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.

Downregulation of IGF2BP2 in TNBC cell could enhance the sensitivity to abemaciclib, a CDK4/6 inhibitor. To sum up, our study revealed IGF2BP2 could facilitate the translation output of CDK6 via recruiting EIF4A1 and also provided a potential therapeutic target for the diagnosis and treatment of TNBC, as well as a new strategy for broadening the drug indications for CDK4/6 inhibitors.

We investigated the link between Roca sensitivity and the response of HMCLs to MM drugs, and found that higher resistance to Bortezomib was associated with higher sensitivity to Roca (n = 10, r = -0.6, p value < 0.05). A synergy between Roca and Lenalidomide was identified in HMCLs, suggesting that the downregulation of MM oncoproteins with Roca could be used to increase the efficacy of IMIDs. In conclusion, Rocaglamide combination with IMIDs or other targeted therapies, such as EZH2 inhibitors, could be of clinical interest and represents a promising strategy to improve the outcome of MM patients.

Surprisingly, Zotatifin significantly synergizes with carboplatin to trigger DNA damage and an even heightened interferon response resulting in T cell-dependent tumor suppression. These studies identified a vulnerability of eIF4A in TNBC, potential pharmacodynamic biomarkers for Zotatifin, and provide a rationale for new combination regimens comprising Zotatifin and chemotherapy or immunotherapy as treatments for TNBC.

P1b, N=36, Completed, Effector Therapeutics | Active, not recruiting --> Completed

P1/2, N=30, Recruiting, Effector Therapeutics | N=228 --> 30 | Trial completion date: Sep 2023 --> Mar 2025 | Trial primary completion date: Jul 2023 --> Dec 2024

P2, N=150, Recruiting, Stanford University | Not yet recruiting --> Recruiting

P2, N=150, Not yet recruiting, Stanford University | N=100 --> 150

Furthermore, in paclitaxel-resistant TNBC cells, there is an upregulation in the total levels of eIF4A1 and its downstream effectors...Similarly, the lung metastatic burden is significantly low in KO than CC mice (n=7 mice; p<0.002)). Taken together, we propose that eIF4A1 is an actionable molecular target for drug-resistant TNBC using chemotherapy/immunotherapy.

In short, we establish the specific effect of mTOR-S6 on translation in cells lacking 4EBP1 and show that mTOR inhibition leads to feedback activation of translation via AKT-RSK1-eIF4E signals. Therefore, targeting translation downstream of mTOR presents a more efficient therapeutic strategy in pancreatic cancer.

Then, a triple regulatory network of mRNA, miRNA, and lncRNA was established. The current study identified EIF4A1, EIF4G3, NCBP1, and WDR4 as prognostic genes for SARC that are associated with m7G.These findings extend our knowledge of m7G methylation in SARC and may guide the development of innovative treatment options.

However, the primary mechanism of PKA effects on MYC in our cell models was translation and could be blocked with the eIF4A inhibitor zotatifin. This compound dramatically reduced c-MYC expression and inhibited FLC cell line growth in vitro. Thus, targeting PKA effects on translation is a potential treatment strategy for FLC and other PKA-driven cancers.

We discovered that chemoresistant MOLM-14 cells rely on eIF4A-dependent cap translation for survival in vitro and in vivo. EIF4A drives an intrinsic metabolic program sustaining bioenergetic and redox homeostasis and regulates the expression of anti-apoptotic proteins. Overall, our work suggests that eIF4A-dependent cap translation contributes to adaptive processes involved in resistance to relevant therapeutic agents in AML.

P2, N=100, Not yet recruiting, Stanford University | N=264 --> 100

Background: Up to 40% of diffuse large B-cell lymphoma (DLBCL) patients do not achieve a cure in response to standard immunochemotherapy R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone)...To further explore the role of the CD98hc counteracting mechanism, we established a doxycycline-inducible (TET-on) CD98hc-overexpressing DLBCL cell line (SU-DHL10), and we consistently found that overexpression of CD98hc was responsible for decreased sensitivity to zotatifin treatment (48h, 72h) by ATP-dependent viability assay... We define for the first time CD98hc as a new putative driver of rocaglate resistance in B-cell lymphoma. Paradoxically, CD98hc is upregulated as part of an overall cellular translational response to rocaglate exposure, but it provides insights and new potential targets for further drug combinations. This study lays the foundation for new treatment strategies to optimize the use of zotatifin to overcome rocaglate resistance in lymphoma patients.

