- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
Journal: MEK/ERK signaling drives the transdifferentiation of supporting cells into functional hair cells by modulating the Notch pathway. (Pubmed Central) - May 6, 2024
We then selected 4 MEK/ERK signaling inhibitors, and PD0325901 (PD03) was found to induce the transdifferentiation of functional supernumerary HCs from SCs in the neonatal mammalian cochlear epithelium...Importantly, delivery of PD03 into the inner ear induced mild HC regeneration in vivo. Our study thus reveals the importance of MEK/ERK signaling in cell fate determination and suggests that PD03 might serve as a new approach for HC regeneration.
- |||||||||| Biomarker, Journal, Tumor microenvironment, IO biomarker: DNA hypomethylation patterns and their impact on the tumor microenvironment in colorectal cancer. (Pubmed Central) - Mar 23, 2024
This study unveils a novel epigenetic phenotype in CRC linked to resistance against immune checkpoint inhibitors, presenting a significant step toward personalized medicine by suggesting epigenetic classifications as a means to identify ideal candidates for immunotherapy in CRC. Our findings also highlight potential therapeutic agents for the DMP subtype, offering new avenues for tailored CRC treatment strategies.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, Ibrance (palbociclib) / Pfizer
Trial completion, Phase classification, Enrollment change, Combination therapy: PALBOCICLIB + PD-0325901 for NSCLC & Solid Tumors (clinicaltrials.gov) - Mar 18, 2024
P1, N=60, Completed,
Our findings also highlight potential therapeutic agents for the DMP subtype, offering new avenues for tailored CRC treatment strategies. Active, not recruiting --> Completed | Phase classification: P1/2 --> P1 | N=139 --> 60
- |||||||||| plixorafenib (FORE-8394) / Fore Biotherap
Plixorafenib (plixo) synergizes with MEK inhibitors (MEKi) in MAPK pathway inhibition in BRAF V600 and non V600 alterations, with higher potency compared to early generation BRAFi and pan-RAFi (Section 25) - Mar 5, 2024 - Abstract #AACR2024AACR_6687;
Using ForeSight assay, a unique platform for testing MAPK signaling, we tested the efficacy of plixo and 4 MEKi (trametinib, cobimetinib, binimetinib and mirdametinib) across a cohort 18 BRAF alterations (V600E, 2 class II and 15 fusions) as single agents and in combinations...Furthermore, we compared the potency of a combination of plixo with binimetinib (bini) to that of another BRAFi (vemurafenib) or pan-RAFi's (tovorafenib and lifirafenib) with bini in 2 class I, 3 class II and 7 BRAF fusions using the foresight assay...These results indicate the improved efficacy of plixo + bini combination in inhibiting MAPK signaling and cancer cell proliferation. Overall results support that maximal suppression of the MAPK pathway with plixo is more potent in combination with a MEK inhibitor in BRAF V600 and non-V600 nonclinical models compared to BRAF or pan-RAF combinations.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, milciclib (TZLS-201) / Tiziana Life Sci
Investigating the synergistic effect of milciclib and PD0325901 in colorectal cancer therapy (Section 21) - Mar 5, 2024 - Abstract #AACR2024AACR_2626;
The discovery of the down-regulation of these proteins and pathways after treatment provides a molecular basis to elucidate the synergistic mechanism underlying Milciclib and PD0325901 combination therapy. In conclusion, our study establishes the combinatorial use of Milciclib and PD0325901 as a potential breakthrough in the treatment of colorectal cancer, offering a promising prospect for enhancing future patient outcomes.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, Mekinist (trametinib) / Novartis, BeiGene, CI-1040 / Pfizer
Preclinical, Journal: MEK1/2 inhibition decreases pro-inflammatory responses in macrophages from people with cystic fibrosis and mitigates severity of illness in experimental murine methicillin-resistant Staphylococcus aureus infection. (Pubmed Central) - Feb 18, 2024
