Targeting EphA3 Inhibits Cancer Growth by Disrupting the Tumor Stromal Microenvironment

Abstract

Eph receptor tyrosine kinases are critical for cell-cell communication during normal and oncogenic tissue patterning and tumor growth. Somatic mutation profiles of several cancer genomes suggest EphA3 as a tumor suppressor, but its oncogenic expression pattern and role in tumorigenesis remain largely undefined. Here, we report unexpected EphA3 overexpression within the microenvironment of a range of human cancers and mouse tumor xenografts where its activation inhibits tumor growth. EphA3 is found on mouse bone marrow-derived cells with mesenchymal and myeloid phenotypes, and activation of EphA3stromal cells with an EphA3 agonist leads to cell contraction, cell-cell segregation, and apoptosis. Treatment of mice with an agonistic a-EphA3 antibody inhibits tumor growth by severely disrupting the integrity and function of newly formed tumor stroma and microvasculature. Our data define EphA3 as a novel target for selective ablation of the tumor microenvironment and demonstrate the potential of EphA3 agonists for anticancer therapy. Cancer Res; 74(16); 4470-81. Ó2014 AACR.

The “less-is-more” in therapeutic antibodies: Afucosylated anti-cancer antibodies with enhanced antibody-dependent cellular cytotoxicity

“… 109 Bispecific human IgG1     Ifabotuzumab/KB004/IIIA4EPHA3afucosylatedFUT8 −/− CHO cells (Potelligent® Technology)Enhanced tumor growth inhibition over control antibody in DU145 or 22Rv1 xenograft miceVail et al. 132 Humanized IgG1     Bemarituzumab /FPA144FGFR2bafucosylatedFUT8 −/− CHO cells (Potelligent® Technology)Enhanced tumour growth inhibition in FGFR2-overexpressing gastric cancer xenograft mouse model over isotype control(b)Humanized IgG1     Afucosylated TrastuzumabHER2afucosylatedFUT8 −/− CHO cells (Potelligent® Technology)Enhanced tumor growth inhibition over fucosylated trastuzumab in KPL-4 xenografts in human FcγRIIIα miceJunttila et al. 133 Humanized IgG1     TrasGEX/ GT-MAB7.3-GEX/Glycooptimized Trastuzumab-GEXHER2ReducedHuman glycoengineered production cell lines (GlycoExpress technology)Potent Her2 + BT474 tumor growth inhibition in nude mice but exhibited similar tumor volume and number of regression between fucosylated and reduced fucosylated antibodies(c)Humanized IgG1     Lumretuzumab /RG7116/RO5479599/ GE-HuMAb-HER3HER3ReducedCoexpression with GnT-III and α-ManII in CHO cells (GlycoMAb Technology)Enhanced survival of SCID-beige mice with A549-B34 NSCLC xenograftsMirschberger et al.…”

Bone marrow fibrosis in myelofibrosis: pathogenesis, prognosis and targeted strategies

“…28 The effects of disrupting the tumor microenvironment by targeting Eph receptor tyrosine kinases are currently being studied in both solid and hematologic malignancies. 100,101 EphA3 is important in cell positioning during fetal development and is not expressed in normal adult tissues. However, EphA3 expression has been demonstrated in various hematologic and solid tumors.…”

“…88,89 In solid malignancies, EphA3 is preferentially expressed in tumor stroma, vasculature, and bone marrow-derived mesenchymal stem cells. 101 Data from Vail et al suggest that Eph is not ligated in stromal cells derived from the solid tumor so it is kinase-dormant. In solid tumors, kinase-dormant Eph lead to cell-cell adhesion, invasion and tumor maintenance.…”

PTP-PEST controls EphA3 activation and ephrin-induced cytoskeletal remodelling

“…Previously, we have found that during ephrin-induced adhesion of leukaemia cells overexpressing EphA3, an important cancer target (Day et al, 2013;Vail et al, 2014), PTP-PEST (also known as PTPN12), together with other focal adhesion proteins such as FAK and paxillin, is recruited into EphA3 signalling complexes (Wimmer-Kleikamp et al, 2008). PTP-PEST is a ubiquitously expressed cytosolic protein tyrosine phosphatase that plays important roles in similar developmental processes to Ephs, including neurogenesis, vasculogenesis and mesenchymal development (Sirois et al, 2006).…”