Abstract 210P
Background
Triple-negative breast cancer (TNBC) represents nearly 20% of all breast cancers and is considered to be more aggressive and to have poorer prognosis due to lack of effective treatments. KDM4 is a family of histone demethylases shown to drive cancer by regulating transcription, cell cycle, and DNA replication/repair. Overexpression of KDM4 leading to mistakes in post-translational histone modification is associated with many. cancers, including TNBC.
Methods
TACH101 was evaluated in in vitro and in vivo studies including RNA knock-down experiments, cell-proliferation assays, apoptotic and cell cycle analyses, and efficacy studies in TNBC xenograft tumor models.
Results
TACH101 is a reversible, α-ketoglutarate competitive, selective and potent inhibitor of KDM4, with IC50 values < 0.1 μM for KDM4 isoforms A-D. Lentiviral shRNA experiments showed knockdown of KDM4 resulted in direct inhibitory effect on colony formation of breast 3D organoid culture models. TACH101 inhibited colony formation in replating experiments, suggesting a role for KDM4 in maintenance and propagation of tumor initiating cells (TIC). Further support for this mechanism was the finding that TACH101 reduced TIC frequency by 4.4-fold. TACH101 was broadly effective in killing 67% (200 out of 300) of cancer cell lines screened, including the MDA-MB-231 TNBC cell line (IC50 of 0.0035 μM). TACH101 treatment of MDA-MB-231 cells increased the cell population in S-phase indicating cell-cycle arrest. TACH101 induced apoptosis in MDA-MB-231 cells with EC50 of 0.132 μM. In vivo, TACH101 triggered effective tumor control in COH70 TNBC xenograft model with tumor growth inhibition > 85%. TACH101 effects on gene expression were evaluated. Protein Phosphatase 1 Regulatory subunit 10 (PPP1R10), a direct target of KDM4, was significant downregulated after 24 hours of treatment with TACH101.
Conclusions
Extensive preclinical work on TACH101 KDM4 inhibitor indicates compelling data and applicability as a potential therapy for TNBC. The preparations to advance the drug into clinical trials are underway.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Tachyon Therapeutics.
Funding
Tachyon Therapeutics.
Disclosure
F.G. Perabo, S. Yoo, C. Chandhasin: Financial Interests, Personal, Full or part-time Employment: Tachyon Therapeutics. J.R. Del Rosario, Y.K. Chen, E. Filvaroff: Financial Interests, Personal, Full or part-time Employment: Bristol Myers Squibb. J. Stafford: Financial Interests, Personal, Full or part-time Employment: 858 Therapeutics. S. Quake, M. Clarke: Financial Interests, Personal, Member of the Board of Directors: Tachyon Therapeutics.