- |||||||||| tomivosertib (eFT508) / eFFECTOR Therap
Journal: Tomivosertib reduces ectopic activity in dorsal root ganglion neurons from patients with radiculopathy. (Pubmed Central) - Sep 3, 2024
Parallel to the effects on electrophysiology, eFT508 treatment led to a profound loss of eIF4E serine 209 phosphorylation in primary sensory neurons, a specific substrate of MNK, within 2 min of drug treatment. Our results create a compelling case for the future testing of MNK inhibitors in clinical trials for neuropathic pain.
- |||||||||| tomivosertib (eFT508) / eFFECTOR Therap
Journal: Interleukin-6 induces nascent protein synthesis in human dorsal root ganglion nociceptors primarily via MNK-eIF4E signaling. (Pubmed Central) - Aug 19, 2024
To pinpoint the specific molecular mechanisms driving this IL-6-driven increase in nascent proteins, we used the specific MNK1/2 inhibitor eFT508...Our findings provide clear evidence that IL-6 drives nascent protein synthesis in human TRPV1+ nociceptors primarily via MNK1/2-eIF4E signaling. The work links animal findings to human nociception, creates a framework for additional hDRG signaling experiments, and substantiates the continued development of MNK inhibitors for pain.
- |||||||||| tomivosertib (eFT508) / eFFECTOR Therap
Journal: Selective and effective suppression of pancreatic cancer through MNK inhibition. (Pubmed Central) - Aug 14, 2024
The MNK-eIF4E-?-catenin axis plays a critical role in pancreatic cancer progression and chemoresistance, distinguishing pancreatic cancer cells from normal cells. Targeting MNK kinases with inhibitors like eFT508 presents a promising therapeutic strategy for pancreatic cancer, with potential for selective efficacy and reduced toxicity.
- |||||||||| zotatifin (eFT226) / eFFECTOR Therap, CR-1-31-B / McGill University
Journal: Pharmacologic inhibition of eIF4A blocks NRF2 synthesis to prevent osteosarcoma metastasis. (Pubmed Central) - Jul 30, 2024
Targeting MNK kinases with inhibitors like eFT508 presents a promising therapeutic strategy for pancreatic cancer, with potential for selective efficacy and reduced toxicity. Collectively, our data reveal that pharmacologic targeting of eIF4A1 is highly effective in blocking OS metastasis by blunting the NRF2 antioxidant response.
- |||||||||| tomivosertib (eFT508) / eFFECTOR Therap
Journal: TSC2 loss in neural progenitor cells suppresses translation of ASD/NDD-associated transcripts in an mTORC1- and MNK1/2-reversible fashion. (Pubmed Central) - Jun 19, 2024
Most notably, numerous non-monogenic ASD-NDD- and epilepsy-associated genes identified in patients harboring putative loss-of-function mutations, including protein truncating, or damaging missense variants, were translationally suppressed in TSC2 -Null NPCs, and their translation were reversed upon RMC-6272 or eFT-508 treatment. Our study here establishes the importance of mTORC1-eIF4F and MNK-eIF4E-mediated mRNA translation in TSC, ASD and other neurodevelopmental disorders and lay the groundwork for evaluating drugs in clinical development that target these pathways as a treatment strategy for TSC as well as ASD/NDD.
- |||||||||| tomivosertib (eFT508) / eFFECTOR Therap
Trial completion date, Trial primary completion date, Combination therapy: Tomivosertib Combined With Pembrolizumab in Subjects With PD-L1 Positive NSCLC (KICKSTART) (clinicaltrials.gov) - Apr 30, 2024
P2, N=68, Active, not recruiting,
Moreover, our data indicate that NETsare an underappreciated feature of extranodal DLBCLs, and that therapeutically targeting eIF4Ephosphorylation may be an effective strategy to reduce NETosis Trial completion date: May 2024 --> Dec 2024 | Trial primary completion date: Mar 2024 --> Oct 2024
- |||||||||| tomivosertib (eFT508) / eFFECTOR Therap
Role of MNK/eIF4E pathway in CD4+ Th2 cytokine-induced lung fibrosis in chronic allergic asthma. (Exhibit Hall F1; Poster Board Number: B655) - Mar 29, 2024 - Abstract #IMMUNOLOGY2024IMMUNOLOGY_1270;
Luminex assay results demonstrated a significant decrease in IL-6, CCL-2, and GM-CSF in the activated MCs upon inhibiting the MNK1/2 pathway. Additionally, eFT-508 exhibited a marked reduction in lymphocyte migration, utilizing the Boyden chamber transwell assay.Our study reveals that targeting the MNK/eIF4E pathway holds promise in mitigating airway remodeling associated with MCs fibrosis and provides valuable molecular insights for future therapeutic interventions related to fibrosis in the airway remodeling of allergic asthma.
