fimepinostat (CUDC-907)

Fimepinostat was tolerable at a dose of 35 mg/m2 in children with relapsed and refractory solid and CNS tumors, but lacked significant clinical activity. Discovery of drugs to target Myc continues to be a high priority for childhood cancers.

Our findings suggest that CUDC-907 is a promising agent that can re-sensitize tumors to progestin therapy and improve outcomes for EC patients. This study supports CUDC-907 as a potent treatment strategy in endometrial cancer and identifies IGF-1 as a potential surrogate serum biomarker for therapeutic response.

P1, N=26, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Oct 2025 --> Feb 2026 | Trial primary completion date: Oct 2025 --> Jan 2026

Combining CUDC-907 with cisplatin further decreased cell growth even in cisplatin-resistant cells. The majority of PM cell models are sensitive to CUDC-907, which may be a potent therapeutic agent in PM.

Additionally, CUDC-907 treatment significantly inhibited tumor growth and reduced tumor weight in the tumor xenograft mouse model. Taken together, this study revealed the cytotoxic effects of CUDC-907 and its underlying mechanism, which suggests that CUDC-907 may be an effective therapeutic approach for treating NSCLC.

Furthermore, this compound's effectiveness and safety were confirmed in both MH/NRASG12D BCP-ALL mouse model and MB patient-derived xenograft (PDX) model, outperforming conventional therapies. These results support the therapeutic potential of dual-pathway inhibition in MEF2D fusion (+) BCP-ALL and suggest CUDC-907 as a promising candidate for precision treatment in fusion-driven leukemias with similar molecular dependencies.

In this study, we identified that multiple HDAC inhibitors, including fimepinostat, romidepsin and panobinostat, downregulate the levels of the RRM1, RRM2, CHK1, and WEE1 proteins in Ewing sarcoma cells, and impair DNA replication. Additionally, proteomic studies identified that HDAC inhibitors also downregulate the level of the BRD4 protein, a BET bromodomain protein that regulates both the transcriptional program of the EWS::FLI1 oncoprotein and DNA replication. Overall, these results provide novel insight into the molecular mechanisms by which HDAC inhibitors target cancer cells, regulate DNA replication, and inhibit the cellular response to DNA replication stress.

Furthermore, when CUDC-907 was combined with chemotherapeutic drug cisplatin, G0/G1 phase blocking effect was further enhanced. CUDC-907 in combination with radiotherapy (RT) inhibited DNA damage repair and increased DNA damage. These findings indicate that CUDC-907, either as a monotherapy or in combination with chemoradiotherapy, represents a promising therapeutic strategy for MYC amplified G3 MB, potentially influencing future clinical trials targeting this patient population.

P1, N=26, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Jan 2025 --> Jun 2025 | Trial primary completion date: Jan 2025 --> Jun 2025

Notably, the combination of MK-1775 and CUDC-907 leads to significant antitumor effects in vivo. Our findings provide a strong basis for a promising combination strategy against prostate cancer.

TRIM21 may represent a therapeutic target for tumors, and inhibiting TRIM21 could be a potential strategy for tumor treatment.

Our study demonstrated most t-SCLC showed neuronal subtypes with low EGFR expression. DEGs analysis and t-SCLC preclinical models identified an epigenetic modifier as a promising treatment strategy for t-SCLC.