Wild-type mice treated with PD0325901 had significant reduction in neutrophil-mediated inflammation compared to vehicle treatment groups, with preserved clearance of bacteria in lung, liver, or spleen 1 day after infection in either wild-type or CF mouse models. In summary, this study provides the first data evaluating the therapeutic potential of MEK1/2 inhibitor to modulate CF immune cells and demonstrates that MEK1/2 inhibitors diminish pro-inflammatory responses without impairing host defense mechanisms required for acute pathogen clearance.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, Keytruda (pembrolizumab) / Merck (MSD)
Trial completion date, Trial initiation date, Trial primary completion date, Metastases: IMMUNOMEK: Clinical Trial Evaluating the Safety and Efficacy of Chemoimmunotherapy Plus Short Course of Mek Inhibitor in First Line of Treatment of Metastatic Non Squamous Non Small Cell Lung Adenocarcinoma With PDL1 < 50 %. (clinicaltrials.gov) - Feb 15, 2024
P1/2, N=24, Not yet recruiting,
In summary, this study provides the first data evaluating the therapeutic potential of MEK1/2 inhibitor to modulate CF immune cells and demonstrates that MEK1/2 inhibitors diminish pro-inflammatory responses without impairing host defense mechanisms required for acute pathogen clearance. Trial completion date: Sep 2028 --> Apr 2029 | Initiation date: Sep 2023 --> Apr 2024 | Trial primary completion date: Sep 2028 --> Apr 2029
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, Ibrance (palbociclib) / Pfizer
Trial completion date, Combination therapy: PALBOCICLIB + PD-0325901 for NSCLC & Solid Tumors (clinicaltrials.gov) - Feb 15, 2024
P1/2, N=139, Active, not recruiting,
Trial completion date: Sep 2028 --> Apr 2029 | Initiation date: Sep 2023 --> Apr 2024 | Trial primary completion date: Sep 2028 --> Apr 2029 Trial completion date: Dec 2023 --> Dec 2024
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, Piqray (alpelisib) / Novartis
Enrollment change, Trial completion date, Trial initiation date, Trial primary completion date: TARGET-VM: A Trial of Targeted Therapies for Patients With Slow-Flow or Fast-Flow Vascular Malformations (clinicaltrials.gov) - Feb 15, 2024
P2, N=50, Not yet recruiting,
Trial completion date: Dec 2023 --> Dec 2024 N=30 --> 50 | Trial completion date: Sep 2028 --> Nov 2026 | Initiation date: Sep 2023 --> Apr 2024 | Trial primary completion date: Sep 2026 --> Jun 2026
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
Trial completion date, Trial initiation date, Trial primary completion date: Mirdametinib in Histiocytic Disorders (clinicaltrials.gov) - Jan 18, 2024
P2, N=50, Recruiting,
These findings may contribute to better management of EC patients, particularly in identifying those at higher risk who may benefit from tailored interventions. Trial completion date: Dec 2030 --> Mar 2031 | Initiation date: Dec 2023 --> Mar 2024 | Trial primary completion date: Dec 2029 --> Mar 2030
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
Journal: Cell division cycle 42 effector protein 4 inhibits prostate cancer progression by suppressing ERK signaling pathway. (Pubmed Central) - Dec 28, 2023
Additionally, the ERK pathway inhibitor PD0325901 was employed, revealing that PD0325901 significantly nullified the effects of CDC42EP4 on PCa cell proliferation, migration, and invasion. Collectively, our findings demonstrate that CDC42EP4 acts as a critical tumor suppressor gene, inhibiting PCa cell proliferation, migration, and invasion through the ERK pathway, thereby presenting potential targets for PCa therapy.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
Journal: Insulin augments angiotensin II-induced myocardial fibrosis via the MEK/STAT3 pathway. (Pubmed Central) - Dec 21, 2023
Total STAT3 expression, but not activation was stimulated by insulin; the effect of insulin on Ang II-induced fibrosis disappeared when STAT3 was blocked and could be entirely suppressed by the MEK inhibitor PD0325901. Our findings suggest a noninsulin-dependent glucose-lowering regimen for patients with type 2 diabetes (T2DM) and heart failure (HF).
