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 journalArticle

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 languageEnglish (US)
Article number12492
JournalScientific reports
Volume9
Issue number1
DOIs
StatePublished - Dec 1 2019

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Triple Negative Breast Neoplasms
Antibodies
Antibody-Dependent Cell Cytotoxicity
Therapeutics
Neoplasms
Antibody Affinity
Surface Antigens
Nude Mice
Natural Killer Cells
Bacteriophages
Blood Cells
Survival Rate
Immunohistochemistry
perlecan
Breast Neoplasms
Phenotype
Survival
Growth
Proteins

PubMed: MeSH publication types

  • Journal Article

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Discovery of HSPG2 (Perlecan) as a Therapeutic Target in Triple Negative Breast Cancer. / Kalscheuer, Stephen; Khanna, Vidhi; Kim, Hyunjoon; Li, Sihan; Sachdev, Deepali; DeCarlo, Arthur; Yang, Da; Panyam, Jayanth.

In: Scientific reports, Vol. 9, No. 1, 12492, 01.12.2019.

Research output: Contribution to journalArticle

Kalscheuer, S, Khanna, V, Kim, H, Li, S, Sachdev, D, DeCarlo, A, Yang, D & Panyam, J 2019, 'Discovery of HSPG2 (Perlecan) as a Therapeutic Target in Triple Negative Breast Cancer', Scientific reports, vol. 9, no. 1, 12492. https://doi.org/10.1038/s41598-019-48993-6
Kalscheuer, Stephen ; Khanna, Vidhi ; Kim, Hyunjoon ; Li, Sihan ; Sachdev, Deepali ; DeCarlo, Arthur ; Yang, Da ; Panyam, Jayanth. / Discovery of HSPG2 (Perlecan) as a Therapeutic Target in Triple Negative Breast Cancer. In: Scientific reports. 2019 ; Vol. 9, No. 1.
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