- |||||||||| enzalutamide capsule / Generic mfg.
The MNK inhibitor EB1 sensitizes AR-V7 positive castration-resistant prostate cancer to enzalutamide (Section 30) - Mar 5, 2024 - Abstract #AACR2024AACR_6774;
Here we demonstrate that the novel MNK inhibitor EB1 shows promising in vitro results, which cannot be obtained with Type-I MNK inhibitors. The combination of EB1 with the standard of care Enzalutamide provide a novel therapeutic opportunity for the treatment of CRPC, particularly in AR-V7 positive patients.
- |||||||||| sorafenib / Generic mfg.
Developing dual FLT3/MNK inhibitors to overcome sorafenib resistance in FLT3-ITD AML cells (Section 20) - Mar 5, 2024 - Abstract #AACR2024AACR_6383;
H104 and H118 decreased the levels of p-eIF4E, c-myc and Mcl-1, the downstream substrates of FLT3-ITD and MNK. Our data indicate that the activated MNK is one mechanism of FLT3-ITD resistance and the dual MNK/FLT3 inhibitors have advantage for FLT3-ITD AML treatment.
- |||||||||| tomivosertib (eFT508) / eFFECTOR Therap
Enrollment open: Tomivosertib in Relapsed or Refractory Acute Myeloid Leukemia (AML) (clinicaltrials.gov) - Feb 7, 2024
P1, N=15, Recruiting,
Additionally, our study underscores the significance of the MNK/eIF4E signaling pathway in modulating HuR alongside fibrotic mediators, including ATX, within the context of lung transplantation. Active, not recruiting --> Recruiting
- |||||||||| tomivosertib (eFT508) / eFFECTOR Therap, cercosporamide / Eli Lilly
Journal: Inhibition of MNK pathway sensitizes nasopharyngeal carcinoma to radiotherapy. (Pubmed Central) - Jan 9, 2024
Our research highlights the activation of MNK-mediated survival mechanisms in NPC in response to radiotherapy and the potential of combining radiation with MNK inhibitors as a sensitizing strategy. Notably, eFT508 is currently being investigated in clinical trials for cancer treatment, and our findings may prompt the initiation of clinical trials using eFT508 in radioresistant NPC patients.
- |||||||||| zotatifin (eFT226) / eFFECTOR Therap
Journal, IO biomarker: Targeting EIF4A triggers an interferon response to synergize with chemotherapy and suppress triple-negative breast cancer. (Pubmed Central) - Dec 17, 2023
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.
- |||||||||| tomivosertib (eFT508) / eFFECTOR Therap
Journal: eIF4E phosphorylation mediated LPS induced depressive-like behaviors via ameliorated neuroinflammation and dendritic loss. (Pubmed Central) - Nov 22, 2023
The causal relation of eIF4E with BDNF signaling was further explored with TrkB antagonist K252a, which could reverse the effects of eFT508, validating the interplay between the eIF4E and TrkB/BDNF signaling in regulating depressive behaviors associated with neuroinflammation via synaptic protein translational regulation. In conclusion, our results support the involvement of eIF4E-associated translational dysregulation in synaptic protein loss via TrkB/BDNF signaling, eventually leading to depressiven-like behaviors upon inflammation-linked stress.
- |||||||||| tomivosertib (eFT508) / eFFECTOR Therap
Enrollment closed: Tomivosertib in Relapsed or Refractory Acute Myeloid Leukemia (AML) (clinicaltrials.gov) - Nov 1, 2023
P1, N=15, Active, not recruiting,
The proteomic basis for ferroptosis sensitization by rocaglate therapy remains under active investigation. Recruiting --> Active, not recruiting
- |||||||||| zotatifin (eFT226) / eFFECTOR Therap
Enrollment change, Trial completion date, Trial primary completion date, Metastases: Study of eFT226 in Subjects With Selected Advanced Solid Tumor Malignancies (clinicaltrials.gov) - Jul 17, 2023
P1/2, N=30, Recruiting,
Initiation date: Apr 2023 --> Apr 2024 N=228 --> 30 | Trial completion date: Sep 2023 --> Mar 2025 | Trial primary completion date: Jul 2023 --> Dec 2024
- |||||||||| tomivosertib (eFT508) / eFFECTOR Therap, SCH772984 / Otsuka
Preclinical, Journal: ZIP9 mediates the effects of DHT on learning, memory and hippocampal synaptic plasticity of male Tfm and APP/PS1 mice. (Pubmed Central) - Jun 16, 2023
Finally, we found that ZIP9 mediated the effects of DHT on the expression of synaptic proteins PSD95, drebrin, SYP, and dendritic spine density in the hippocampus of APP/PS1 mice through the ERK1/2-eIF4E pathway and affected learning and memory. This study demonstrated that androgen affected learning and memory in mice through ZIP9, providing new experimental evidence for improvement in learning and memory in Alzheimer's disease with androgen supplementation.
