Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
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
_version_ 1785035329345945600
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
work_keys_str_mv AT vonroemelingchristinaa oralirak4inhibitorca4948isbloodbrainbarrierpenetrantandhassingleagentactivityagainstcnslymphomaandmelanomabrainmetastases
AT doonanbentlyp oralirak4inhibitorca4948isbloodbrainbarrierpenetrantandhassingleagentactivityagainstcnslymphomaandmelanomabrainmetastases
AT klippelkelena oralirak4inhibitorca4948isbloodbrainbarrierpenetrantandhassingleagentactivityagainstcnslymphomaandmelanomabrainmetastases
AT schultzdaniel oralirak4inhibitorca4948isbloodbrainbarrierpenetrantandhassingleagentactivityagainstcnslymphomaandmelanomabrainmetastases
AT hoangminhlan oralirak4inhibitorca4948isbloodbrainbarrierpenetrantandhassingleagentactivityagainstcnslymphomaandmelanomabrainmetastases
AT trivedivrunda oralirak4inhibitorca4948isbloodbrainbarrierpenetrantandhassingleagentactivityagainstcnslymphomaandmelanomabrainmetastases
AT lichenglong oralirak4inhibitorca4948isbloodbrainbarrierpenetrantandhassingleagentactivityagainstcnslymphomaandmelanomabrainmetastases
AT russellrylynna oralirak4inhibitorca4948isbloodbrainbarrierpenetrantandhassingleagentactivityagainstcnslymphomaandmelanomabrainmetastases
AT kanumurirajus oralirak4inhibitorca4948isbloodbrainbarrierpenetrantandhassingleagentactivityagainstcnslymphomaandmelanomabrainmetastases
AT sharmaabhisheak oralirak4inhibitorca4948isbloodbrainbarrierpenetrantandhassingleagentactivityagainstcnslymphomaandmelanomabrainmetastases
AT tunhanw oralirak4inhibitorca4948isbloodbrainbarrierpenetrantandhassingleagentactivityagainstcnslymphomaandmelanomabrainmetastases
AT mitchellduanea oralirak4inhibitorca4948isbloodbrainbarrierpenetrantandhassingleagentactivityagainstcnslymphomaandmelanomabrainmetastases