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
Enrollment open: Mirdametinib in Histiocytic Disorders (clinicaltrials.gov) - Dec 7, 2023
P2, N=50, Recruiting,
We identified a necroptosis signature in LUSC that can predict prognosis and identify patients who can benefit from targeted therapies. Not yet recruiting --> Recruiting
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
New P2 trial: Mirdametinib in Histiocytic Disorders (clinicaltrials.gov) - Dec 1, 2023
P2, N=50, Not yet recruiting,
Not yet recruiting --> Recruiting .
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
Trial completion, Trial completion date, Trial primary completion date, Combination therapy, Monotherapy, Metastases: A Study of Mirdametinib on Its Own or in Combination With Fulvestrant in People With Solid Tumor Cancer (clinicaltrials.gov) - Oct 30, 2023
P1b, N=6, Completed,
These findings suggested that our method would be useful for the induction of DCs that efficiently activate effector T cells for cancer immunotherapy. Active, not recruiting --> Completed | Trial completion date: Sep 2027 --> Oct 2023 | Trial primary completion date: Sep 2027 --> Oct 2023
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
Journal: Oligodendrocyte progenitor cells differentiation induction with MAPK/ERK inhibitor fails to support repair processes in the chronically demyelinated CNS. (Pubmed Central) - Aug 23, 2023
PD0325901, a MAPK/ERK inhibitor, was previously shown to induce OPC differentiation, non-specific immunosuppression, and a significant therapeutic effect in acute demyelinating MS models...Thus, the highly complex mission of creating a pro-regenerative environment depends upon an appropriate immune response controlled in time, place, and intensity. We suggest the need to employ a multi-systematic therapeutic approach, which cannot be achieved through a single molecule-based therapy.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, Mekinist (trametinib) / Novartis, BeiGene
Journal, Tumor mutational burden, IO biomarker, Pan tumor: Pan-cancer and single-cell analysis reveal the prognostic value and immune response of NQO1. (Pubmed Central) - Aug 16, 2023
NQO1 expression was significantly associated with prognosis, immune infiltrates, and drug resistance in multiple cancer types. The inhibition of the NQO1-dependent signaling pathways may provide a promising strategy for developing new cancer-targeted therapies.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
Journal: MEK1/2 regulate normal BCR and ABL1 tumor-suppressor functions to dictate ATO response in TKI-resistant Ph+ leukemia. (Pubmed Central) - Aug 7, 2023
Additionally, the allosteric activation of nuclear ABL1 was consistently found to enhance the anti-leukemic effects of the MEK1/2 inhibitor Mirdametinib, which when combined with ATO, significantly prolonged the survival of mice bearing BCR::ABL1-T315I-induced leukemia. These findings highlight the therapeutic potential of MEK1/2-inhibitors/ATO combination for the treatment of TKI-resistant leukemia.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, Koselugo (selumetinib) / Merck (MSD), AstraZeneca
Journal: Cancer-associated fibroblast infiltration in osteosarcoma: the discrepancy in subtypes pathways and immunosuppression. (Pubmed Central) - Jul 13, 2023
The risk score expression of risk score model genes could predict the drug resistance, and significant differences could be found between the high and low scoring groups for 17-AAG, AZD6244, PD-0325901 and Sorafenib. To sum up, this article validated the prediction role of CAF infiltration in the prognosis of OS, which might shed light on the treatment of OS.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, Ibrance (palbociclib) / Pfizer
Trial completion date, Trial primary completion date, Combination therapy: PALBOCICLIB + PD-0325901 for NSCLC & Solid Tumors (clinicaltrials.gov) - Jul 12, 2023
P1/2, N=139, Active, not recruiting,
To sum up, this article validated the prediction role of CAF infiltration in the prognosis of OS, which might shed light on the treatment of OS. Trial completion date: Aug 2023 --> Dec 2023 | Trial primary completion date: May 2023 --> Aug 2023
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, navitoclax (ABT 263) / AbbVie
Journal: Five cuprotosis-related lncRNA signatures for prognosis prediction in acute myeloid leukaemia. (Pubmed Central) - Jul 11, 2023
The high- and low-risk groups differed significantly in immune-related biological processes and the IC50 values of WH-4.023, mitomycin C, navitoclaxin, and PD-0325901. Five cuprotosis-related lncRNA signatures were screened as prognostic predictors to provide new insights into lncRNA-based diagnostic and therapeutic strategies for AML.
