Discovery of HSPG2 (Perlecan) as a Therapeutic Target in Triple Negative Breast Cancer

Stephen Kalscheuer; Vidhi Khanna; Hyunjoon Kim; Sihan Li; Deepali Sachdev; Arthur DeCarlo; Da Yang; Jayanth Panyam

doi:10.1038/s41598-019-48993-6

Discovery of HSPG2 (Perlecan) as a Therapeutic Target in Triple Negative Breast Cancer

Stephen Kalscheuer, Vidhi Khanna, Hyunjoon Kim, Sihan Li, Deepali Sachdev, Arthur DeCarlo, Da Yang, Jayanth Panyam

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

In recent years, there have been significant advances in the treatment of breast cancer resulting in remarkably high survival rates. However, treatment options for metastatic triple negative breast cancer (TNBC) are quite limited due to a lack of identifiable, unique markers. Using a phage display-based whole cell biopanning procedure, we developed two human antibodies that bind to tumor cells with a metastatic TNBC phenotype. Our studies further identified domain 1 of HSPG2 (perlecan) protein as the cognate cell surface antigen bound by the antibody. Immunohistochemistry studies utilizing patient tissue samples revealed significant cell surface expression of HSPG2 in both primary tumors and metastatic lesions. Further, higher HSPG2 expression correlated with poor survival in TNBC. The affinity-matured antibody inhibited the growth of triple negative MDA-MB-231 tumors to a greater extent in nude mice than in NSG mice, pointing to the potential role of natural killer cell-mediated antibody-dependent cell cytotoxicity. This mechanism of action was confirmed through in vitro assays using mouse splenocytes and human peripheral blood mononuclear cells (PBMCs). These results suggest that HSPG2 is a promising target in metastatic TNBC and HSPG2-targeted antibodies could represent a potentially novel class of targeted therapeutics for TNBC.

Original language	English (US)
Article number	12492
Journal	Scientific reports
Volume	9
Issue number	1
DOIs	https://doi.org/10.1038/s41598-019-48993-6
State	Published - Dec 1 2019

Bibliographical note

Funding Information:
The authors would like to thank Professor Robert Weinberg at the Massachusetts Institute of Technology (Cambridge, Massachusetts) for providing the HMLE cell lines, the Comparative Pathology Shared Resource (UMN, Minneapolis) for IHC workup and Resha Tejpaul (UMN, Minneapolis). Live animal imaging and confocal microscopy was performed at the University Imaging Center (UMN, Minneapolis). Funding was provided by the Community of Pharmaceutical Development (CPD), Office of Discovery and Translation (ODAT) at the University of Minnesota, the Randy Shaver Foundation and NIH R01EB019893 (to J.P.).

Publisher Copyright:
© 2019, The Author(s).

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title = "Discovery of HSPG2 (Perlecan) as a Therapeutic Target in Triple Negative Breast Cancer",

abstract = "In recent years, there have been significant advances in the treatment of breast cancer resulting in remarkably high survival rates. However, treatment options for metastatic triple negative breast cancer (TNBC) are quite limited due to a lack of identifiable, unique markers. Using a phage display-based whole cell biopanning procedure, we developed two human antibodies that bind to tumor cells with a metastatic TNBC phenotype. Our studies further identified domain 1 of HSPG2 (perlecan) protein as the cognate cell surface antigen bound by the antibody. Immunohistochemistry studies utilizing patient tissue samples revealed significant cell surface expression of HSPG2 in both primary tumors and metastatic lesions. Further, higher HSPG2 expression correlated with poor survival in TNBC. The affinity-matured antibody inhibited the growth of triple negative MDA-MB-231 tumors to a greater extent in nude mice than in NSG mice, pointing to the potential role of natural killer cell-mediated antibody-dependent cell cytotoxicity. This mechanism of action was confirmed through in vitro assays using mouse splenocytes and human peripheral blood mononuclear cells (PBMCs). These results suggest that HSPG2 is a promising target in metastatic TNBC and HSPG2-targeted antibodies could represent a potentially novel class of targeted therapeutics for TNBC.",

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N2 - In recent years, there have been significant advances in the treatment of breast cancer resulting in remarkably high survival rates. However, treatment options for metastatic triple negative breast cancer (TNBC) are quite limited due to a lack of identifiable, unique markers. Using a phage display-based whole cell biopanning procedure, we developed two human antibodies that bind to tumor cells with a metastatic TNBC phenotype. Our studies further identified domain 1 of HSPG2 (perlecan) protein as the cognate cell surface antigen bound by the antibody. Immunohistochemistry studies utilizing patient tissue samples revealed significant cell surface expression of HSPG2 in both primary tumors and metastatic lesions. Further, higher HSPG2 expression correlated with poor survival in TNBC. The affinity-matured antibody inhibited the growth of triple negative MDA-MB-231 tumors to a greater extent in nude mice than in NSG mice, pointing to the potential role of natural killer cell-mediated antibody-dependent cell cytotoxicity. This mechanism of action was confirmed through in vitro assays using mouse splenocytes and human peripheral blood mononuclear cells (PBMCs). These results suggest that HSPG2 is a promising target in metastatic TNBC and HSPG2-targeted antibodies could represent a potentially novel class of targeted therapeutics for TNBC.

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Discovery of HSPG2 (Perlecan) as a Therapeutic Target in Triple Negative Breast Cancer

Abstract

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Discovery of HSPG2 (Perlecan) as a Therapeutic Target in Triple Negative Breast Cancer

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