Introduction: Due in great part to its diffuse infiltrative nature, molecular heterogeneity, and immunological escape ability, glioblastoma continues to be one of the deadliest and treatment-refractory human cancers. Proliferation, anti-apoptosis, angiogenesis, stem cell maintenance, and immunological suppression are just a few of the protumor-genic actions that the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signalling pathway significantly supports. We discuss the present level of knowledge about the therapeutic options, future directions for the field, and the biological function of JAK/STAT signaling in glioblastoma. The aim of this study was to investigate The Role and Therapeutic Targeting of JAK/STAT Signaling in Glioblastoma.
Methods: This review study has been written from scientific databases such as Science Direct, Springer, Google Scholar, and PubMed.
Results: The STAT family of transcription factors is comprised of seven proteins—STAT1, STAT2, STAT3, STAT4, STAT-5a, STAT-5b, and STAT6—which reside in the cytoplasm and are activated by phosphorylation as a downstream consequence of a number of signalling pathways, including cytokines, growth factors, or non-receptor tyrosine kinases. In the classical JAK-mediated pathway, cytokine binding of its cognate receptor leads to receptor dimerization followed by docking of JAK and consequent phosphorylation of the receptor’s cytoplasmic tail. STAT proteins are then recruited via their SH2 domains to the activated receptor where tyrosine phosphorylation occurs, STAT hetero- or homodimerization ensues, and activated STAT then undergoes translocation to the nucleus to bind DNA elements such as promoters or enhancers to both, directly and indirectly, regulate transcription of associated genes. Although tyrosine phosphorylation of STAT is the most important activating step, STAT can be phosphorylated on serine residues to modulate their activity. To date, a vast number of agents ranging from antisense oligonucleotides and repurposed drugs, JAK1/2 to direct STAT3 inhibitors have been the subject of investigation in numerous cancers. Targeting aberrant upstream IL-6/IL-6R signaling is one potential avenue of JAK/STAT blockade. Treatment with IL-6 pathway blockade via its receptor (IL-6R, tocilizumab) or binding soluble IL-6 (siltuximab) has been shown to inhibit glioma growth in vitro and reduce the expression of coinhibitory molecules such as PD-L1 on infiltrative myeloid cells. A number of repurposed pharmacologic agents have been found to have STAT3 inhibitory activity; however, off-target effects due to lack of specificity and questionable CNS penetrance have limited their utility. Atovaquone is an anti-malarial drug FDA-approved for pneumocystis pneumonia that was found to have STAT3 inhibitory effects; notably, it appears to be poorly bioavailable in the CNS. Arsenic trioxide (ATO) was shown to reduce STAT3 activation via JAK inhibition and induce apoptosis and stemness of GSCs. Despite encouraging safety data, a phase II trial combining ATO with radiation and temozolomide for newly diagnosed malignant glioma did not demonstrate a survival benefit.
Conclusion: Sorafenib, a multi-kinase (Raf, VEGFR2, and PDGFR-) inhibitor with STAT3 inhibitory activity that has been FDA-approved for treating other solid tumors, was demonstrated to reduce the growth of GBM in vitro, most likely due to its effects on AKT and MAPK. For patients with newly diagnosed or recurrent GBM, later clinical trials combining sorafenib with temozolomide, radiotherapy, or mTOR inhibition failed to show a survival benefit.