Format

Send to

Choose Destination
PLoS One. 2015 Nov 23;10(11):e0142612. doi: 10.1371/journal.pone.0142612. eCollection 2015.

Regorafenib: Antitumor Activity upon Mono and Combination Therapy in Preclinical Pediatric Malignancy Models.

Author information

1
Université Paris-Sud 11, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France.
2
CNRS, Vectorology and Anticancer Therapeutics, UMR 8203, Orsay, France.
3
Gustave Roussy, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France.
4
University Children's Hospital, Department of Pediatric Hematology and Oncology, Münster, Germany.
5
PFEP (Plateforme d'évaluation préclinique), Gustave Roussy, Villejuif, France.
6
Tribvn, Châtillon, France.
7
Pathology Laboratory, Gustave Roussy, Villejuif, France.
8
Department of Neuropathology, Sainte-Anne's Hospital, Paris, France.
9
Paris Descartes University, Paris, France.
10
Bayer Pharma Aktiengesellschaft, Berlin, Germany.

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.

PMID:
26599335
PMCID:
PMC4658168
DOI:
10.1371/journal.pone.0142612
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center