Abstract
Effect of dual properties of regorafenib in osteosarcoma on tumor progression and bone parameters in mouse preclinical models.
Author
person
Javier Munoz Garcia
ICO institut de cancerologie de l'ouest, Saint-Herblain, France
info_outline
Javier Munoz Garcia, Jorge William Vargas-Franco, Emmanuelle Bompas, Denis Cochonneau, Emilie Ollivier, Jerome Kerzerho, Mehdi Brahmi, Jean-Yves Blay, Maire-Francoise Heymann, Frederic Lezot, Dominique Heymann
Full text
Authors
person
Javier Munoz Garcia
ICO institut de cancerologie de l'ouest, Saint-Herblain, France
info_outline
Javier Munoz Garcia, Jorge William Vargas-Franco, Emmanuelle Bompas, Denis Cochonneau, Emilie Ollivier, Jerome Kerzerho, Mehdi Brahmi, Jean-Yves Blay, Maire-Francoise Heymann, Frederic Lezot, Dominique Heymann
Organizations
ICO institut de cancerologie de l'ouest, Saint-Herblain, France, Department of Basic Studies, Faculty of Odontology, University of Antioquia, Medellin, Colombia, Institut de Cancérologie de l'Ouest (ICO)-site René Gauducheau, Saint-Herblain, France, Hephaistos Pharma, Paris, France, Léon Bérard Centre, Lyon, France, Centre Léon Bérard, Lyon, France, Sorbonne Université, INSERM UMR 933, Hôpital Trousseau (AP-HP), Paris, France
Abstract Disclosures
Research Funding
No funding received
None.
Background:
Osteosarcoma (OS) constitutes the most frequent malignant primary bone tumor in children and young adults. Actual treatments in OS are based in a multimodal therapy that combines pre- and post-surgery polychemotherapies including cisplatin, doxorubicin, ifosfamide and/or methotrexate. Regardless the use of this polychemotherapeutic approach, the five years overall survival for patients has not improved during the last four decades and there is a clinical need to identify new active drugs in OS. An interesting strategy implies the use of compounds that showed therapeutic benefits in other solid tumors. Regorafenib, a small molecule with multi-target tyrosine kinase inhibitory activity against FGFR-1 and -2, KIT, PDGFR, RAF, RET, TIE2 and VEGFR-1, -2 and -3, showed an anti-angiogenic/oncogenic properties in various solid tumors that includes metastatic colorectal cancer, hepatocarcinoma and breast cancer. In addition, regorafenib also inhibits
in vitro
the proliferation of several pediatric solid tumor cell lines such as rhabdomyosarcoma, Ewing sarcoma and OS.
Methods:
The present work aims to decipher the
in vitro
and
in vivo
effects of regorafenib in OS preclinical models.
Results:
The treatment of MNNG-HOS, KHOS and 143B osteosarcoma cell lines with Regorafenib resulted in the inhibition of cell proliferation in a dose dependent manner. The gene expression profiles of MNNG-HOS and 143B cells treated or not with regorafenib and analyzed by NanoString technology revealed a specific regulation of molecular pathways by regorafenib in both cell lines. The
in vivo
effect of regorafenib was then analyzed in immunocompetent (mouse MOS-J cells inoculated in C57Bl/6 mice) and immunodeficient (human MNNG-HOS and 143B OS cells injected in Nude mice) murine osteosarcoma models. In all the cases, a significant reduction of primary tumor growth was observed as well as a significant decrease of lung metastases compared to untreated mice. Interestingly, the cortical and trabecular bone mineral density were significantly increased in regorafenib treated mice compared to untreated groups as demonstrated by X ray microtomodensitometry in all models.
Conclusions:
Our results support the use of regorafenib as an alternative treatment in metastatic OS and demonstrated for the first time the its bone protective effect.
Clinical status
Pre-clinical
8 organizations
5 drugs
13 targets
Organization
ICO Institut de Cancerologie de l'OuestOrganization
Hephaistos PharmaOrganization
Léon Bérard CentreOrganization
Centre Léon BérardOrganization
Sorbonne UniversitéOrganization
INSERM UMR 933, Hôpital Trousseau (AP-HP)Drug
CisplatinDrug
doxorubicinDrug
ifosfamideDrug
methotrexateDrug
RegorafenibTarget
VEGFR-1Target
KITTarget
TIE2Target
FGFR-2Target
FGFR-1Target
RETTarget
Topoisomerase IITarget
PDGFR-αTarget
RAF kinaseTarget
VEGFR-3Target
VEGFR-2Target
DNA