Glioblastoma multiforme (GBM) remains one of the most lethal primary brain tumors despite surgical and therapeutic advancements. Targeted therapies of neoplastic diseases, including GBM, have received a great deal of interest in recent years. A highly studied target of GBM is interleukin-13 receptor α chain variant 2 (IL13Rα2). Targeted therapies against IL13Rα2 in GBM include fusion chimera proteins of IL-13 and bacterial toxins, nanoparticles, and oncolytic viruses. In addition, immunotherapies have been developed using monoclonal antibodies and cell-based strategies such as IL13Rα2-pulsed dendritic cells and IL13Rα2-targeted chimeric antigen receptor-modified T cells. Advanced therapeutic development has led to the completion of phase I clinical trials for chimeric antigen receptor-modified T cells and phase III clinical trials for IL-13-conjugated bacterial toxin, with promising outcomes. Selective expression of IL13Rα2 on tumor cells, while absent in the surrounding normal brain tissue, has motivated continued study of IL13Rα2 as an important candidate for targeted glioma therapy. Here, we review the preclinical and clinical studies targeting IL13Rα2 in GBM and discuss new advances and promising applications.

Summary The last decade has seen a dramatic increase in stem cell research that focuses on glioma stem cells and their mechanisms of action, revealing multiple potential targets for primary malignant brain tumors. We present a novel framework for considering glioma stem cell targets based on direct and indirect strategies. Direct strategies target glioma stem cells molecular pathways to overcome their resistance to radiation and chemotherapy, block their function or induce their differentiation. Indirect ones target the glioma stem cell microenvironment, namely the perivascular, hypoxic and immune niches. Progress made on glioma stem cell targets is reviewed in detail and specific pathways are identified in context of the proposed framework. The potential barriers for translation to the clinical setting are also discussed. Overall, targeting glioma stem cells provides an unprecedented opportunity for revolutionary approaches to treat high-grade gliomas that continue to have a poor patient prognosis.