Monoclonal Antibody against Cell Surface GRP78 as a Novel Agent in Suppressing PI3K/AKT Signaling, Tumor Growth, and Metastasis
| Autor: | Satyajit Sujit Kumar Mitra, Amy S. Lee, Shiuan Wey, Wenming Gao, Xiuqing Li, Yue Zhou, Peter S. Conti, Parkash S. Gill, Valery Krasnoperov, Ren Liu, Genyuan Zhu, Shuanglong Liu, Zibo Li, Dan Li, Dezheng Dong, Stan G. Louie |
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| Rok vydání: | 2013 |
| Předmět: |
Cancer Research
Apoptosis Tumor M2-PK Antibodies Monoclonal Humanized Article Metastasis Mice Neoplasms medicine Animals Humans PTEN Neoplasm Metastasis Endoplasmic Reticulum Chaperone BiP Heat-Shock Proteins PI3K/AKT/mTOR pathway Cell Proliferation biology Cell growth Antibodies Monoclonal Cancer medicine.disease Xenograft Model Antitumor Assays Molecular biology Elafin Oncology Tumor progression Cancer cell Cancer research biology.protein HT29 Cells Proto-Oncogene Proteins c-akt Signal Transduction |
| Zdroj: | Clinical Cancer Research. 19:6802-6811 |
| ISSN: | 1557-3265 1078-0432 |
| Popis: | Purpose: The ER chaperone GRP78 translocates to the surface of tumor cells and promotes survival, metastasis, and resistance to therapy. An oncogenic function of cell surface GRP78 has been attributed to the activation of the phosphoinositide 3-kinase (PI3K) pathway. We intend to use a novel anti-GRP78 monoclonal antibody (MAb159) to attenuate PI3K signaling and inhibit tumor growth and metastasis. Experimental Design: MAb159 was characterized biochemically. Antitumor activity was tested in cancer cell culture, tumor xenograft models, tumor metastasis models, and spontaneous tumor models. Cancer cells and tumor tissues were analyzed for PI3K activity. MAb159 was humanized and validated for diagnostic and therapeutic application. Results: MAb159 specifically recognized surface GRP78, triggered GRP78 endocytosis, and localized to tumors but not to normal organs in vivo. MAb159 inhibited tumor cell proliferation and enhanced tumor cell death both in vitro and in vivo. In MAb159-treated tumors, PI3K signaling was inhibited without compensatory MAPK pathway activation. Furthermore, MAb159 halted or reversed tumor progression in the spontaneous PTEN–loss-driven prostate and leukemia tumor models, and inhibited tumor growth and metastasis in xenograft models. Humanized MAb159, which retains high affinity, tumor specific localization, and the antitumor activity, was nontoxic in mice, and had desirable pharmacokinetics. Conclusions: GRP78-specific antibody MAb159 modulates the PI3K pathway and inhibits tumor growth and metastasis. Humanized MAb159 will enter human trials shortly. Clin Cancer Res; 19(24); 6802–11. ©2013 AACR. |
| Databáze: | OpenAIRE |
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