Noemie Luong1, Diana Gomes1, Sebastien Lofek2, Victor Rodriguez Freixinos1
1 Debiopharm International SA
2 Debiopharm Research & Manufacturing SA
Abstract
Debio 0432 is a potent and selective inhibitor of Ubiquitin specific protease 1 (USP1). USP1 is key for DNA damage repair and is upregulated in some BRCA-mutated tumors, contributing to DNA replication stability. In such tumors, genetic deletion of USP1 is lethal. Debio 0432 was previously shown to have single agent activity in models from several tumor types.
About 100 organoids were used for in vitro screening of indications of interest for Debio 0432 as a single agent and in combination with poly ADP ribose polymerase inhibitors (PARPi). Bliss independence model was used to determine the degree of synergism of these combinations in vitro. The combination with PARPi was also tested in in vivo studies, including relevant cell line-derived (CDX) and patient-derived xenograft (PDX) models. The proximal pharmacodynamic marker ubiquitinated-proliferating cell nuclear antigen (Ub-PCNA), directly modulated by USP1, was assessed by western blot.
Debio 0432 exhibited better growth inhibition activity when combined with PARPi, across different tumor types in organoids. In ovarian cancer organoids, a positive Bliss score (>0) was observed in 17/29 of models, suggesting good combination potential with possible synergy. A positive Bliss score was also found in 7/16 and 4/10 pancreatic and breast cancer organoids, respectively. In vivo models confirmed the potentiating effect of combining Debio 0432 with PARPi. The BRCA1 mutated MDA-MB-436 breast cancer model demonstrated improved tumor growth inhibition (TGI) upon combination compared to individual treatments. Other models resistant to both Debio 0432 and PARPi, revealed that the compounds acted synergistically to generate efficient TGI. In these models, Ub-PCNA increased upon treatment indicating effective target engagement.
Here, we show that the inhibition of USP1 through Debio 0432 potentiates the effect of PARPi across several tumor types in vitro and in vivo. Furthermore, Debio 0432 has the potential to overcome PARPi resistance, as demonstrated by sensitization of resistant models to the combination of both compounds. Debio 0432 is currently undergoing IND-enabling studies and is poised to enter clinical development later in 2024.