In an early clinical trial (NCT04092673), the eIF4A inhibitor zotatifin was combined with either fulvestrant or fulvestrant plus CDK4 inhibitor, abemaciclib, in patients with acquired resistance to these agents. Multiple clinical responses including a handful of durable regressions were observed, with little toxicity. Thus, eIF4A inhibition could be useful for treating ER+ breast cancer resistant to other modalities.

P2, N=19, Suspended, Stanford University | Active, not recruiting --> Suspended

Moreover, the Bcl-xl inhibitors A-1155463 and DT2216 profoundly augmented apoptotic cell death when administered in association with zotatifin. From a clinical standpoint, these results suggest that zotatifin improves patient outcomes by inhibiting iCCA growth and reducing tumor aggressiveness. Furthermore, combining zotatifin with other drugs could represent a promising therapeutic strategy for targeting iCCA.

P2, N=180, Recruiting, Dana-Farber Cancer Institute | Active, not recruiting --> Recruiting | N=130 --> 180 | Trial completion date: Aug 2030 --> Aug 2031 | Trial primary completion date: Aug 2027 --> Aug 2028

Remarkably, tumors treated with zotatifin become more sensitive to anti-androgen therapy and radiotherapy. Therefore, "translatome therapy" provides additional strategies to treat the deadliest cancers.

In conclusion, eIF4A1 is a detrimental factor in myocardial I/R injury via promoting expression and nuclear translocation of Tagln and p53 and might be a potential target for myocardial I/R injury. This study highlights a novel biological role of eIF4A1 by interacting with non-translational-related factor Tagln in myocardial I/R injury.

P2, N=130, Active, not recruiting, Dana-Farber Cancer Institute | Recruiting --> Active, not recruiting | Trial completion date: Aug 2029 --> Aug 2030 | Trial primary completion date: Aug 2026 --> Aug 2027

P2, N=19, Active, not recruiting, Stanford University | Recruiting --> Active, not recruiting | N=150 --> 19

P2, N=130, Recruiting, Dana-Farber Cancer Institute | N=60 --> 130 | Trial completion date: May 2026 --> Aug 2029 | Trial primary completion date: May 2024 --> Aug 2026

Moreover, we show that mTORC1 and S6K1, two key regulators of protein synthesis, directly phosphorylate IBTK to augment eIF4A1 ubiquitination and sustained oncogenic translation. This link between the CRL3IBTK complex and the mTORC1/S6K1 signaling pathway, which is frequently dysregulated in cancer, represents a promising target for anti-cancer therapies.

IGF2BPs, as m6A reader, IGF2BPs were oncogenic genes in ESCC by regulating the expression of EIF4A1 through m6A sites. IGF2BP2, EIF4A1 and their targets could serve as potential biomarkers and therapeutic targets for ESCC, offering promising novel approaches for the diagnosis and treatment of ESCC.

After B cell activation in vitro, EIF4A1 facilitates an increased rate of protein synthesis, MYC expression, and expression of cell cycle regulators. However, EIF4A1-deficient cells remain viable, whereas inhibition of EIF4A1 and EIF4A2 by Hippuristanol treatment induces cell death.