mirdametinib (PD-0325901)

No neurosphere lines exhibited enhanced sensitivity to temozolomide combined with mirdametinib. In sensitive models, benefits were observed at least three weeks beyond the completion of treatment, including sustained phosphor-ERK inhibition on immunoblot and decreased Ki-67 expression. These observations demonstrate synergistic activity between mirdametinib and irradiation in NF1-deficient glioma models and may have clinical implications for patients with gliomas that harbor germline or somatic NF1 alterations.

P1, N=60, Completed, Dana-Farber Cancer Institute | Active, not recruiting --> Completed | Phase classification: P1/2 --> P1 | N=139 --> 60

Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.

P1/2, N=24, Recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins | Not yet recruiting --> Recruiting

P1/2, N=24, Not yet recruiting, Centre Georges Francois Leclerc | Trial completion date: Sep 2028 --> Apr 2029 | Initiation date: Sep 2023 --> Apr 2024 | Trial primary completion date: Sep 2028 --> Apr 2029

P1/2, N=139, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Dec 2023 --> Dec 2024

P2, N=50, Not yet recruiting, Murdoch Childrens Research Institute | N=30 --> 50 | Trial completion date: Sep 2028 --> Nov 2026 | Initiation date: Sep 2023 --> Apr 2024 | Trial primary completion date: Sep 2026 --> Jun 2026

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.

P2, N=114, Active, not recruiting, SpringWorks Therapeutics, Inc. | Phase classification: P2b --> P2

We identified a necroptosis signature in LUSC that can predict prognosis and identify patients who can benefit from targeted therapies.

P1/2, N=24, Not yet recruiting, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

This system established an efficient and safe resource of pluripotent cells from autologous germline, and provide new avenues for regenerative medicine and animal cloning.

We have developed a robust DNA methylation-based prognostic model for EC, which holds promise for improving prognosis prediction and personalized treatment approaches. These findings may contribute to better management of EC patients, particularly in identifying those at higher risk who may benefit from tailored interventions.

Despite the clinical success of BRAF/MEK inhibitors for the treatment of advanced melanoma, dabrafenib and vemurafenib have limited intracranial overall response rates of 42-50% and median progression-free survival of 3.6-5.5 months...KIN-7136 showed improved rodent brain exposure compared to conventional agents; the brain-to-plasma concentration ratio (Kp) of KIN-7136 was >1.0, much higher than comparators binimetinib and mirdametinib...In vivo, daily oral treatment with KIN-7136 was well tolerated and produced a significant extension of overall survival compared to the vehicle control (p=0.0289, log-rank test) in the A375 intracranial tumor model in athymic mice. These preclinical data confirm activity of KIN-7136 in BRAF-mutant melanoma brain metastases models and support further research to advance its clinical progression.

We observed an increase in the percentage of CD11cI-A/I-E cells, representing DCs, by adding four small molecular inhibitors: Y27632, PD0325901, PD173074, and PD98059 (abbreviated as YPPP), in mouse bone marrow (BM) culture with granulocyte-macrophage colony stimulating factor (GM-CSF). In tumor models treated with anti-programmed death (PD) -1 therapies, mice injected intratumorally with YPPP-DCs as a DCs vaccine exhibited reduced tumor growth and increased survival. These findings suggested that our method would be useful for the induction of DCs that efficiently activate effector T cells for cancer immunotherapy.

P1b, N=6, Completed, Memorial Sloan Kettering Cancer Center | Active, not recruiting --> Completed | Trial completion date: Sep 2027 --> Oct 2023 | Trial primary completion date: Sep 2027 --> Oct 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.

Conversely, a negative association was noted between various drugs (17-AAG, Lapatinib, Trametinib, PD-0325901) and the NQO1 mRNA expression levels. 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.

TYK2 inhibitors decrease proliferation of MPNST cells while upregulating MEK/ERK pathway signaling in an apparent compensatory mechanism. Combining TYK2 and MEK inhibitors synergistically blocks MPNST growth in vitro and in vivo as well as other soft tissue sarcomas in vitro. These findings support the development of a combination deucravacitinib and mirdametinib phase 1/2 clinical trial in soft tissue sarcomas with an emphasis on MPNST.

We provide mechanistic insights into a previously undisclosed MEK1/2/BCR::ABL1/BCR/ABL1-driven signaling loop that may determine the efficacy of arsenic trioxide (ATO) in TKI-resistant leukemic patients. 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.

