ArticleClinical cancer research : an official journal of the American Association for Cancer Research2023
Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 15 papers.
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Who cites it
15 citing papers in PubMed, 21 citations in OpenAlex.
- Review
- Primary central nervous system lymphoma in the molecular era: genomic drivers, liquid biopsy, and targeted therapeutic strategies.Annals of hematology · 2026Review
- Unraveling the immune microenvironment in primary CNS lymphoma.Biomarker research · 2026Review
- Cystatin C regulates cell division in primary central nervous system lymphoma.Scientific reports · 2026Article
- An Update on Treatments for Recurrent Primary Central Nervous System Lymphoma.Current oncology reports · 2026Review
- Meeting Report From the 2024 Symposium on IRAK4 in Cancer: Highlights and Clinical Updates.Clinical lymphoma, myeloma & leukemia · 2025Review
- Bing-Neel Syndrome in Waldenström Macroglobulinemia: Updates on Clinical Management and BTK Inhibitor Efficacy.Cancers · 2025Review
- Padlock-designed MOFs triggers an "avalanche effect" to enhance apoptosis and suppress metastasis in central nervous system lymphoma.Science advances · 2025Article
- Novel Agents and Immunotherapies for Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System: Innovating for Impact in a Disease With Unmet Needs.Journal of hematology · 2025Review
- IRAK signaling in cancers: mechanisms, targeting, and clinical implications.Expert opinion on investigational drugs · 2025Review
- Review
- Smoking-Associated Carcinogen-Induced Inflammation Promotes Lung Carcinogenesis via IRAK4 Activation.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- In the era of targeted therapy and immunotherapy: advances in the treatment of large B-cell lymphoma of immune-privileged sites.Frontiers in immunology · 2025Review
- Emerging interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors or degraders as therapeutic agents for autoimmune diseases and cancer.Acta pharmaceutica Sinica. B · 2024Review
- IRAK-4 inhibition: emavusertib for the treatment of lymphoid and myeloid malignancies.Frontiers in immunology · 2023Review
Corrections and comments
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Authors and funding
12 authors at 5 institutions in 1 country.
Funding
Abstract
purposeAn ongoing challenge in cancer is the management of primary and metastatic brain malignancies. This is partly due to restrictions of the blood-brain barrier and their unique microenvironment. These challenges are most evident in cancers such as lymphoma and melanoma, which are typically responsive to treatment in systemic locations but resistant when established in the brain. We propose interleukin-1 receptor-associated kinase-4 (IRAK-4) as a potential target across these diseases and describe the activity and mechanism of oral IRAK-4 inhibitor CA-4948. EXPERIMENTAL
designHuman primary central nervous system lymphoma (PCNSL) and melanoma brain metastases (MBM) samples were analyzed for expression of IRAK-4 and downstream transcription pathways. We next determined the central nervous system (CNS) applicability of CA-4948 in naïve and tumor-bearing mice using models of PCNSL and MBM. The mechanistic effect on tumors and the tumor microenvironment was then analyzed.
resultsHuman PCNSL and MBM have high expression of IRAK-4, IRAK-1, and nuclear factor kappa B (NF-κB). This increase in inflammation results in reflexive inhibitory signaling. Similar profiles are observed in immunocompetent murine models. Treatment of tumor-bearing animals with CA-4948 results in the downregulation of mitogen-activated protein kinase (MAPK) signaling in addition to decreased NF-κB. These intracellular changes are associated with a survival advantage.
conclusionsIRAK-4 is an attractive target in PCNSL and MBM. The inhibition of IRAK-4 with CA-4948 downregulates the expression of important transcription factors involved in tumor growth and proliferation. CA-4948 is currently being investigated in clinical trials for relapsed and refractory lymphoma and warrants further translation into PCNSL and MBM.
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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 Socratic graph.