Evofosfamide Is Effective against Pediatric Aggressive Glioma Cell Lines in Hypoxic Conditions and Potentiates the Effect of Cytotoxic Chemotherapy and Ionizing Radiations

Hypoxia is a hallmark of many solid tumors and is associated with resistance to anticancer treatments. Hypoxia-activated prodrugs (HAPs) were developed to target the hypoxic regions of these tumors. Among 2nd generation HAPs, Evofosfamide (Evo, also known as TH-302) exhibits preclinical and clinical...

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Bibliographic Details
Published in:Cancers 2021-04, Vol.13 (8), p.1804
Main Authors: Bailleul, Quentin, Navarin, Pauline, Arcicasa, Mélanie, Bal-Mahieu, Christine, Carcaboso, Angel Montero, Le Bourhis, Xuefen, Furlan, Alessandro, Meignan, Samuel, Leblond, Pierre
Format: Article
Language:English
Subjects:
Apoptosis
Brain cancer
Brain tumors
Cancer
Cell lines
Chemotherapy
Children
Clinical trials
Cytotoxicity
Doxorubicin
Drug dosages
Etoposide
Glioblastoma
Glioma cells
Growth factors
Human health and pathology
Hypoxia
Ionizing radiation
Life Sciences
Medical prognosis
Neurobiology
Neurons and Cognition
Oncology
Pediatrics
Pharmaceutical sciences
Pharmaceuticals
Pharmacology
Prodrugs
Radiation therapy
Solid tumors
Tumors
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Summary:Hypoxia is a hallmark of many solid tumors and is associated with resistance to anticancer treatments. Hypoxia-activated prodrugs (HAPs) were developed to target the hypoxic regions of these tumors. Among 2nd generation HAPs, Evofosfamide (Evo, also known as TH-302) exhibits preclinical and clinical activities against adult glioblastoma. In this study, we evaluated its potential in the field of pediatric neuro-oncology. We assessed the efficacy of Evo in vitro as a single drug, or in combination with SN38, doxorubicin, and etoposide, against three pediatric high-grade glioma (pHGG) and three diffuse intrinsic pontine glioma (DIPG) cell lines under hypoxic conditions. We also investigated radio-sensitizing effects using clonogenic assays. Evo inhibited the growth of all cell lines, mainly under hypoxia. We also highlighted a significant synergism between Evo and doxorubicin, SN38, or etoposide. Finally, Evo radio-sensitized the pHGG cell line tested, both with fractionated and single-dose irradiation schedules. Altogether, we report here the first preclinical proof of evidence about Evofosfamide efficiency against hypoxic pHGG and DIPG cells. Since such tumors are highly hypoxic, and Evo potentiates the effect of ionizing radiation and chemotherapy, it appears as a promising therapeutic strategy for children with brain tumors.
ISSN:2072-6694
2072-6694
DOI:10.3390/cancers13081804