Dual HER/VEGF receptor targeting inhibits in vivo ovarian cancer tumor growth

• Published in: Molecular cancer therapeutics Vol. 12; no. 12; pp. 2909 - 2916
• Main Authors: Becker, Marc A, Farzan, Thahir, Harrington, Sean C, Krempski, James W, Weroha, S John, Hou, Xiaonan, Kalli, Kimberly R, Wong, Tai W, Haluska, Paul
• Format: Journal Article
• Language: English
• Published: United States 01.12.2013
• Subjects: Animals; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacology; Cell Line, Tumor; Cluster Analysis; Disease Models, Animal; Disease Progression; Female; Humans; Mice; Neoplasm Grading; Ovarian Neoplasms - drug therapy; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - mortality; Ovarian Neoplasms - pathology; Piperidines - administration & dosage; Piperidines - pharmacology; Protein Kinase Inhibitors - administration & dosage; Protein Kinase Inhibitors - pharmacology; Proteomics; Pyrroles - administration & dosage; Pyrroles - pharmacology; Quinazolines - administration & dosage; Quinazolines - pharmacology; Receptors, Vascular Endothelial Growth Factor - antagonists & inhibitors; Receptors, Vascular Endothelial Growth Factor - metabolism; Signal Transduction; Triazines - administration & dosage; Triazines - pharmacology; Tumor Burden - drug effects; Xenograft Model Antitumor Assays
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-13-0547

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.