HER2 Support Group Forums - View Single Post - Is prevention of her2+ brain mets around the corner? Oral TKI Pazopanib

Lani · 04-16-2013, 04:15 PM

(a tyrosine kinase inhibitor like lapatinib) holds promise to do just that!

Am J Pathol. 2013 Apr 11. pii: S0002-9440(13)00222-8. doi: 10.1016/j.ajpath.2013.02.043. [Epub ahead of print]
Pazopanib Inhibits the Activation of PDGFRβ-Expressing Astrocytes in the Brain Metastatic Microenvironment of Breast Cancer Cells.
Gril B, Palmieri D, Qian Y, Anwar T, Liewehr DJ, Steinberg SM, Andreu Z, Masana D, Fernández P, Steeg PS, Vidal-Vanaclocha F.
Source
Women's Cancers Section, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Electronic address: grilbrun@mail.nih.gov.
Abstract
Brain metastases of breast cancer occur in more than one-third of metastatic breast cancer patients whose tumors overexpress HER2 or are triple negative. Brain colonization of cancer cells occurs in a unique environment, containing microglia, oligodendrocytes, astrocytes, and neurons. Although a neuroinflammatory response has been documented in brain metastasis, its contribution to cancer progression and therapy remains poorly understood. Using an experimental brain metastasis model of breast cancer, we characterized the brain metastatic microenvironment of brain tropic, HER2-transfected MDA-MB-231 human breast carcinoma cells (231-BR-HER2). A previously unidentified subpopulation of metastasis-associated astrocytes expressing phosphorylated platelet-derived growth factor receptor β (at tyrosine 751; p751-PDGFRβ) was identified around perivascular brain micrometastases. This subpopulation of p751-PDGFRβ+ astrocytes was also identified in human brain metastases from eight different craniotomy specimens and in primary cultures of astrocyte-enriched glial cells. Previously, we reported that pazopanib, a multispecific tyrosine kinase inhibitor, prevented the outgrowth of 231-BR-HER2 large brain metastases by 73%. Here, we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment. Pazopanib treatment resulted in 70% (P = 0.023) decrease of the p751-PDGFRβ+ astrocyte population, at the lowest dose of 30 mg/kg, twice daily. Collectively, the data identify a new subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib, suggesting its potential to prevent the development of subclinical perivascular micrometastases in breast cancer patients.
Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
PMID: 23583652 [PubMed - as supplied by publisher]

04-16-2013, 04:15 PM	#1
Lani Senior Member Join Date: Mar 2006 Posts: 4,778	Is prevention of her2+ brain mets around the corner? Oral TKI Pazopanib (a tyrosine kinase inhibitor like lapatinib) holds promise to do just that! Am J Pathol. 2013 Apr 11. pii: S0002-9440(13)00222-8. doi: 10.1016/j.ajpath.2013.02.043. [Epub ahead of print] Pazopanib Inhibits the Activation of PDGFRβ-Expressing Astrocytes in the Brain Metastatic Microenvironment of Breast Cancer Cells. Gril B, Palmieri D, Qian Y, Anwar T, Liewehr DJ, Steinberg SM, Andreu Z, Masana D, Fernández P, Steeg PS, Vidal-Vanaclocha F. Source Women's Cancers Section, Laboratory of Molecular Pharmacology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland. Electronic address: grilbrun@mail.nih.gov. Abstract Brain metastases of breast cancer occur in more than one-third of metastatic breast cancer patients whose tumors overexpress HER2 or are triple negative. Brain colonization of cancer cells occurs in a unique environment, containing microglia, oligodendrocytes, astrocytes, and neurons. Although a neuroinflammatory response has been documented in brain metastasis, its contribution to cancer progression and therapy remains poorly understood. Using an experimental brain metastasis model of breast cancer, we characterized the brain metastatic microenvironment of brain tropic, HER2-transfected MDA-MB-231 human breast carcinoma cells (231-BR-HER2). A previously unidentified subpopulation of metastasis-associated astrocytes expressing phosphorylated platelet-derived growth factor receptor β (at tyrosine 751; p751-PDGFRβ) was identified around perivascular brain micrometastases. This subpopulation of p751-PDGFRβ+ astrocytes was also identified in human brain metastases from eight different craniotomy specimens and in primary cultures of astrocyte-enriched glial cells. Previously, we reported that pazopanib, a multispecific tyrosine kinase inhibitor, prevented the outgrowth of 231-BR-HER2 large brain metastases by 73%. Here, we evaluated the effect of pazopanib on the brain neuroinflammatory microenvironment. Pazopanib treatment resulted in 70% (P = 0.023) decrease of the p751-PDGFRβ+ astrocyte population, at the lowest dose of 30 mg/kg, twice daily. Collectively, the data identify a new subpopulation of activated astrocytes in the subclinical perivascular stage of brain metastases and show that they are inhibitable by pazopanib, suggesting its potential to prevent the development of subclinical perivascular micrometastases in breast cancer patients. Copyright © 2013 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved. PMID: 23583652 [PubMed - as supplied by publisher]