Of Ephs and Ephrins: Companies Target Guidance Molecules in Cancer

Abstract

E nzymes with the mysterious name of Ephs, which help the axons of neurons find their way forward during embryonic development, have been linked to cancer for more than two decades. Now, although much about them remains a mystery, at least two biotech companies are on the verge of targeting Ephs in cancer treatment trials. Ephs are not the only link between development and cancer. Tumors, to grow and spread, hijack many processes from embryonic development: cell proliferation, clonal expansion (forming tissues from a single cell), and cell migration to new organ sites. On the molecular level, signaling pathways involving Notch, Hedgehog, and Wnt proteins are important in both development and cancer. Another such system is Eph – ephrin signaling, which has gained much visibility in the past few years. Ephs and ephrins “are really important to tumor progression,” said Waldemar Debinski, M.D., Ph.D., a professor of neurosurgery at Wake Forest University in Winston-Salem, N.C. “[They have] effects on tumor cell migration, invasion, metastasis, as well as a prominent effect on neovascularization.” The ephrin fi eld is grappling with a high level of complexity, some confl icting experimental results, and an initial clinical trial that was discontinued for undisclosed reasons. But companies are pushing ahead with new drugs targeted at the pathway, drawn especially to certain Eph receptors that are highly overexpressed in many cancers. Links to Cancer Japanese researchers discovered the fi rst Eph receptor in 1987, using a cancer cell line called erythropoietin-producing hepatocellular — hence the acronym. Eph ligands, discovered later, were dubbed “ephrins.” There are now 16 known Eph receptors, all of them kinases, and nine ephrins. Although researchers found the fi rst Eph receptor in a cancer cell line, attention soon shifted to the developing nervous system because of widespread Eph expression there. The peculiar way that Ephs and ephrins function, by alternately triggering cell repulsion and adhesion, was largely worked out by neuroscientists and developmental biologists ( see sidebar). Ephs resurfaced in cancer in 1998, when researchers reported that EphB4 and its receptor, ephrin-B2, defi ne veins and arteries, respectively, in the developing capillary bed and that knocking out either gene in mice produced gross defects in vessel branching, remodeling, and maturation. This fi nding suggested a novel antiangiogenic target in tumors. Then, in 2001, Purdue University researchers reported that expression of EphA2 was suffi cient to transform mammary epithelial cells, establishing EphA2 as an oncogene. (Many cancers overexpress EphA2.) These studies made EphB4 and EphA2 potential anticancer drug targets, and a few biotech companies, including MedImmune in Gaithersburg, Md., began developing antibodies against them. But Eph receptors are more complicated than other kinases. Unlike famous kinases such as the epidermal growth factor receptor and Her-2/neu, Ephs do not act primarily to trigger cell proliferation (although they sometimes can). As in development, they mainly determine cell positioning through repulsion and adhesion; this process can involve both ligand-dependent kinase signaling and ligandindependent nonkinase signaling, as well as “reverse signaling” through ephrins. Different studies identify the same Eph receptors as oncogenes and tumor suppressors, creating much confusion in the fi eld. “For many issues, there are publications with totally opposite conclusions,” said Elena Pasquale, Ph.D., a biologist at the Sanford-Burnham Medical Research Institute in La Jolla, Calif. For example, Pasquale’s studies show that EphB4 acts as a tumor suppressor in a xenograft model of breast cancer but enhances migration and invasion in melanoma, whereas Parkash Gill, M.D., at the University of Southern California, Los Angeles, has reported that EphB4 is a survival factor in breast cancer (and many other tumor types). The same group showing that overexpression of EphA2 transformed breast cancer cells also found that ligand stimulation of the receptor decreases growth and invasiveness of the transformed cells.