gC1qR/HABP1/p32 Is a Potential New Therapeutic Target Against Mesothelioma

• Main Authors: Ellinor Peerschke, Kenneth Stier, Xiaoyu Li, Evelyn Kandov, Elisa de Stanchina, Qing Chang, Yuquan Xiong, Katia Manova-Todorova, Ning Fan, Afsar Barlas, Berhane Ghebrehiwet, Prasad S. Adusumilli
• Format: Article
• Language: English
• Published: Frontiers Media S.A. 2020-08-01
• Series: Frontiers in Oncology
• Subjects: mesothelioma; complement; gC1qR/HABP1/p32; monoclonal antibody therapy; therapeutic target
• Online Access: https://www.frontiersin.org/article/10.3389/fonc.2020.01413/full

Mesothelioma is an aggressive cancer of the serous membranes with poor prognosis despite combination therapy consisting of surgery, radiotherapy, and platinum-based chemotherapy. Targeted therapies, including immunotherapies, have reported limited success, suggesting the need for additional therapeutic targets. This study investigates a potential new therapeutic target, gC1qR/HABP1/p32 (gC1qR), which is overexpressed in all morphologic subtypes of mesothelioma. gC1qR is a complement receptor that is associated with several cellular functions, including cell proliferation and angiogenesis. In vitro and in vivo experiments were conducted to test the hypothesis that targeting gC1qR with a specific gC1qR monoclonal antibody 60.11 reduces mesothelioma tumor growth, using the biphasic mesothelioma cell line MSTO-211H (MSTO). In vitro studies demonstrate cell surface and extracellular gC1qR expression by MSTO cells, and a modest 25.3 ± 1.8% (n = 4) reduction in cell proliferation by the gC1qR blocking 60.11 antibody. This inhibition was specific for targeting the C1q binding domain of gC1qR at aa 76–93, as a separate monoclonal antibody 74.5.2, directed against amino acids 204–218, had no discernable effect. In vivo studies, using a murine orthotopic xenotransplant model, demonstrated an even greater reduction in MSTO tumor growth (50% inhibition) in mice treated with the 60.11 antibody compared to controls. Immunohistochemical studies of resected tumors revealed increased cellular apoptosis by caspase 3 and TUNEL staining, in 60.11 treated tumors compared to controls, as well as impaired angiogenesis by decreased CD31 staining. Taken together, these data identify gC1qR as a potential new therapeutic target against mesothelioma with both antiproliferative and antiangiogenic properties.