction.
- In vivo, the combination significantly improved progression-free survival and increased tumor necrosis.
Conclusions:
- The combination of a PARP inhibitor and trabectedin shows significant preclinical benefit in soft-tissue sarcoma.
- This combination warrants further investigation in clinical trials for STS patients.