The eIF4A1- STAT1-PD-L1 axis is highly active in TNBC especially in drug-resistant situations. Currently, we are evaluating emerging immune checkpoints such as VISTA, TIGIT, and LAG3.

Hsa-miR-139-5p-JUN, hsa-miR-324-5p-SP1 axis pairs were found in the miRNA-mRNA network, which could promote ISR development. The above results indicate that the miRNA-mRNA network constructed in ISR has a regulatory role in the development of ISR, and may provide new approaches for clinical treatment and experimental development.

Based on the results from the present study, we hypothesize that the dysregulation of EIF4A1 might be involved in the pathophysiology of LUAD development by promoting cancer growth and changing the tumor immune microenvironment. This can be used to develop potential diagnostic biomarkers or therapeutic targets for LUAD.

ccRCC patients with high eIF4A1 expression are at increased risk of poor prognosis, furthermore eIF4A1 plays a prominent role in facilitating tumor cell proliferation and migration which may further be a potential prognostic biomarker and therapeutic target.

JQ1-GSK2801 synergistically inhibits proliferation and results in selective gene regulation. Besides suggesting that combinatorial use could be useful therapeutics for the treatment of TNBC, the findings provide a glimpse into potential mechanisms of action for this combination therapy approach.

Finally, we found a positive correlation between expression levels of eIF4A1 and BRD2 in primary prostate cancers. Our results demonstrate, for prostate cancer cells, epigenetic regulation of EIF4A1 transcripts through DNA methylation and an oncogenic role of eIF4A1 through BRD2 signaling.

eIF4A inhibitor zotatifin achieves pharmacologically relevant exposures with on-target AEs that are manageable at the MTD, with evidence of target knockdown from on-treatment biopsies. Part 2 indication-specific expansions (including in ER+ FGFR-amplified MBC as single agent, ER+ MBC in combination with fulvestrant and abemaciclib, and KRAS NSCLC in combination with sotorasib) are on-going.

P1/2, N=198, Recruiting, Effector Therapeutics | N=45 --> 198 | Trial primary completion date: Dec 2022 --> Jul 2023

These data suggest that (±)14,15-EET can induce an estradiol-like immediate early gene response in ER+/HER2- breast cancer cells correlating with c-Myc activation. In summary, while the effect of (±)14,15-EET on nuclear translocation may be partially cargo agnostic, (±)14,15-EET promotes ER and c-Myc nuclear translocation and associated transcription, mimicking a tandem hormonal and growth factor response.

P1/2, N=45, Recruiting, Effector Therapeutics | Trial completion date: Dec 2021 --> Jul 2023 | Trial primary completion date: Oct 2021 --> Dec 2022

Overexpression of eIF4A1 downregulated E-cadherin expression through the c-MYC/miR-9 axis, which promoted EMT and metastasis of pancreatic cancer cells. Despite the potential feedback loop between eIF4A1 and c-MYC, RocA monotherapy is a promising treatment inhibiting eIF4A1-induced PDAC metastasis.

This dependency identifies the potential for rational combination strategies aimed at vertical inhibition of the PI3K/AKT/eIF4F pathway. Combination of zotatifin with PI3K or AKT inhibitors was beneficial across RTK-driven cancer models by blocking RTK-driven resistance mechanisms demonstrating the clinical potential of these combination strategies.

Lastly, tumors derived from Eif4e/Eμ-Myc or Eif4a1/Eμ-Myc mice show increased sensitivity to the chemotherapeutic agent doxorubicin, in vivo. Our study reveals that eIF4A2 and eIF4G3 play non-essential roles in gene expression regulation during embryogenesis; whereas reductions in eIF4E or eIF4A1 levels are protective against tumor development in a murine Myc-driven lymphoma setting.

These two interactions of FXR1 result in the circularization of cMYC mRNA and facilitate the recruitment of eukaryotic translation initiation factors to the translation start site. In brief, we uncover a mechanism by which FXR1 promotes cMYC levels in cancer cells.

The advantages of using circulating mRNA derived from mutated genes, over other non- invasive techniques, as well as the possibility that this approach can be used for HCC surveillance, patient stratification and clinical management, is highly novel and provocative .

Of the proteins determined to be differentially degraded by both acquisition methods, we find known proteins that are degraded by the ubiquitin-proteasome pathway, such as HNRNPK, EIF3A, and IF4A1/EIF4A-1, and a slower turnover for CATD, a protein implicated in invasive breast cancer. With improved quantification from DIA, we anticipate that this workflow will make SILAC-based experiments like protein turnover more sensitive.