Molecular Targeting of IL-13Rα2 and EphA2 Receptor in GBM

Abstract

Finding widely overexpressed proteins specific to glioblastoma multiforme (GBM) was considered unlikely. Contrary to expectations, a number of such factors have been identified to be expressed in a majority of GBM but not in normal brain. These tumor-specific proteins are very attractive targets for novel, specific, rationally designed molecular therapies. Here we discuss the opportunities presented by two such factors, IL-13Rα2 and EphA2 receptor. IL-13Rα2 is a nonsignaling form of interleukin-13 receptor, which, in contrast to its physiological counterpart, is not bound by interleukin-4. IL-13Rα2 is overexpressed in 75% of GBM, and its presence in normal organs is very low or nonexistent, with the exception of the testes. EphA2 receptor belongs to the largest family of receptor tyrosine kinases. EphA2 is present in nearly all GBM, is highly overexpressed in 66% of them, is absent in normal brain, and is strongly associated with poor patient survival. Molecularly targeted cytotoxins that contain derivatives of bacterial toxins that specifically and potently kill GBM cells overexpressing either IL-13Rα2 or EphA2 receptor were produced. The first generation of an IL-13-based cytotoxin reached Phase III clinical trial, demonstrated safety of the approach in humans, improved progression-free survival of GBM patients in some centers, but did not modify mean survival of the whole cohort. The first EphA2-targeted cytotoxin has already demonstrated attractive features in recent preclinical examination. The overexpression of either IL-13Rα2 or EphA2 is seen in 95% of GBM, which means that by cotargeting these two receptors almost all patients will be eligible, making the need for pretherapy screening for marker expression unnecessary. The future efforts in exploiting potent cytotoxins for the treatment of GBM should focus on combinatorial targeted therapy that involves either a multivalent approach or combination cocktails of the cytotoxins. In this way, multiple compartments of GBM tumors will be targeted benefiting all the patients.KeywordsIL-13Rα2EphA2Glioblastoma multiformeAstrocytomaReceptorRecombinant cytotoxins