- |||||||||| Review, Journal: Treatment decisions and the use of MEK inhibitors for children with neurofibromatosis type 1-related plexiform neurofibromas. (Pubmed Central) - Jun 21, 2023
Understanding the genetic underpinnings of PN led to the investigation of targeted therapies as medical treatment options, and the MEK1/2 inhibitor selumetinib has shown promising efficacy in pediatric patients with NF1 and symptomatic, inoperable PN...Several other MEK inhibitors (binimetinib, mirdametinib, trametinib) and the tyrosine kinase inhibitor cabozantinib are also being investigated as medical therapies for NF1-PN...Treatment should be individualized based on recommendations from a multidisciplinary team, considering the size and location of PN, effects on adjacent tissues, and patient and family preferences. This review outlines the treatment strategies currently available for patients with NF1-PN and the evidence supporting the use of MEK inhibitors, and discusses key considerations in clinical decision-making.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
Enrollment closed, Enrollment change, Combination therapy, Monotherapy, Metastases: A Study of Mirdametinib on Its Own or in Combination With Fulvestrant in People With Solid Tumor Cancer (clinicaltrials.gov) - Jun 15, 2023
P1b, N=6, Active, not recruiting,
Separately, the phosphorylation of S6rp may be a promising biomarker of responsiveness to this combination. Recruiting --> Active, not recruiting | N=150 --> 6
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, Yondelis (trabectedin) / Otsuka, PharmaMar, Valeo Pharma, Lynparza (olaparib) / Merck (MSD), AstraZeneca
Preclinical, Journal, PARP Biomarker: Ex vivo to in vivo model of malignant peripheral nerve sheath tumors for precision oncology. (Pubmed Central) - May 29, 2023
Recruiting --> Active, not recruiting | N=150 --> 6 These data support the successful establishment of a novel 3D platform for drug discovery and MPNST biology exploration in a system representative of the human condition.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
Trial completion date, Trial primary completion date, Combination therapy, Monotherapy, Metastases: A Study of Mirdametinib on Its Own or in Combination With Fulvestrant in People With Solid Tumor Cancer (clinicaltrials.gov) - May 25, 2023
P1b, N=150, Recruiting,
These data support the successful establishment of a novel 3D platform for drug discovery and MPNST biology exploration in a system representative of the human condition. Trial completion date: Sep 2024 --> Sep 2027 | Trial primary completion date: Sep 2024 --> Sep 2027
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
Preclinical, Journal: A clinically relevant selective ERK-pathway inhibitor reverses core deficits in a mouse model of autism. (Pubmed Central) - May 15, 2023
Our data indicate that selectively inhibiting ERK pathway using PD325901 is beneficial in the BTBR model, thus further support the notion that ERK pathway is critically involved in the pathophysiology of autism. These results suggest that a similar approach could be applied to animal models of syndromic autism with dysregulated ERK signaling, to further test selectively targeting ERK pathway as a new approach for treating autism.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
Journal: The Modulation of Immune Responses in Tilapinevirus tilapiae-Infected Fish Cells through MAPK/ERK Signalling. (Pubmed Central) - May 2, 2023
Furthermore, when p-ERK was suppressed using the inhibitor PD0325901, a significant reduction in the TiLV load and decrease in the mx and rsad2 gene expression levels were observed in the TiB cells in days 1-7 following infection. These findings highlight the role of the MAPK/ERK signalling pathway and provide new insights into the cellular mechanisms during TiLV infection that could be useful in developing new strategies to control this virus.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
Journal: SALL4 correlates with proliferation, metastasis, and poor prognosis in prostate cancer by affecting MAPK pathway. (Pubmed Central) - Apr 29, 2023
