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

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.

Use of Antiangiogenic Therapies in Pediatric Solid Tumors

“…Ramucirumab inhibits cord formation by neuroblastoma cells and its analog DC101 delays or regresses xenograft growth, decreases vasculature, and increases chemotherapy effectiveness [ 105 , 122 ]. Pazopanib does not reduce cell viability as a single agent, but it does when combine with topotecan [ 123 ].…”

“…The results obtained with ramucirumab in preclinical models are not very promising either. Ramucirumab inhibits the cord formation of osteosarcoma cells in vitro, but its analogue DC101 has limited efficacy in xenografts as single agent or combined with chemotherapy [ 122 ].…”

“…With regard to antiangiogenics that have only been tested in preclinical models, sunitinib has a high activity in four out of five cell lines of Ewing’s sarcoma of PPTP [ 127 ] and ramucirumab inhibits cord formation in vitro [ 122 ]. The ramucirumab analogue for in vivo studies, DC101, also generates response in xenograft models [ 122 ].…”

The Osteosarcoma Microenvironment: A Complex but Targetable Ecosystem

“…Results showed that the highly specific VEGFR-2 inhibitor, apatinib, was associated with direct anti-tumoral activity through VEGFR2/STAT3/BCL2 signaling [121,128]. Targeting VEGFR-2 with the monoclonal antibody ramucirumab was also shown to exert anti-angiogenic activity in vitro [129]. Surprisingly, injection of anti-mouse Vegfr-2 antibody in preclinical OS pediatric cancer models did not affect tumor growth, even when combined with cytotoxic chemotherapy using doxorubucin, suggesting that targeting both tumor and vascular microenvironment is mandatory in OS, even if it is difficult to achieve efficiently.…”

Focus on Hypoxia-Related Pathways in Pediatric Osteosarcomas and Their Druggability

“…This bone cancer is known as a highly necrotic tumor even at diagnosis, where this histological feature is frequently observed on biopsies. This necrosis might be the consequence of the excessive and rapid growth of cancer cells, which are proficient in creating a hypoxic microenvironment [ 6 , 7 ] and an abnormal neoangiogenesis [ 8 , 9 ]. Besides finding tumor necrosis at biopsy, OTS is also characterized by necrotic rate assessment on surgical tumor resection after a neoadjuvant multichemotherapy approach.…”