Dual HER/VEGF Receptor Targeting Inhibits In Vivo Ovarian Cancer Tumor Growth
Autor: | Thahir Farzan, Kimberly R. Kalli, Paul Haluska, Marc A. Becker, S. John Weroha, Tai W. Wong, Sean C. Harrington, James Krempski, Xiaonan Hou |
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Rok vydání: | 2013 |
Předmět: |
Proteomics
Cancer Research medicine.medical_specialty medicine.medical_treatment Antineoplastic Agents medicine.disease_cause Article Cediranib Mice Piperidines In vivo Cell Line Tumor Internal medicine medicine Animals Cluster Analysis Humans Pyrroles Receptor Protein Kinase Inhibitors Ovarian Neoplasms biology Triazines Growth factor medicine.disease Xenograft Model Antitumor Assays Tumor Burden Disease Models Animal Receptors Vascular Endothelial Growth Factor Endocrinology Oncology Disease Progression Quinazolines Cancer research biology.protein Female Neoplasm Grading Antibody Signal transduction Carcinogenesis Ovarian cancer Signal Transduction medicine.drug |
Zdroj: | Molecular Cancer Therapeutics. 12:2909-2916 |
ISSN: | 1538-8514 1535-7163 |
Popis: | Ovarian cancer mortality ranks highest among all gynecologic cancers with growth factor pathways playing an integral role in tumorigenesis, metastatic dissemination, and therapeutic resistance. The HER and VEGF receptor (VEGFR) are both overexpressed and/or aberrantly activated in subsets of ovarian tumors. While agents targeting either the HER or VEGF pathways alone have been investigated, the impact of these agents have not led to overall survival benefit in ovarian cancer. We tested the hypothesis that cotargeting HER and VEGFR would maximize antitumor efficacy at tolerable doses. To this end, ovarian cancer xenografts grown intraperitoneally in athymic nude mice were tested in response to AC480 (pan-HER inhibitor, “HERi”), cediranib (pan-VEGFR inhibitor “VEGFRi”), or BMS-690514 (combined HER/VEGFR inhibitor “EVRi”). EVRi was superior to both HERi and VEGFRi in terms of tumor growth, final tumor weight, and progression-free survival. Correlative tumor studies employing phosphoproteomic antibody arrays revealed distinct agent-specific alterations, with EVRi inducing the greatest overall effect on growth factor signaling. These data suggest that simultaneous inhibition of HER and VEGFR may benefit select subsets of ovarian cancer tumors. To this end, we derived a novel HER/VEGF signature that correlated with poor overall survival in high-grade, late stage, serous ovarian cancer patient tumors. Mol Cancer Ther; 12(12); 2909–16. ©2013 AACR. |
Databáze: | OpenAIRE |
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