- |||||||||| zotatifin (eFT226) / eFFECTOR Therap
Trial completion date: PROPEL: Intravenous Zotatifin in Adults With Mild or Moderate COVID-19 (clinicaltrials.gov) - May 17, 2023
P1b, N=36, Active, not recruiting,
This study demonstrated that androgen affected learning and memory in mice through ZIP9, providing new experimental evidence for improvement in learning and memory in Alzheimer's disease with androgen supplementation. Trial completion date: Apr 2023 --> Jul 2023
- |||||||||| zotatifin (eFT226) / eFFECTOR Therap
Transcriptional response to rocaglate translation inhibitors in lymphoma shows cellular adaptation through induction of stress and survival pathways (Section 13; Poster Board #21) - Mar 14, 2023 - Abstract #AACR2023AACR_7224;
These results implicate induction of specific survival pathways that induce transcriptionally mediated adaptation to the stress of rocaglate therapy, but it is unclear if these responses can result in altered protein production in the context of eIF4A inhibition. Parallel assessment of the translatome currently under analysis will provide a more complete picture of overall adaptation and provide rational combination targets for rocaglates in lymphoma as clinical development progresses.
- |||||||||| arsenic trioxide / Generic mfg.
Potentiation of arsenic trioxide in glioblastoma (Section 16; Poster Board #24) - Mar 14, 2023 - Abstract #AACR2023AACR_3749;
Clinical trials of ATO in combination with radiation and temozolomide show therapeutic effects in a modest subset of glioblastoma patients...In addition, drug dosing with combination therapies utilizing the MAPK interacting serine/threonine kinase 1 (MNK1) inhibitors eFT-508 and EFT-206 also show synergistic effects in GBM cell lines...Identification and development of sensitization targets for ATO will allow for greater effectiveness of treatment and a greater potency of the drug in combating resistance which arises in response to treatment. Discovery of a predictive molecular signature of synergy from ATO and other targeted agents may pave the way for a successful clinical trial of these combinations in an identifiable subpopulation of GBM patients.
- |||||||||| zotatifin (eFT226) / eFFECTOR Therap
Enrollment closed, Trial completion date: PROPEL: Intravenous Zotatifin in Adults With Mild or Moderate COVID-19 (clinicaltrials.gov) - Jan 12, 2023
P1b, N=36, Active, not recruiting,
Thus, targeting PKA effects on translation is a potential treatment strategy for FLC and other PKA-driven cancers. Recruiting --> Active, not recruiting | Trial completion date: Jan 2023 --> Apr 2023
- |||||||||| tomivosertib (eFT508) / eFFECTOR Therap
Preclinical, Journal: MNK1/2 contributes to periorbital hypersensitivity and hyperalgesic priming in preclinical migraine models. (Pubmed Central) - Oct 28, 2022
Furthermore, treatment with the selective MNK inhibitor, eFT508, in WT mice prevented hypersensitivity caused by dural IL-6 or pH 7.0. Together, these results implicate MNK-eIF4E signaling in the development of pain originating from the dura and strongly suggest that targeting MNK inhibition may have significant therapeutic potential as a treatment for migraine.
- |||||||||| zotatifin (eFT226) / eFFECTOR Therap
Trial completion date, Trial primary completion date: PROPEL: Intravenous Zotatifin in Adults With Mild or Moderate COVID-19 (clinicaltrials.gov) - Oct 7, 2022
P1b, N=36, Recruiting,
Together, these results implicate MNK-eIF4E signaling in the development of pain originating from the dura and strongly suggest that targeting MNK inhibition may have significant therapeutic potential as a treatment for migraine. Trial completion date: Sep 2022 --> Jan 2023 | Trial primary completion date: Jul 2022 --> Jan 2023
- |||||||||| tomivosertib (eFT508) / eFFECTOR Therap
Trial completion, Enrollment change, Combination therapy, Monotherapy, Metastases: Safety, Pharmacodynamics, Pharmacokinetics, and Efficacy of Tomivosertib Combined With Paclitaxel in Advanced Breast Cancer (clinicaltrials.gov) - Jul 20, 2022
P1, N=19, Completed,
Trial completion date: Sep 2022 --> Jan 2023 | Trial primary completion date: Jul 2022 --> Jan 2023 Active, not recruiting --> Completed | N=45 --> 19
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