ArticleNeuro-oncology2022
The PI3K/Akt/mTOR pathway as a preventive target in melanoma brain metastasis.
Article in Neuro-oncology, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 56 papers, 2 of them syntheses that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
56 citing papers in PubMed, 2 syntheses or guidelines pooled it, 84 citations in OpenAlex.
- Chronic Infections as Catalysts for Melanoma Aggressiveness: Insights into Tumour Microenvironment Modulation.Asian Pacific journal of cancer prevention : APJCP · 2025Pooled it
- Brain metastases: A Society for Neuro-Oncology (SNO) consensus review on current management and future directions.Neuro-oncology · 2022Guideline
- Plasma proteome-metabolome signatures enable non-invasive early detection and lymph node risk stratification in breast cancer.Molecular cancer · 2026Article
- Review
- Preventive strategies against brain metastases: current state of the art and future directions.Neurological research and practice · 2026Review
- GNE-317 ameliorates neuroinflammation stimulated by lipopolysaccharide via PI3K/Akt/mTOR pathway.Pharmacological reports : PR · 2026Article
- Novel insights into extracellular vesicles: An update on biomolecules, immunomodulation and clinical strategies in skin melanoma.Clinical and translational medicine · 2026Review
- Unraveling the Enigma of Melanoma Brain Metastasis: New Molecular Insights and Therapeutic Directions.International journal of molecular sciences · 2026Review
- The evolving landscape of brain metastasis: volume II.Trends in cancer · 2026Review
- Breast cancer brain metastasis: from molecular insights to therapeutic innovation.Frontiers in immunology · 2026Review
- Voxel-accurate MRI-microscopy Correlation Enables AI-powered Prediction of Brain Disease States.Theranostics · 2026Article
- Brain neurovascular unit in response to intra- and extra-central nervous system cancers: implications, mechanisms, and challenges.Cancer cell international · 2025Review
- HMGB3 promotes brain metastasis of lung adenocarcinoma by recruiting SSBP1 for nuclear translocation to remodel mitochondrial metabolism.Cancer communications (London, England) · 2025Article
- Impact of gastrointestinal dysbiosis on tryptophan metabolism and neurological cancer progression.Medical oncology (Northwood, London, England) · 2025Review
- Genomic and immunological profiling reveals novel prognostic biomarkers for limited-stage small cell lung cancer.Discover oncology · 2025Article
- Molecular evolution of central nervous system metastasis and therapeutic implications.Trends in molecular medicine · 2025Review
- GNE-317 Reverses MSN-Mediated Proneural-to-Mesenchymal Transition and Suppresses Chemoradiotherapy Resistance in Glioblastoma via PI3K/mTOR.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Multidimensional Proteomic Landscape Reveals Distinct Activated Pathways Between Human Brain Tumors.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Global trends and emerging insights in BRAF and MEK inhibitor resistance in melanoma: a bibliometric analysis.Frontiers in molecular biosciences · 2025Article
- The joint role of the immune microenvironment and NFrontiers in genetics · 2025Article
Corrections and comments
- Commented on by
Authors and funding
14 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundBrain metastases (BM) are a frequent complication of malignant melanoma (MM), with limited treatment options and poor survival. Prevention of BM could be more effective and better tolerated than treating established BM in various conditions.
methodsTo investigate the temporospatial dynamics of PI3K/Akt/mTOR (PAM) pathway activation during BM formation and the preventive potential of its inhibition, in vivo molecular imaging with an Akt biosensor was performed, and long-term intravital multiphoton microscopy through a chronic cranial window in mice.
resultsIn vivo molecular imaging revealed invariable PAM pathway activation during the earliest steps of brain colonization. In order to perform a long-term intravascular arrest and to extravasate, circulating MM cells needed to activate their PAM pathway during this process. However, the PAM pathway was quite heterogeneously activated in established human brain metastases, and its inhibition with the brain-penetrant PAM inhibitor GNE-317 resulted in only modest therapeutic effects in mice. In contrast, giving GNE-317 in preventive schedules that included very low doses effectively reduced the growth rate and number of BM in two MM mouse models over time, and led to an overall survival benefit. Longitudinal intravital multiphoton microscopy found that the first, rate-limiting steps of BM formation-permanent intravascular arrest, extravasation, and initial perivascular growth-are most vulnerable to dual PI3K/mTOR inhibition.
conclusionThese findings establish a key role of PAM pathway activation for critical steps of early metastatic brain colonization and reveal its pharmacological inhibition as a potent avenue to prevent the formation of clinically relevant BM.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.