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.

P1/2, N=139, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Aug 2023 --> Dec 2023 | Trial primary completion date: May 2023 --> Aug 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.

P1/2, N=24, Not yet recruiting, Centre Georges Francois Leclerc

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.

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.

Studies have demonstrated the efficacy of Palbociclib (CDK 4/6 inhibitor), Gedatolisib (PI3K/mTOR dual inhibitor) and PD0325901 (MEK1/2 inhibitor) in colorectal cancer (CRC), however single agent therapeutics are often limited by the development of resistance. This study shows that the combination of Palbociclib and Gedatolisib has synergistic anti-proliferative effects in both wild-type and mutated CRC cell lines. Separately, the phosphorylation of S6rp may be a promising biomarker of responsiveness to this combination.

P1b, N=6, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Recruiting --> Active, not recruiting | N=150 --> 6

Both xenoline and PDX were resistant to the MEK inhibitors trametinib or mirdametinib at clinically relevant doses, recapitulating the patient's resistance to such treatment in the clinic. This set of APXA models will serve as a preclinical resource for developing novel therapeutic regimens for rare anaplastic PXAs and pediatric high-grade gliomas bearing BRAF fusions.

P1b, N=105, Recruiting, BeiGene | Trial completion date: Apr 2024 --> Feb 2026 | Trial primary completion date: Mar 2024 --> Sep 2025

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.

P1b, N=150, Recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Sep 2024 --> Sep 2027 | Trial primary completion date: Sep 2024 --> Sep 2027

These data provide the preclinical rationale for the development of a phase 1 clinical trial of deucravacitinib and mirdametinib in NF1-assosciated MPNST.

High expression of TIGIT results in poor survival of KIRC and high drug sensitivity to sunitinib. Besides, Selumetinib and PD0325901 may be potential drugs targeting TIGIT, and combined therapy of anti-TIGIT and other treatments show great potential in treating KIRC.

Current strategies for treating JMML include using the hypomethylating agent, 5-azacitidine (5-Aza) or MEK inhibitors trametinib and PD0325901 (PD-901), but none of these are curative as monotherapy. Additionally, a decrease in the expression of genes associated with inflammation and myeloid leukemia was also observed in Shp2 mice treated with the combination of the two drugs. Finally, we report two patients with JMML and PTPN11 mutations treated with 5-Aza, trametinib and chemotherapy who experienced a clinical response because of the combination treatment.

Our results suggest that the mitochondrial-related risk model could be a reliable prognostic biomarker for personalized treatment of STAD patients.

We have identified six drugs named Palbociclib, Panobinostat, PD-0325901, PLX4720, Selumetinib, and Tanespimycin that significantly perform on breast cancer cell lines. Also, five biomarkers named TNFSF15, DCAF6, KDM6A, PHETA2, and IFNGR1 are sensitive to all six shortlisted drugs and show sensitivity to the radiations. The proposed biomarkers and drug sensitivity analysis are helpful in translational cancer studies and provide valuable insights for clinical trial design.

We and others recently demonstrated that inhibition of the RAF-MEK-ERK pathway resulted in upregulated autophagy, and that dual treatment with the autophagy inhibitor hydroxychloroquine (HCQ)/chloroquine (CQ) and MEK or ERK inhibitors (MEKi, ERKi) synergistically blocked PDAC growth. 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.

Our model was derived from a pediatric patient who was diagnosed with rare high-grade subtype of glioma, anaplastic pleomorphic xanthoastrocytoma, and did not respond to MEK inhibitor, trametinib. In summary, our results demonstrated that combination SHP099 and mirdametinib is superior to single agent alone in the pediatric A-PXA brain tumor model with proteome and phosphoproteome reprogramming of multiple networks as potential molecular mechanisms underlying therapeutic benefit of combination therapy. Ultimately, clinical translation of this finding will potentially benefit patient of this malignant rare pediatric glioma subset which currently does not have standard therapy.

Standard cheminformatics method including in silico ADMET and molecular docking study substantiated PD0325901 and Selumetinib as the most potent candidate-drug for CC treatment. Overall, this meticulous study holds promises for further in vitro and in vivo research on CC diagnosis, prognosis and therapies.Communicated by Ramaswamy H. Sarma.