Todhunter et al. encircling IL-13R2-targeted therapies in pre-clinical and clinical study, including potential strategies to improve IL-13R2-directed cancer treatment efficacy. receptor modulation/signaling, and variety of strategies available for selective targeting. Interleukin-13 receptor subunit alpha-2 (IL-13R2) is PD98059 usually a high-affinity membrane receptor for the anti-inflammatory cytokine interleukin 13 (IL-13). IL-13R2 was originally considered a decoy receptor that sequestered IL-13 and inhibited signaling since: i) IL-13R2 has a short cytoplasmic tail and cannot transmission through canonical JAK/STAT signaling pathway (1); ii) IL-13 has higher affinity for IL-13R2 than its other receptor, the interleukin 13 receptor subunit alpha 1/interleukin 4 receptor subunit alpha (IL-4R/IL-13R1) heterodimer (2); and iii) overexpression of IL-13R2 can inhibit IL-13 signaling (3). However, recent studies exhibited that IL-13-mediated IL-13R2 signaling occurs STAT6-impartial pathways, including activation of activator protein 1 (AP-1) and extracellular signal-related kinase (ERK), promoting tumor invasion, metastasis, and production of transforming growth factor beta (TGF) (4C9). Differential binding of IL-13 by IL-13R1 and IL-13R2 Cd33 has been discussed elsewhere (10, 11). More recently, Chitinase 3-like-1 (CHI3L1) was also identified as an IL-13R2 ligand, and a membrane protein TMEM219 was shown to be involved in IL13-R2 signaling (12, 13). CHI3L1 binding induces activation of mitogen-activated protein kinase (MAPK), protein kinase B (PKB)/Akt, and/or Wnt/-catenin signaling to promote TGF production and tumor metastasis (12C14). IL-13R2 is usually overexpressed in melanoma (8, 15), renal cell carcinoma (RCC) (16), adrenocortical carcinoma (ACC) (17, 18), and a variety of brain tumors (19C21). Additionally, IL-13R2 overexpression correlates with advanced disease and poor prognosis in colorectal carcinoma (CRC) (22), gastric malignancy (23), breast malignancy (24, 25), obvious cell ovarian malignancy (26), lung malignancy (27), ACC (28), papillary thyroid malignancy (29), pancreatic ductal adenocarcinoma (30), and glioblastoma (GBM) (31C33). While IL-13R2 is usually a biomarker of prognosis for many solid tumors after therapeutic intervention, research has focused on GBM. GBM is the most common and aggressive malignant main brain tumor in humans, and the existing treatments (i.e., tumor resection, radiotherapy, temozolomide) have limited impact on patient survival (34). IL-13R2 is usually overexpressed in ~76% of GBM but is not detected in normal brain tissue, making it a highly selective immunotherapy target (32, 33, 35). In this mini-review, we focus on recent research improvements for?IL-13R2-targeted therapies. An overview of the therapies discussed and advantages/disadvantages of each are summarized in Physique?1 . In addition, we PD98059 discuss strategies to improve therapy efficacy and remaining questions in the field. Open in a separate window Figure?1 Advantages and disadvantages of the therapeutic strategies used to target IL-13R2 in malignancy. ADCC, antibody-dependent cellular cytotoxicity; CDC, complement-dependent cytotoxicity; CRS, cytokine release syndrome; mAb, monoclonal antibody; MHC, major histocompatability complex; MOA, mechanism of action; TAA, tumor associated antigen. IL-13R2-Targeted Immunotoxins Recombinant immunotoxins were the first strategy to target IL-13R2 in malignancy. These chimeric fusion proteins kill malignancy cells receptor binding, receptor internalization, and cleavage of the toxin moiety in the cell cytosol, which inhibits protein synthesis and induces apoptosis (36). To induce IL-13R2-directed killing of tumor cells, IL-13 was fused to truncated exotoxin A (PE) (37) PD98059 or diphtheria toxin (DT) (38). IL13-PE (IL13-PE38QQR or cintredekin besudotox) has been used extensively in preclinical and several Phase 1-3 clinical studies. The PE38QQR exotoxin is usually mutated to prevent ubiquitous eukaryotic cell targeting 2-macroglobulin and to enhance endoplasmic reticulum localization for production (36, 39). IL13-PE is usually highly cytotoxic to human solid tumor cell lines, including those derived from RCC, GBM, and head and neck squamous cell carcinoma (HNSCC) (32, 37, 40C42). IL13-PE cytotoxicity is usually correlated with expression of IL-13R2 (40, 43), and lack of expression on normal PD98059 cells confers significant if not complete resistance to IL13-PE (43C45). IL13-PE treatment of orthotopic GBM and pancreatic xenografts significantly reduced tumor burden and increased overall survival (20, 45, 46). IL13-PE also decreased subcutaneous pheochromocytoma, pancreatic, and ACC xenograft tumor burden (18, 47, 48). After intracerebral convection-enhanced delivery (CED) of IL13-PE was decided to be feasible and safe in Phase 1/2 clinical trials (49, 50), a randomized Phase 3 trial (PRECISE) with intraparenchymal IL-13PE administration was initiated in GBM patients. IL13-PE was well-tolerated but showed similar overall survival to carmustine-releasing Gliadel wafers, the only FDA-approved local treatment for recurrent GBM (51). During retrospective analysis, it was decided that only ~50% of patients had fully conforming catheters.