BACKGROUND: High-grade endometrial cancers (EAC) are aggressive tumors with a high risk of progression after treatment. As EAC may harbor mutations in the RAS/MAPK pathways, we evaluated the preclinical in vitro and in vivo efficacy of avutometinib, a RAF/MEK clamp, in combination with the focal adhesion kinase (FAK) inhibitors defactinib or VS-4718, against multiple primary EAC cell lines and xenografts.
METHODS: Whole-exome sequencing (WES) was used to evaluate the genetic landscape of five primary EAC cell lines. The in vitro activity of avutometinib and defactinib as single agents and in combination was evaluated using cell viability, cell cycle, and cytotoxicity assays. Mechanistic studies were performed using Western blot assays while in vivo experiments were completed in UTE10 engrafted mice treated with either vehicle, avutometinib, VS-4718, or their combination through oral gavage.
RESULTS: WES results demonstrated multiple EAC cell lines to harbor genetic derangements in the RAS/MAPK pathway including KRAS/PTEN/PIK3CA/BRAF/ARID1A, potentially sensitizing to FAK and RAF/MEK inhibition. Five out of five of the EAC cell lines demonstrated in vitro sensitivity to FAK and/or RAF/MEK inhibition. By Western blot assays, exposure of EAC cell lines to defactinib, avutometinib, and their combination demonstrated decreased phosphorylated FAK (p-FAK) as well as decreased p-MEK and p-ERK. In vivo the combination of avutometinib/VS-4718 demonstrated superior tumor growth inhibition compared to single-agent treatment and controls starting at Day 9 (p < 0.02 and p < 0.04) in UTE10 xenografts.
CONCLUSIONS: Avutometinib, defactinib, and to a larger extent their combinations, demonstrated promising in vitro and in vivo activity against EAC cell lines and xenografts. These preclinical data support the potential clinical evaluation of this combination in high-grade EAC patients.

UNASSIGNED: BRAF mutations in bladder cancer are rare. MEK inhibitors have excellent clinical benefits in the treatment of melanoma.
UNASSIGNED: A 60-year-old male was diagnosed with muscle-invasive bladder cancer and underwent total cystectomy and ileal conduit diversion. Despite 4 cycles of gemcitabine and cisplatin chemotherapy and 3 courses of pembrolizumab, the left obturator lymph node enlarged. Cancer multi-gene panel testing confirmed the BRAF G469A mutation and trametinib was recommended. Three months after the initiation of trametinib (2 mg, qd), the left obturator lymph node shrank by more than 50%. The disease has remained stable for more than 18 months.
UNASSIGNED: The present case indicates the potential of trametinib to treat mBUC patients with the BRAF G469A mutation in this setting.

Effectively utilizing MEK inhibitors in the clinic remains challenging due to off-target toxicity and lack of predictive biomarkers. Recent findings propose E-cadherin, a breast cancer diagnostic indicator, as a predictor of MEK inhibitor success. To address MEK inhibitor toxicity, traditional methodologies have systemically delivered nanoparticles, which require frequent, high-dose injections. Here, we present a different approach, employing a thermosensitive, biodegradable hydrogel with functionalized liposomes for local, sustained release of MEK inhibitor PD0325901 and doxorubicin. The poly(δ-valerolactone-co-lactide)-b-poly(ethylene-glycol)-b-poly(δ-valerolactone-co-lactide) triblock co-polymer gels at physiological temperature and has an optimal degradation time in vivo. Liposomes were functionalized with PR_b, a biomimetic peptide targeting the α5β1 integrin receptor, which is overexpressed in E-cadherin-positive triple negative breast cancer (TNBC). In various TNBC models, the hydrogel-liposome system delivered via local injection reduced tumor progression and improved animal survival without toxic side effects. Our work presents the first demonstration of local, sustained delivery of MEK inhibitors to E-cadherin-positive tumors alongside traditional chemotherapeutics, offering a safe and promising therapeutic strategy.

