Giuditta Illuzzi

Dr. Giuditta Illuzzi- AstraZeneca, Cambridge, United Kingdom

Abstract

Unravelling PARP Inhibitor Mechanisms: from HRRm/BRCAm to broader non-HRRm tumours

Giuditta Illuzzi, PhD

OTD Bioscience, Early Oncology, AstraZeneca, Cambridge, United Kingdom.

Clinically approved PARP inhibitors (PARPi) have shown significant efficacy as monotherapy in homologous recombination repair (HRR)-deficient cancers. PARPi not only suppress the PARylation activity of PARP1 but also induce PARP1 trapping on DNA lesions; there is an ongoing debate about which of these properties is key in determining their clinical efficacy as single agents. We will present our latest study, where we demonstrated that the enzymatic activity of PARP1 is dispensable while PARP1 expression is necessary for the efficacy of PARPi in a BRCA-mutant (BRCAm) breast cancer model ⁽¹⁾.

Furthermore, recently phase 3 clinical trial readouts have shown that PARPi provide benefits in metastatic, castration-resistant prostate cancer (mCRPC), in combination with Androgen Receptor Pathway inhibition (ARPi), in tumours with or without homologous recombination repair deficiency. We explored the mechanisms of action contributing to this observed combination benefit in preclinical models, HRR-deficient and -proficient, treated with saruparib, olaparib r veliparib and the data obtained provide mechanistic evidence that combination benefit is driven by PARP1 trapping inducing DNA damage, and PARP1 inhibition and ARPi inhibiting the repair of this damage, leading to accumulation of cytotoxic genomic instability to the cancer cells ⁽²⁾ .

1. Ribeiro et al., Genetic evidence for PARP1 trapping as a driver of PARP inhibitor efficacy in BRCAmutant cancer cells, Nucleic Acids Research, 2025
2. Illuzzi et al., Androgen receptor inhibition extends PARP inhibitor activity in prostate cancer models beyond BRCA mutations and defects in homologous recombination repair, NAR Cancer, 2025

Biography:

Giuditta Illuzzi is Associate Principal Scientist in the Small Molecule Bioscience department of Oncology R&D Astrazeneca in Cambridge, UK since 2017 working on new target identification and validation. Her contributions were key for the development of the new generation of PARP1 inhibitors now in clinical trials.

Giuditta Illuzzi is Italian but grew-up in Munich, Germany; she obtained degree in Biology Applied to Biomedical Research and then PhD in Biochemistry from the University of Milan in 2010 studying sphingolipid-protein complexes in tumour invasion and drug-resistance mechanisms. She then moved to the CNRS of Strasbourg, France to work on the role of PARylation and PARG in DNA replication stress and DNA damage repair processes. Recognised member of the scientific PARP field and motivated to give her maximum contribution in the fight against cancer she is enjoying drug discovery at Astrazeneca.