Anti-VEGFR2 therapy delays growth of preclinical pediatric tumor models and enhances anti-tumor activity of chemotherapy

Abstract

// Caitlin D. Lowery 1 , Wayne Blosser 1 , Michele Dowless 1 , Matthew Renschler 1 , Lisa V. Perez 1 , Jennifer Stephens 1 , Bronislaw Pytowski 1 , Heather Wasserstrom 1 , Louis F. Stancato 1 and Beverly Falcon 1 1 Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN, USA Correspondence to: Beverly Falcon, email: falcon_beverly_l@lilly.com Keywords: angiogenesis; pediatric cancer; VEGFR2; ramucirumab; DC101 Received: May 24, 2019     Accepted: July 21, 2019     Published: September 17, 2019 ABSTRACT Vascular endothelial growth factor receptor 2 (VEGFR2) is an attractive therapeutic target in solid malignancies due to its central role in tumor angiogenesis. Ramucirumab (Cyramza ® , LY3009806) is a human monoclonal antibody specific for VEGFR2 approved for several adult indications and currently in a phase 1 clinical trial for pediatric patients with solid tumors (NCT02564198). Here, we evaluated ramucirumab in vitro and the anti-murine VEGFR2 antibody DC101 in vivo with or without chemotherapy across a range of pediatric cancer models. Ramucirumab abrogated in vitro endothelial cord formation driven by cancer cell lines representing multiple pediatric histologies; this response was independent of the origin of the tumor cell-line. Several pediatric cancer mouse models responded to single agent DC101-mediated VEGFR2 inhibition with tumor growth delay. Preclinical stable disease and partial xenograft regressions were observed in mouse models of Ewing’s sarcoma, synovial sarcoma, neuroblastoma, and desmoplastic small round cell tumor treated with DC101 and cytotoxic chemotherapy. In contrast, DC101 treatment in osteosarcoma models had limited efficacy alone or in combination with chemotherapeutics. Our data indicate differential efficacy of targeting the VEGFR2 pathway in pediatric models and support the continued evaluation of VEGFR2 inhibition in combination with cytotoxic chemotherapy in multiple pediatric indications.