The two types of craniopharyngioma, adamantinomatous (ACP) and papillary (PCP), are clinically relevant tumours in children and adults. Although the biology of primary craniopharyngioma is starting to be unravelled, little is known about the biology of recurrence. To fill this gap in knowledge, we have analysed through methylation array, RNA sequencing and pERK1/2 immunohistochemistry a cohort of paired primary and recurrent samples (32 samples from 14 cases of ACP and 4 cases of PCP). We show the presence of copy number alterations and clonal evolution across recurrence in 6 cases of ACP, and analysis of additional whole genome sequencing data from the Children\'s Brain Tumour Network confirms chromosomal arm copy number changes in at least 7/67 ACP cases. The activation of the MAPK/ERK pathway, a feature previously shown in primary ACP, is observed in all but one recurrent cases of ACP. The only ACP without MAPK activation is an aggressive case of recurrent malignant human craniopharyngioma harbouring a CTNNB1 mutation and loss of TP53. Providing support for a functional role of this TP53 mutation, we show that Trp53 loss in a murine model of ACP results in aggressive tumours and reduced mouse survival. Finally, we characterise the tumour immune infiltrate showing differences in the cellular composition and spatial distribution between ACP and PCP. Together, these analyses have revealed novel insights into recurrent craniopharyngioma and provided preclinical evidence supporting the evaluation of MAPK pathway inhibitors and immunomodulatory approaches in clinical trials in against recurrent ACP.

The treatment landscape for advanced and metastatic melanoma has drastically changed in recent years, with the advent of novel therapeutic options such as immune checkpoint inhibitors and targeted therapies offering remarkable efficacy and significantly improved patient outcomes compared to traditional approaches. Approximately 50% of melanomas harbor activating BRAF mutations, with over 90% resulting in BRAF V600E. Tumors treated with BRAF inhibitor monotherapy have a high rate of developing resistance within six months. Combination therapy with MEK inhibitors helped to mitigate this treatment resistance and led to improved outcomes. Due to the up-regulation of PD-1/PD-L1 receptors in tumors treated with BRAF/MEK inhibitor therapy, further studies included a third combination agent, anti-PD-1/PD-L1 inhibitors. This triple combination therapy may have superior efficacy and a manageable safety profile when compared with single or double agent therapy regimens.
Effective treatment of advanced and metastatic melanoma can be challenging. Newer treatment methods for patients with BRAF-mutated tumors include a combination of drugs with different complementary mechanisms. These drugs include BRAF-inhibitors, MEK-inhibitors, and PD-1/PD-L1 inhibitors. When these three medications are used in combination, patients may have better response rates and survival outcomes, when compared to using just one or two of these medications together. Toxicity rates are higher with a triple-medication regimen, so careful patient selection is important to consider.

BACKGROUND: Lung cancer, accounting for a significant proportion of global cancer cases and deaths, poses a considerable health burden. Non-small cell lung cancer (NSCLC) patients have a poor prognosis and limited treatment options due to late-stage diagnosis and drug resistance. Dysregulated of the mitogen-activated protein kinase (MAPK) pathway, which is implicated in NSCLC pathogenesis, underscores the potential of MEK inhibitors such as binimetinib. Despite promising results in other cancers, comprehensive studies evaluating the safety and efficacy of binimetinib in lung cancer are lacking. This systematic review aimed to investigate the safety and efficacy of binimetinib for lung cancer treatment.
METHODS: We searched PubMed, Scopus, Web of Science, and Google Scholar until September 2023. Clinical trials evaluating the efficacy or safety of binimetinib for lung cancer treatment were included. Studies were excluded if they included individuals with conditions unrelated to lung cancer, investigated other treatments, or had different types of designs. The quality assessment was conducted utilizing the National Institutes of Health tool.
RESULTS: Seven studies with 228 participants overall were included. Four had good quality judgments, and three had fair quality judgments. The majority of patients experienced all-cause adverse events, with diarrhea, fatigue, and nausea being the most commonly reported adverse events of any grade. The objective response rate (ORR) was up to 75%, and the median progression-free survival (PFS) was up to 9.3 months. The disease control rate after 24 weeks varied from 41% to 64%. Overall survival (OS) ranged between 3.0 and 18.8 months. Notably, treatment-related adverse events were observed in more than 50% of patients, including serious adverse events such as colitis, febrile neutropenia, and pulmonary infection. Some adverse events led to dose limitation and drug discontinuation in five studies. Additionally, five studies reported cases of death, mostly due to disease progression. The median duration of treatment ranged from 14.8 weeks to 8.4 months. The most common dosage of binimetinib was 30 mg or 45 mg twice daily, sometimes used in combination with other agents like encorafenib or hydroxychloroquine.
CONCLUSIONS: Only a few studies have shown binimetinib to be effective, in terms of improving OS, PFS, and ORR, while most of the studies found nonsignificant efficacy with increased toxicity for binimetinib compared with traditional chemotherapy in patients with lung cancer. Further large-scale randomized controlled trials are recommended.

