P1, N=6, Not yet recruiting, Pfizer | Trial completion date: Aug 2024 --> Nov 2024 | Initiation date: May 2024 --> Aug 2024 | Trial primary completion date: Aug 2024 --> Nov 2024
6 months ago
Trial completion date • Trial initiation date • Trial primary completion date
Ebvaciclib, is a CDK2/4/6 inhibitor designed to be co-dosed with hormone therapy (letrozole or fulvestrant) to treat HR+ breast cancer. PF-06821497 is an EZH2 inhibitor currently being evaluated alone and in combination with enzalutamide to treat patients with castration resistant prostate cancer who have received either abiraterone and/or enzalutamide treatment and have evidence of prostate cancer progression. Discovery, synthesis, and early clinical results will be presented.
EZH2i EPZ-6438 (tazemetostat) or PF-06821497 and HDACi vorinostat were combined with ONC201 to treat multiple cancer cell lines and cell viability and histone modifications were analyzed. Although synergy was observed with ONC201 and vorinostat, there was no significant increase in H3K27 acetylation in cell lines including DIPG as compared to vorinostat alone, and in some cases the acetylation was less than vorinostat alone at 72 H. H3K27 methylation reduction correlated with synergy from combinations of either EPZ-6438 or vorinostat with ONC201 or triple combination. Our findings provide a rationale for combination of ONC201 and epigenetic modulators including triple therapy for in vivo and clinical testing in treatment of human malignancies including brain tumors and DIPG.
EPZ-6438 or PF-06821497 decreased H3K27 tri-methylation. Our study results unravel potent synergy between ONC201 and EZH2i, highlight the role of ISR in the synergy, and provide further insights into the role of H3K27me3 in ONC201 drug sensitivity.