Oral Presentations

Background: Poly(ADP-ribose) polymerase (PARP) is a family of 17 enzymes involved in DNA damage repair, particularly in single-strand break (SSB) repair.PARP inhibitors (PARPi) prevent this process through catalytic inhibition and PARP trapping, leading to the accumulation of toxic DNA-protein complexes and cell death.These effects are particularly pronounced in BRCA-mutant and homologous recombination deficiency (HRD) cancers, where PARPi-induced DNA damage cannot be repaired.While PARPi are approved for ovarian, breast, prostate, and pancreatic cancers, their role in rectal cancer remains under investigation.Additionally, emerging evidence suggests that targeting other PARP family members (e.g., PARP7 and pan-PARP) may influence immune regulation, making them promising candidates for combination therapy with radiotherapy.Objective: This study examines the effects of radiotherapy with or without PARPi in rectal cancer organoids, assessing their impact on tumour viability and treatment response to explore their potential therapeutic value.Methods: Patient-derived rectal cancer organoids were used as a preclinical model, maintaining the genetic and molecular characteristics of the original tumour.HRD analysis was performed, followed by a PARPi screen in combination with irradiation.Organoid viability was assessed using ATP quantitation at the study endpoint.Results: A multivariate stepwise logistic regression model showed a significant inverse association (coef -0.222, 95% CI = -0.325 to -0.119, p < 0.001) between viability and increasing PARPi doses, adjusted for radiation dose and organoid line.Conclusion: This study demonstrates that PARPi enhances the effects of radiotherapy in rectal cancer organoids.These findings support further research into PARPi-based combination therapies to improve treatment outcomes.