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.
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.
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.
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
Legal entity responsible for the study
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.