Journal
CLINICAL CANCER RESEARCH
Volume 21, Issue 2, Pages 448-459Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-14-1578
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Funding
- U.S. National Institutes of Health [P50CA083639, P50CA098258, P50 CA083639, CA109298, U54 CA151668, CA140933, CA177909, UH2TR000943, T32CA101642, CA16672]
- Department of Defense [OC120547, OC093416]
- Program Project Development grant from the Ovarian Cancer Research Fund [CPRIT RP110595]
- Bettyann Asche Murray Distinguished Professorship
- Chapman Foundation
- Meyer and Ida Gordon Foundation
- Gilder Foundation
- Judi A. Rees Ovarian Cancer Research Fund
- RGK Foundation
- Blanton-Davis Ovarian Cancer Research Program
- NIH [5 P50]
- SPORE CDP [CA116199]
- Developmental Project Award
- Marsha Rivkin Center
- Foundation for Women's Cancer
- National Cancer Institute T32 Training Grant [T32 CA101642]
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Purpose: Cancer cells are highly dependent on folate metabolism, making them susceptible to drugs that inhibit folate receptor activities. Targeting overexpressed folate receptor alpha (FR alpha) in cancer cells offers a therapeutic opportunity. We investigated the functional mechanisms of MORAB-003 (farletuzumab), a humanized mAb against FR alpha, in ovarian cancer models. Experimental Design: We first examined FR alpha 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 tum or 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-FR alpha IGROV1 and SKOV3ip1 models but not in the low-FR alpha 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 FR alpha at high levels. Blockade of folate receptor by MORAB-003 induced sustained autophagy and suppressed cell proliferation. (C) 2014 AACR.
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