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Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases
PURPOSE: An 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 res...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150246/ https://www.ncbi.nlm.nih.gov/pubmed/36749885 http://dx.doi.org/10.1158/1078-0432.CCR-22-1682 |
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author | Von Roemeling, Christina A. Doonan, Bently P. Klippel, Kelena Schultz, Daniel Hoang-Minh, Lan Trivedi, Vrunda Li, Chenglong Russell, Rylynn A. Kanumuri, Raju S. Sharma, Abhisheak Tun, Han W. Mitchell, Duane A. |
author_facet | Von Roemeling, Christina A. Doonan, Bently P. Klippel, Kelena Schultz, Daniel Hoang-Minh, Lan Trivedi, Vrunda Li, Chenglong Russell, Rylynn A. Kanumuri, Raju S. Sharma, Abhisheak Tun, Han W. Mitchell, Duane A. |
author_sort | Von Roemeling, Christina A. |
collection | PubMed |
description | PURPOSE: An 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 DESIGN: Human 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. RESULTS: Human 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. CONCLUSIONS: IRAK-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. |
format | Online Article Text |
id | pubmed-10150246 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-101502462023-05-02 Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases Von Roemeling, Christina A. Doonan, Bently P. Klippel, Kelena Schultz, Daniel Hoang-Minh, Lan Trivedi, Vrunda Li, Chenglong Russell, Rylynn A. Kanumuri, Raju S. Sharma, Abhisheak Tun, Han W. Mitchell, Duane A. Clin Cancer Res Translational Cancer Mechanisms and Therapy PURPOSE: An 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 DESIGN: Human 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. RESULTS: Human 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. CONCLUSIONS: IRAK-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. American Association for Cancer Research 2023-05-01 2023-02-07 /pmc/articles/PMC10150246/ /pubmed/36749885 http://dx.doi.org/10.1158/1078-0432.CCR-22-1682 Text en ©2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Translational Cancer Mechanisms and Therapy Von Roemeling, Christina A. Doonan, Bently P. Klippel, Kelena Schultz, Daniel Hoang-Minh, Lan Trivedi, Vrunda Li, Chenglong Russell, Rylynn A. Kanumuri, Raju S. Sharma, Abhisheak Tun, Han W. Mitchell, Duane A. Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases |
title | Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases |
title_full | Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases |
title_fullStr | Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases |
title_full_unstemmed | Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases |
title_short | Oral IRAK-4 Inhibitor CA-4948 Is Blood-Brain Barrier Penetrant and Has Single-Agent Activity against CNS Lymphoma and Melanoma Brain Metastases |
title_sort | oral irak-4 inhibitor ca-4948 is blood-brain barrier penetrant and has single-agent activity against cns lymphoma and melanoma brain metastases |
topic | Translational Cancer Mechanisms and Therapy |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10150246/ https://www.ncbi.nlm.nih.gov/pubmed/36749885 http://dx.doi.org/10.1158/1078-0432.CCR-22-1682 |
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