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. Molecularmechanismsof tumorcell death induced byMORAB-003 were investigated by cDNAand 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.
Original language | English (US) |
---|---|
Pages (from-to) | 448-459 |
Number of pages | 12 |
Journal | Clinical Cancer Research |
Volume | 21 |
Issue number | 2 |
DOIs | |
State | Published - Jan 15 2015 |
ASJC Scopus subject areas
- Oncology
- Cancer Research
MD Anderson CCSG core facilities
- Advanced Technology Genomics Core
- Bioinformatics Shared Resource
- Flow Cytometry and Cellular Imaging Facility
- Functional Proteomics Reverse Phase Protein Array Core
- High Resolution Electron Microscopy Facility
- Research Animal Support Facility
- Cytogenetics and Cell Authentication Core