Immunotherapy targeting folate receptor induces cell death associated with autophagy in ovarian cancer.

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.

EXPERIMENTAL DESIGN:

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.

• Authors: Yunfei Wen, Whitney S Graybill, Rebecca A Previs, Wei Hu, Cristina Ivan, Lingegowda S Mangala, Behrouz Zand, Alpa M Nick, Nicholas B Jennings, Heather J Dalton, Vasudha Sehgal, Prahlad Ram, Ju-Seog Lee, Pablo E Vivas-Mejia, Robert L Coleman, Anil K Sood
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 21 Issue 2 Pg. 448-59 (Jan 15 2015) ISSN: 1557-3265 [Electronic] United States
• PMID: 25416196 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• Folate Receptor 1
• farletuzumab

Topics

• Animals
• Antibodies, Monoclonal, Humanized (pharmacology)
• Antineoplastic Agents (pharmacology)
• Autophagy
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival (drug effects)
• Female
• Folate Receptor 1 (immunology, metabolism)
• Humans
• Immunotherapy
• Kaplan-Meier Estimate
• Mice, Nude
• Ovarian Neoplasms (drug therapy, mortality)
• Treatment Outcome
• Xenograft Model Antitumor Assays