Immunotherapy targeting folate receptor induces cell death associated with autophagy in ovarian cancer.
Clin Cancer Res
; 21(2): 448-59, 2015 Jan 15.
Article
em En
| MEDLINE
| ID: mdl-25416196
ABSTRACT
PURPOSE:
Cancer cells are highly dependent on folate metabolism, making them susceptible to drugs that inhibit folate receptor activities. Targeting overexpressed folate receptor alpha (FRα) in cancer cells offers a therapeutic opportunity. We investigated the functional mechanisms of MORAB-003 (farletuzumab), a humanized mAb against FRα, in ovarian cancer models. EXPERIMENTALDESIGN:
We first examined FRα expression in an array of human ovarian cancer cell lines and then assessed the in vivo effect of MORAB-003 on tumor growth and progression in several orthotopic mouse models of ovarian cancer derived from these cell lines. Molecular mechanisms of tumor cell death induced by MORAB-003 were investigated by cDNA and protein expression profiling analysis. Mechanistic studies were performed to determine the role of autophagy in MORAB-003-induced cell death.RESULTS:
MORAB-003 significantly decreased tumor growth in the high-FRα IGROV1 and SKOV3ip1 models but not in the low-FRα A2780 model. MORAB-003 reduced proliferation, but had no significant effect on apoptosis. Protein expression and cDNA microarray analyses showed that MORAB-003 regulated an array of autophagy-related genes. It also significantly increased expression of LC3 isoform II and enriched autophagic vacuolization. Blocking autophagy with hydroxychloroquine or bafilomycin A1 reversed the growth inhibition induced by MORAB-003. In addition, alteration of FOLR1 gene copy number significantly correlated with shorter disease-free survival in patients with ovarian serous cancer.CONCLUSIONS:
MORAB-003 displays prominent antitumor activity in ovarian cancer models expressing FRα at high levels. Blockade of folate receptor by MORAB-003 induced sustained autophagy and suppressed cell proliferation.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Neoplasias Ovarianas
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Autofagia
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Receptor 1 de Folato
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Anticorpos Monoclonais Humanizados
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Antineoplásicos
Tipo de estudo:
Risk_factors_studies
Limite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
Clin Cancer Res
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2015
Tipo de documento:
Article