Abstract 1330: Immunotherapy targeting folate receptor induces autophagy in ovarian cancer

Abstract

Abstract Objective Cancer cells are highly dependent on folate metabolism for replication of DNA, making these cells susceptible to drugs that inhibit folate metabolism. Herein, we investigated the functional mechanism underlying blockade of folate receptor (FR) in human ovarian cancer with MORAb-003 antibody, a humanized monoclonal antibody directly against folate receptor 1 (FRα). Methods We first used FACS analysis and real-time PCR to compare the expression of FRα in several human ovarian cancer cells. We then examined the tumor growth in the orthotopic models of human ovarian cancer cells SKOV3 and A2780. Consequently, we performed in vitro genomic and proteomic profiling in these cells to identify the functional mechanism of MORAb-003. Results Among 7 human ovarian cancer cell lines, SKOV3ip1 cells have the highest levels of FRα and A2780 cells have the lowest. In vivo, MORAb-003 monotherapy led to significantly decreased tumor growth in the SKOV3ip1 model, but not in the A2780 model. Combination of MORAb-003 and docetaxel resulted in significantly greater reduction in tumor growth in the SKOV3ip1 model, but not in the A2780 model. MORAb-003 reduced proliferation but had no significant effect on apoptosis. Reverse-phase array analysis in SKOV3 cells revealed MORAb-003 up-regulated autophagic factors including PEA-15, Beclin-1, and ATG3 and down-regulated mTOR. cDNA microarray further showed that MORAb-003 up-regulated the expression of BECN1, ATG8, ATG3 and LC3B. Levels of Beclin-1 and LC3B were substantially increased in SKOV3 tumors treated with MORAb-003 alone or in combination with docetaxel, but not in A2780 tumors. Using FACS analysis with acridine orange (AO) staining, we observed significantly more AO positive population in SKOV3 cells treated with MORAb-003 alone (16.9%) or MORAb-003+docetaxel (21.2%) than in cells treated with control IgG (5.24%). Such differences were not observed in A2780 cells. Finally, we measured conversion of LC3 from isoform I to isoform II in cells treated with MORAb-003, and observed the significantly increased LC3II in SKOV3 cells but not in A2780 cells. Conclusion Taken together, our results indicate that MORAb-003 results in prominent anti-tumor activity through inducing sustained autophagy in ovarian cancer cells. Citation Format: Yun-Fei Wen, Whitney Spannuth Graybill, Department of Gyneocologic Oncology, Anil Sood. Immunotherapy targeting folate receptor induces autophagy in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1330. doi:10.1158/1538-7445.AM2014-1330