Abstract

Ewing sarcoma (EWS) manifests one of the lowest somatic mutation rates of any cancer, leading to a scarcity of druggable mutations and neoantigens. Immunotherapeutics targeting differentially expressed cell surface antigens could provide therapeutic benefit for such tumors. Pregnancy-associated plasma protein A (PAPP-A) is a cell membrane-associated proteinase produced by the placenta that promotes fetal growth by inducing insulinlike growth factor (IGF) signaling.By comparing RNA expression of cell surface proteins in EWS (n?=?120) versus normal tissues (n?=?42), we comprehensively characterized the surfaceome of EWS to identify highly differentially expressed molecules. Using CRISPR/Cas-9 and anti-PAPP-A antibodies, we investigated biological roles for PAPP-A in EWS in vitro and in vivo in NSG xenograft models and performed RNA-sequencing on PAPPA knockout clones (n?=?5) and controls (n?=?3). All statistical tests were two-sided.EWS surfaceome analysis identified 11 highly differentially overexpressed genes, with PAPPA ranking second in differential expression. In EWS cell lines, genetic knockout of PAPPA and treatment with anti-PAPP-A antibodies revealed an essential survival role by regulating local IGF-1 bioavailability. MAb-mediated PAPPA inhibition diminished EWS growth in orthotopic xenografts (leg area mm2 at day 49 IgG2a control (CTRL) [n?=?14], mean?=?397.0, SD?=?86.1 vs anti-PAPP-A [n?=?14], mean?=?311.7, SD?=?155.0; P =?.03; median OS anti-PAPP-A?=?52.5?days, 95% CI?=?46.0 to 63.0?days vs IgG2a?=?45.0?days, 95% CI?=?42.0 to 52.0?days; P?=?.02) and improved the efficacy of anti-IGF-1R treatment (leg area mm2 at day 49 anti-PAPP-A + anti-IGF-1R [n?=?15], mean?=?217.9, SD?=?148.5 vs IgG2a-CTRL; P?

View details for DOI 10.1093/jnci/djy209

View details for PubMedID 30698726