Abstract
Cancer-specific plectin (CSP) is a pro-tumorigenic protein selectively expressed on the cell surface of major cancers, including ovarian cancer (OC). Despite its assessable localization, abundance, and functional significance, the therapeutic efficacy of targeting CSP remains unexplored. Here, we generated and investigated the anticancer effects of a novel CSP-targeting monoclonal antibody, 1H11, in OC models. Its therapeutic efficacy as a monotherapy and in combination with chemotherapy was evaluated in vitro using two OC cell lines and in vivo by a subcutaneous ovarian cancer model. 1H11 demonstrated rapid internalization and high affinity and specificity for both human and murine CSP. Moreover, 1H11 induced significant and selective cytotoxicity (EC50 = 260 nM), G0/G1 arrest, and decreased OC cell migration. Mechanistically, these results are associated with increased ROS levels and reduced activation of the JAK2-STAT3 pathway. In vivo, 1H11 decreased Ki67 expression, induced 65% tumor growth inhibition, and resulted in 30% tumor necrosis. Moreover, 1H11 increased chemosensitivity to cisplatin resulting in 60% greater tumor growth inhibition compared to cisplatin alone. Taken together, CSP-targeting with 1H11 exhibits potent anticancer activity against ovarian cancer and is deserving of future clinical development.
Highlights
In 2008, Kelly et al pioneered a phage-display-based functional proteomic approach to identify a subset of proteins with aberrant cell-surface localization in cancer
cancerspecific plectin (CSP) was previously identified to be expressed on the cell surface of high-grade serous carcinoma, the most common ovarian cancer (OC) subtype characterized by ubiquitous TP53 mutations [8,9,28]
A patient survival analysis using the Kaplan–Meier (KM) plotter database, which integrates Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data, revealed that for this subset of patients, high plectin (PLEC) mRNA expression was significantly associated with worse overall survival (OS) (n = 493, hazard ratio (HR) = 1.4, 95% combination index (CI): 1.09–1.79, p = 7.8 × 10−3; Figure 1A)
Summary
In 2008, Kelly et al pioneered a phage-display-based functional proteomic approach to identify a subset of proteins with aberrant cell-surface localization in cancer. Most notably amongst these is plectin, which was ubiquitously expressed on 100% of cancer tissues analyzed [1,2]. Multiple studies have further demonstrated that cancer cells have an altered cell-surface proteome, representing a highly attractive class of proteins for targeted therapeutics and immunotherapy [3,4,5,6]. Plectin expression was significantly elevated in mice with recurrent disease after initial paclitaxel treatment [25] These findings demonstrate the functional importance of CSP in cancer, prompting us to hypothesize that CSP could be a clinically relevant therapeutic target. We generated and characterized a novel CSP-targeting antibody, 1H11, evaluated its therapeutic efficacy as a monotherapy and in combination with chemotherapy, as well as investigated 1H11 s anticancer mechanism in ovarian cancer
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