Abstract
The multikinase inhibitor regorafenib (BAY 73–4506) exerts both anti-angiogenic and anti-tumorigenic activity in adult solid malignancies mainly advanced colorectal cancer and gastrointestinal stromal tumors. We intended to explore preclinically the potential of regorafenib against solid pediatric malignancies alone and in combination with anticancer agents to guide the pediatric development plan. In vitro effects on cell proliferation were screened against 33 solid tumor cell lines of the Innovative Therapies for Children with Cancer (ITCC) panel covering five pediatric solid malignancies. Regorafenib inhibited cell proliferation with a mean half maximal growth inhibition of 12.5 μmol/L (range 0.7 μmol/L to 28 μmol/L). In vivo, regorafenib was evaluated alone at 10 or 30 mg/kg/d or in combination with radiation, irinotecan or the mitogen-activated protein kinase kinase (MEK) inhibitor refametinib against various tumor types, including patient-derived brain tumor models with an amplified platelet-derived growth factor receptor A (PDGFRA) gene. Regorafenib alone significantly inhibited tumor growth in all xenografts derived from nervous system and connective tissue tumors. Enhanced effects were observed when regorafenib was combined with irradiation and irinotecan against PDGFRA amplified IGRG93 glioma and IGRM57 medulloblastoma respectively, resulting in 100% tumor regressions. Antitumor activity was associated with decreased tumor vascularization, inhibition of PDGFR signaling, and induction of apoptotic cell death. Our work demonstrates that regorafenib exhibits significant antitumor activity in a wide spectrum of preclinical pediatric models through inhibition of angiogenesis and induction of apoptosis. Furthermore, radio- and chemosensitizing effects were observed with DNA damaging agents in PDGFR amplified tumors.
Highlights
Angiogenesis plays a pivotal role in tumor growth and metastatic spread of solid malignancies [1]
Regorafenib was previously demonstrated to broadly inhibit tumor growth in preclinical models derived from adult tumors [18]
Regorafenib revealed dose-dependent anti-proliferative activity in a panel of 33 cell lines derived from five different pediatric solid tumor indications
Summary
Angiogenesis plays a pivotal role in tumor growth and metastatic spread of solid malignancies [1]. Antiangiogenic therapies inhibiting VEGF or its receptors VEGFR-1-3 appeared conceptually very promising, targeting VEGF alone has only shown limited efficacy in patients with solid tumors. Regorafenib (BAY 73–4506) is a new generation multi-tyrosine kinase inhibitor which potently inhibits angiogenic and oncogenic kinases, mainly VEGFR1-3, PDGFRA/B, FGFR1, Tie, KIT, RET and BRAF[18]. Clinical phase I to III trials have shown activity in various advanced solid tumors and regorafenib was approved for metastatic colorectal cancer and gastro-intestinal stromal tumors (GIST) [26,27,28,29,30] following the CORRECT and the GRID pivotal trials respectively [31,32]
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