We present the clinical course of a 4-year-old girl with neurofibromatosis type 1-associated, unresectable, symptomatic urinary bladder ganglioneuroma. She was initially trialed on sirolimus without response and subsequently responded to MEK inhibitor trametinib, with improvement clinically and radiographically over 10 months. This report broadens the repertoire of therapeutic strategies for MEK inhibition in diseases related to the MAPK pathway.

Background: The treatment of BRAF V600E gliomas with BRAF inhibitors (BRAFis) and MEK inhibitors (MEKis) has been increasingly integrated into clinical practice for pediatric low-grade gliomas (PLGGs) and pediatric high-grade gliomas (HGGs). However, some questions remain unanswered, such as the best time to start targeted therapy, duration of treatment, and discontinuation of therapy. Given that no clinical trial has been able to address these critical questions, we developed a Canadian Consensus statement for the treatment of BRAF V600E mutated pediatric as well as adolescent and young adult (AYA) gliomas. Methods: Canadian neuro-oncologists were invited to participate in the development of this consensus. The consensus was discussed during monthly web-based national meetings, and the algorithms were revised until a consensus was achieved. Results: A total of 26 participants were involved in the development of the algorithms. Two treatment algorithms are proposed, one for the initiation of treatment and one for the discontinuation of treatment. We suggest that most patients with BRAF V600E gliomas should be treated with BRAFis ± MEKis upfront. Discontinuation of treatment can be considered in certain circumstances, and we suggest a slow wean. Conclusions: Based on expert consensus in Canada, we developed algorithms for treatment initiation of children and AYA with BRAF V600E gliomas as well as a discontinuation algorithm.

Cardiovascular disease (CVD) represents the leading cause of mortality and disability all over the world. Identifying new targeted therapeutic approaches has become a priority of biomedical research to improve patient outcomes and quality of life. The RAS-RAF-MEK (mitogen-activated protein kinase kinase)-ERK (extracellular signal-regulated kinase) pathway is gaining growing interest as a potential signaling cascade implicated in the pathogenesis of CVD. This pathway is pivotal in regulating cellular processes like proliferation, growth, migration, differentiation, and survival, which are vital in maintaining cardiovascular homeostasis. In addition, ERK signaling is involved in controlling angiogenesis, vascular tone, myocardial contractility, and oxidative stress. Dysregulation of this signaling cascade has been linked to cell dysfunction and vascular and cardiac pathological remodeling, which contribute to the onset and progression of CVD. Recent and ongoing research has provided insights into potential therapeutic interventions targeting the RAS-RAF-MEK-ERK pathway to improve cardiovascular pathologies. Preclinical studies have demonstrated the efficacy of targeted therapy with MEK inhibitors (MEKI) in attenuating ERK activation and mitigating CVD progression in animal models. In this article, we first describe how ERK signaling contributes to preserving cardiovascular health. We then summarize current knowledge of the roles played by ERK in the development and progression of cardiac and vascular disorders, including atherosclerosis, myocardial infarction, cardiac hypertrophy, heart failure, and aortic aneurysm. We finally report novel therapeutic strategies for these CVDs encompassing MEKI and discuss advantages, challenges, and future developments for MEKI therapeutics.

Optic pathway gliomas (OPG) are primary tumors of the optic nerve, chiasm, and/or tract that can be associated with neurofibromatosis type 1 (NF1). OPG generally have a benign histopathology, but a variable clinical course. Observation is generally recommended at initial diagnosis if vision is stable or normal for age, however, treatment may include chemotherapy, radiotherapy, or surgery in select cases. This manuscript reviews the literature on OPG with an emphasis on recent developments in treatment.