These findings highlight the role of the MAPK/ERK signalling pathway and provide new insights into the cellular mechanisms during TiLV infection that could be useful in developing new strategies to control this virus. SALL4 predicts unfavorable outcome and is closely associated with PCa progression, suggesting that SALL4 may be a promising prognostic marker and potential therapeutic target for PCa.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, Sotyktu (deucravacitinib) / BMS
Journal: MEK inhibition synergizes with TYK2 inhibitors in NF1-associated Malignant Peripheral Nerve Sheath Tumors. (Pubmed Central) - Apr 17, 2023
SALL4 predicts unfavorable outcome and is closely associated with PCa progression, suggesting that SALL4 may be a promising prognostic marker and potential therapeutic target for PCa. These data provide the preclinical rationale for the development of a phase 1 clinical trial of deucravacitinib and mirdametinib in NF1-assosciated MPNST.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
Journal: Optically activated MEK1/2 inhibitors (Opti-MEKi) as potential antimelanoma agents. (Pubmed Central) - Apr 4, 2023
In this study, a series of mirdametinib-based optically activatable MEK1/2 inhibitors (opti-MEKi) were designed and synthesized...We demonstrated the robust photoactivation of MEK1/2 inhibition and antimelanoma activity in cultured human cells, as well as in a xenograft zebrafish model. Taken together, the modular approach presented herein provides a method for the optical control of MEK1/2 inhibitor activity, and these data support the further development of optically activatable agents for light-mediated antimelanoma phototherapy.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene
Journal: KAP1 modulates osteogenic differentiation via the ERK/Runx2 cascade in vascular smooth muscle cells. (Pubmed Central) - Mar 29, 2023
Taken together, the modular approach presented herein provides a method for the optical control of MEK1/2 inhibitor activity, and these data support the further development of optically activatable agents for light-mediated antimelanoma phototherapy. The present study suggested that KAP1 participated in the osteoblast differentiation of VSMCs via the ERK/Runx2 cascade and served as a potential diagnostics and therapeutics target for vascular calcification.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, temuterkib (LY3214996) / Eli Lilly, Mektovi (binimetinib) / Ono Pharma, Pierre Fabre, Pfizer
Improving the efficacy of dual ERK-MAPK and autophagy inhibition as a therapeutic strategy for pancreatic ductal adenocarcinoma (Section 12; Poster Board #24) - Mar 14, 2023 - Abstract #AACR2023AACR_7607;
P1, P2
These findings provided rationale for our initiation of Phase I/II clinical trials evaluating the combination of MEKi (binimetinib; NCT04132505) or ERKi (LY3214996; NCT04386057) with HCQ in PDAC...Importantly, when we inhibited MEK, with the clinical stage MEKi mirdametinib, and PIKfyve (with apilimod) together, we observed decreased MEKi-induced autophagic flux and synergistic impairment of PDAC cell proliferation...Furthermore, combining ERK-MAPK inhibition with vertical inhibition of autophagy improves the in vitro efficacy of this treatment strategy. Ongoing studies are aimed at delineating the mechanism underlying the synergy observed with anti-autophagy inhibitor combinations and further validation in more advanced preclinical models of PDAC.
- |||||||||| mirdametinib (PD-0325901) / SpringWorks Therap, BeiGene, MG132 / Jilin University, Dorothy M. Davis Heart and Lung Research Institute
Loss of KDM5A supports KRAS-driven pancreatic cancer (Section 9; Poster Board #20) - Mar 14, 2023 - Abstract #AACR2023AACR_7556;
Pharmaceutical inhibition of MEK, proteasome, and Kdm5a were performed by treating iKPCs with mirdametinib, MG-132, and CPI-455, respectively. We conclude that Kdm5a plays a tumor suppressor role in pancreatic cancer by epigenetically repressing transcriptional programs necessary for KRAS-driven oncogenesis.
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