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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Wen, Y; Graybill, WS; Previs, RA; Hu, W; Ivan, C; Mangala, LS; Zand, B; Nick, AM; Jennings, NB; Dalton, HJ; Sehgal, V; Ram, P; Lee, J-S; Vivas-Mejia, PE; Coleman, RL; Sood, AK

Published Date

  • January 15, 2015

Published In

Volume / Issue

  • 21 / 2

Start / End Page

  • 448 - 459

PubMed ID

  • 25416196

Pubmed Central ID

  • 25416196

International Standard Serial Number (ISSN)

  • 1078-0432

Digital Object Identifier (DOI)

  • 10.1158/1078-0432.CCR-14-1578

Language

  • eng

Conference Location

  • United States