Targeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other MUC16/CA-125-expressing malignancies

Abstract The lectin, galectin-3 (Gal3), has been implicated in a variety of inflammatory and oncogenic processes, including tumor growth, invasion, and metastasis. The interactions of Gal3 and MUC16 represent a potential targetable pathway for the treatment of MUC16-expressing malignancies. We found...

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Autores principales:	Marina Stasenko, Evan Smith, Oladapo Yeku, Kay J. Park, Ian Laster, Kwangkook Lee, Sven Walderich, Elizabeth Spriggs, Bo Rueda, Britta Weigelt, Dmitriy Zamarin, Thapi Dharma Rao, David R. Spriggs
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/07f8316150054d388efdf8ddb85cc8eb
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spelling	oai:doaj.org-article:07f8316150054d388efdf8ddb85cc8eb2021-12-02T12:09:51ZTargeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other MUC16/CA-125-expressing malignancies10.1038/s41598-021-82686-32045-2322https://doaj.org/article/07f8316150054d388efdf8ddb85cc8eb2021-02-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-82686-3https://doaj.org/toc/2045-2322Abstract The lectin, galectin-3 (Gal3), has been implicated in a variety of inflammatory and oncogenic processes, including tumor growth, invasion, and metastasis. The interactions of Gal3 and MUC16 represent a potential targetable pathway for the treatment of MUC16-expressing malignancies. We found that the silencing of Gal3 in MUC16-expressing breast and ovarian cancer cells in vitro inhibited tumor cell invasion and led to attenuated tumor growth in murine models. We therefore developed an inhibitory murine monoclonal anti–Gal3 carbohydrate-binding domain antibody, 14D11, which bound human and mouse Gal3 but did not bind human Galectins-1, -7, -8 or -9. Competition studies and a docking model suggest that the 14D11 antibody competes with lactose for the carbohydrate binding pocket of Gal3. In MUC16-expressing cancer cells, 14D11 treatment blocked AKT and ERK1/2 phosphorylation, and led to inhibition of cancer cell Matrigel invasion. Finally, in experimental animal tumor models, 14D11 treatment led to prolongation of overall survival in animals bearing flank tumors, and retarded lung specific metastatic growth by MUC16 expressing breast cancer cells. Our results provide evidence that antibody based Gal3 blockade may be a viable therapeutic strategy in patients with MUC16-expressing tumors, supporting further development of human blocking antibodies against Gal3 as potential cancer therapeutics.Marina StasenkoEvan SmithOladapo YekuKay J. ParkIan LasterKwangkook LeeSven WalderichElizabeth SpriggsBo RuedaBritta WeigeltDmitriy ZamarinThapi Dharma RaoDavid R. SpriggsNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-13 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Marina Stasenko Evan Smith Oladapo Yeku Kay J. Park Ian Laster Kwangkook Lee Sven Walderich Elizabeth Spriggs Bo Rueda Britta Weigelt Dmitriy Zamarin Thapi Dharma Rao David R. Spriggs Targeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other MUC16/CA-125-expressing malignancies
description	Abstract The lectin, galectin-3 (Gal3), has been implicated in a variety of inflammatory and oncogenic processes, including tumor growth, invasion, and metastasis. The interactions of Gal3 and MUC16 represent a potential targetable pathway for the treatment of MUC16-expressing malignancies. We found that the silencing of Gal3 in MUC16-expressing breast and ovarian cancer cells in vitro inhibited tumor cell invasion and led to attenuated tumor growth in murine models. We therefore developed an inhibitory murine monoclonal anti–Gal3 carbohydrate-binding domain antibody, 14D11, which bound human and mouse Gal3 but did not bind human Galectins-1, -7, -8 or -9. Competition studies and a docking model suggest that the 14D11 antibody competes with lactose for the carbohydrate binding pocket of Gal3. In MUC16-expressing cancer cells, 14D11 treatment blocked AKT and ERK1/2 phosphorylation, and led to inhibition of cancer cell Matrigel invasion. Finally, in experimental animal tumor models, 14D11 treatment led to prolongation of overall survival in animals bearing flank tumors, and retarded lung specific metastatic growth by MUC16 expressing breast cancer cells. Our results provide evidence that antibody based Gal3 blockade may be a viable therapeutic strategy in patients with MUC16-expressing tumors, supporting further development of human blocking antibodies against Gal3 as potential cancer therapeutics.
format	article
author	Marina Stasenko Evan Smith Oladapo Yeku Kay J. Park Ian Laster Kwangkook Lee Sven Walderich Elizabeth Spriggs Bo Rueda Britta Weigelt Dmitriy Zamarin Thapi Dharma Rao David R. Spriggs
author_facet	Marina Stasenko Evan Smith Oladapo Yeku Kay J. Park Ian Laster Kwangkook Lee Sven Walderich Elizabeth Spriggs Bo Rueda Britta Weigelt Dmitriy Zamarin Thapi Dharma Rao David R. Spriggs
author_sort	Marina Stasenko
title	Targeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other MUC16/CA-125-expressing malignancies
title_short	Targeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other MUC16/CA-125-expressing malignancies
title_full	Targeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other MUC16/CA-125-expressing malignancies
title_fullStr	Targeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other MUC16/CA-125-expressing malignancies
title_full_unstemmed	Targeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other MUC16/CA-125-expressing malignancies
title_sort	targeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other muc16/ca-125-expressing malignancies
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/07f8316150054d388efdf8ddb85cc8eb
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Targeting galectin-3 with a high-affinity antibody for inhibition of high-grade serous ovarian cancer and other MUC16/CA-125-expressing malignancies

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