Abstract 16P
Background
Targeting DNA damage response (DDR) is one of the most promising but challenging ways to treat cancer, with PARP inhibitors being the only approved therapies in the field. Here, we describe the antineoplastic and immunomodulatory effects of VIO-01, a first-in-class pan-DDR DNA decoy-cholesterol conjugate, operating as a pan DDR decoy, resulting in constitutive DDR exhaustion.
Methods
Homologous recombination proficient (HRP) and deficient (HRD) cancer models were used to investigate VIO-01-induced DDR protein trapping and cellular cytotoxicity. Analysis of repair proteins recruitment to damages site allowed to monitor the DNA repair efficiency. RNAseq analysis in HRP/HRD ovarian cancer cells was used to uncover the molecular mechanisms underlying the effects of VIO-01. Effects on innate and adaptive immune responses were assessed by monitoring T-cell-mediated antitumor cytotoxicity. The biodistribution and antitumor efficacy of VIO-01 were also evaluated in relevant in vivo models.
Results
VIO-01 binds several DDR proteins with high affinity, resulting in an abrogation of single and double strand break repair and leading in notable VIO-01-induced downregulation of BER, NHEJ and NER pathways in both HRP/HRD cell lines. VIO-01 elicited immune system activation and inflammatory responses in ovarian cancer cells. This activity was specific to tumor cells, while sparing healthy and immune cells, at odds with PARP inhibitors. VIO-01 mediated antitumor efficacy in vivo coupled to tumor-targeting T-cell responses. These effects were driven by a favorable ADME/PK profile, showing a long-lasting VIO-01 residence time into tumors, a clear hijacking from the liver and a rapid blood clearance, ensuring minimal toxicity. Also, regulatory toxicology studies demonstrated a favorable safety profile of VIO-01 in non-human primate with the major findings being a transient increase in specific cytokines and complement factors, which was not confirmed in human serum at relevant VIO-01 concentrations.
Conclusions
Our results provide a preclinical rationale for using VIO-01 to trigger DNA damage exhaustion and an antitumor immune response, paving the way for rapid clinical application in patients bearing HRD or HRP tumors.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.