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BSCI-04. TARGETING TRIPLE-NEGATIVE BREAST CANCER BRAIN METASTASES WITH A RE-ENGINEERED LUPUS AUTOANTIBODY

An unusual lupus anti-DNA autoantibody, 3E10, has potential to be used against triple-negative breast cancer (TNBC) brain metastases. 3E10 penetrates live cell nuclei, inhibits DNA repair, and is selectively toxic to cancer cells with the PTEN and/or DNA-damage response (DDR)-deficiencies that are a...

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Autores principales: Zhang, Shenqi, May, Christopher, Shirali, Anupama, Dubljevic, Valentina, Campbell, James, Zhou, Jiangbing, Hansen, James
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213175/
http://dx.doi.org/10.1093/noajnl/vdz014.003
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author Zhang, Shenqi
May, Christopher
Shirali, Anupama
Dubljevic, Valentina
Campbell, James
Zhou, Jiangbing
Hansen, James
author_facet Zhang, Shenqi
May, Christopher
Shirali, Anupama
Dubljevic, Valentina
Campbell, James
Zhou, Jiangbing
Hansen, James
author_sort Zhang, Shenqi
collection PubMed
description An unusual lupus anti-DNA autoantibody, 3E10, has potential to be used against triple-negative breast cancer (TNBC) brain metastases. 3E10 penetrates live cell nuclei, inhibits DNA repair, and is selectively toxic to cancer cells with the PTEN and/or DNA-damage response (DDR)-deficiencies that are associated with brain metastases in TNBC. The ENT2 nucleoside transporter that 3E10 uses to cross cell membranes is highly expressed in tumors and in brain endothelial cells (BECs) at the blood-brain barrier (BBB), and 3E10 has previously delivered cargo proteins to ischemic brain in a rat stroke model. We have re-engineered 3E10 into an optimized fragment, called Deoxymab-1 (PAT-DX1), that has increased effect on PTEN/DDR-deficient tumor cells. In the present study we tested the ability of PAT-DX1 to cross the BBB and improve outcomes in a mouse model of TNBC brain metastases. PAT-DX1 crossed from apical to basolateral chambers in an hCMEC/D3 Transwell filter model of the BBB, and penetrated the nuclei of and was toxic to the brain-seeking 231-BR subclone of MDA-MB-231 TNBC cells, which harbors a loss of PTEN compared to parental cells. Brain metastases were generated in nude mice by intracardiac injection of 1.75x10(5) 231-BR cells engineered for expression of luciferase, as confirmed by IVIS one week after injection. Mice with brain metastases were treated by tail vein injection of control (PBS, n=7) or DX1 (20 mg/kg, n=7) 3x/week for 4 weeks. Mice were observed for behavior and weights, and brain radiance efficiency was monitored by weekly IVIS to track metastatic tumor growth. PAT-DX1 significantly suppressed growth of brain metastases based on absolute and relative radiance efficiencies in the brain, increased the median survival of the mice from 38 to 52 days (P< 0.02), and was well tolerated. These results provide proof of concept for use of a re-engineered autoantibody against brain metastases.
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spelling pubmed-72131752020-07-07 BSCI-04. TARGETING TRIPLE-NEGATIVE BREAST CANCER BRAIN METASTASES WITH A RE-ENGINEERED LUPUS AUTOANTIBODY Zhang, Shenqi May, Christopher Shirali, Anupama Dubljevic, Valentina Campbell, James Zhou, Jiangbing Hansen, James Neurooncol Adv Abstracts An unusual lupus anti-DNA autoantibody, 3E10, has potential to be used against triple-negative breast cancer (TNBC) brain metastases. 3E10 penetrates live cell nuclei, inhibits DNA repair, and is selectively toxic to cancer cells with the PTEN and/or DNA-damage response (DDR)-deficiencies that are associated with brain metastases in TNBC. The ENT2 nucleoside transporter that 3E10 uses to cross cell membranes is highly expressed in tumors and in brain endothelial cells (BECs) at the blood-brain barrier (BBB), and 3E10 has previously delivered cargo proteins to ischemic brain in a rat stroke model. We have re-engineered 3E10 into an optimized fragment, called Deoxymab-1 (PAT-DX1), that has increased effect on PTEN/DDR-deficient tumor cells. In the present study we tested the ability of PAT-DX1 to cross the BBB and improve outcomes in a mouse model of TNBC brain metastases. PAT-DX1 crossed from apical to basolateral chambers in an hCMEC/D3 Transwell filter model of the BBB, and penetrated the nuclei of and was toxic to the brain-seeking 231-BR subclone of MDA-MB-231 TNBC cells, which harbors a loss of PTEN compared to parental cells. Brain metastases were generated in nude mice by intracardiac injection of 1.75x10(5) 231-BR cells engineered for expression of luciferase, as confirmed by IVIS one week after injection. Mice with brain metastases were treated by tail vein injection of control (PBS, n=7) or DX1 (20 mg/kg, n=7) 3x/week for 4 weeks. Mice were observed for behavior and weights, and brain radiance efficiency was monitored by weekly IVIS to track metastatic tumor growth. PAT-DX1 significantly suppressed growth of brain metastases based on absolute and relative radiance efficiencies in the brain, increased the median survival of the mice from 38 to 52 days (P< 0.02), and was well tolerated. These results provide proof of concept for use of a re-engineered autoantibody against brain metastases. Oxford University Press 2019-08-12 /pmc/articles/PMC7213175/ http://dx.doi.org/10.1093/noajnl/vdz014.003 Text en © The Author(s) 2019. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology. http://creativecommons.org/licenses/by-nc/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Abstracts
Zhang, Shenqi
May, Christopher
Shirali, Anupama
Dubljevic, Valentina
Campbell, James
Zhou, Jiangbing
Hansen, James
BSCI-04. TARGETING TRIPLE-NEGATIVE BREAST CANCER BRAIN METASTASES WITH A RE-ENGINEERED LUPUS AUTOANTIBODY
title BSCI-04. TARGETING TRIPLE-NEGATIVE BREAST CANCER BRAIN METASTASES WITH A RE-ENGINEERED LUPUS AUTOANTIBODY
title_full BSCI-04. TARGETING TRIPLE-NEGATIVE BREAST CANCER BRAIN METASTASES WITH A RE-ENGINEERED LUPUS AUTOANTIBODY
title_fullStr BSCI-04. TARGETING TRIPLE-NEGATIVE BREAST CANCER BRAIN METASTASES WITH A RE-ENGINEERED LUPUS AUTOANTIBODY
title_full_unstemmed BSCI-04. TARGETING TRIPLE-NEGATIVE BREAST CANCER BRAIN METASTASES WITH A RE-ENGINEERED LUPUS AUTOANTIBODY
title_short BSCI-04. TARGETING TRIPLE-NEGATIVE BREAST CANCER BRAIN METASTASES WITH A RE-ENGINEERED LUPUS AUTOANTIBODY
title_sort bsci-04. targeting triple-negative breast cancer brain metastases with a re-engineered lupus autoantibody
topic Abstracts
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213175/
http://dx.doi.org/10.1093/noajnl/vdz014.003
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