With a median patient survival of 15 months, glioblastoma (GBM) is still one of the deadliest malign tumors. Despite immense efforts, therapeutic regimens fail to prolong GBM patient overall survival due to various resistance mechanisms. Chemokine signaling as part of the tumor microenvironment plays a key role in gliomagenesis, proliferation, neovascularization, metastasis and tumor progression. In this review, we aimed to investigate novel therapeutic approaches targeting various chemokine axes, including CXCR2/CXCL2/IL-8, CXCR3/CXCL4/CXCL9/CXCL10, CXCR4/CXCR7/CXCL12, CXCR6/CXCL16, CCR2/CCL2, CCR5/CCL5 and CX3CR1/CX3CL1 in preclinical and clinical studies of GBM. We reviewed targeted therapies as single therapies, in combination with the standard of care, with antiangiogenic treatment as well as immunotherapy. We found that there are many antagonist-, antibody-, cell- and vaccine-based therapeutic approaches in preclinical and clinical studies. Furthermore, targeted therapies exerted their highest efficacy in combination with other established therapeutic applications. The novel chemokine-targeting therapies have mainly been examined in preclinical models. However, clinical applications are auspicious. Thus, it is crucial to broadly investigate the recently developed preclinical approaches. Promising preclinical applications should then be investigated in clinical studies to create new therapeutic regimens and to overcome therapy resistance to GBM treatment.

We aimed to evaluate the angiogenic capacity of CXCL2 and IL8 affecting human endothelial cells to clarify their potential role in glioblastoma (GBM) angiogenesis. Human GBM samples and controls were stained for proangiogenic factors. Survival curves and molecule correlations were obtained from the TCGA (The Cancer Genome Atlas) database. Moreover, proliferative, migratory and angiogenic activity of peripheral (HUVEC) and brain specific (HBMEC) primary human endothelial cells were investigated including blockage of CXCR2 signaling with SB225502. Gene expression analyses of angiogenic molecules from endothelial cells were performed. Overexpression of VEGF and CXCL2 was observed in GBM patients and associated with a survival disadvantage. Molecules of the VEGF pathway correlated but no relation for CXCR1/2 and CXCL2/IL8 was found. Interestingly, receptors of endothelial cells were not induced by addition of proangiogenic factors in vitro. Proliferation and migration of HUVEC were increased by VEGF, CXCL2 as well as IL8. Their sprouting was enhanced through VEGF and CXCL2, while IL8 showed no effect. In contrast, brain endothelial cells reacted to all proangiogenic molecules. Additionally, treatment with a CXCR2 antagonist led to reduced chemokinesis and sprouting of endothelial cells. We demonstrate the impact of CXCR2 signaling on endothelial cells supporting an impact of this pathway in angiogenesis of glioblastoma.

Tumor recurrence is the main challenge in glioblastoma (GBM) treatment. Gold standard therapy temozolomide (TMZ) is known to induce upregulation of IL8/CXCL2/CXCR2 signaling that promotes tumor progression and angiogenesis. Our aim was to verify the alterations on this signaling pathway in human GBM recurrence and to investigate the impact of TMZ in particular. Furthermore, a combi-therapy of TMZ and CXCR2 antagonization was established to assess the efficacy and tolerability. First, we analyzed 76 matched primary and recurrent GBM samples with regard to various histological aspects with a focus on the role of TMZ treatment and the assessment of predictors of overall survival (OS). Second, the combi-therapy with TMZ and CXCR2-antagonization was evaluated in a syngeneic mouse tumor model with in-depth immunohistological investigations and subsequent gene expression analyses. We observed a significantly decreased infiltration of tumor-associated microglia/macrophages (TAM) in recurrent tumors, while a high TAM infiltration in primary tumors was associated with a reduced OS. Additionally, more patients expressed IL8 in recurrent tumors and TMZ therapy maintained CXCL2 expression. In mice, enhanced anti-tumoral effects were observed after combi-therapy. In conclusion, high TAM infiltration predicts a survival disadvantage, supporting findings of the tumor-promoting phenotype of TAMs. Furthermore, the combination therapy seemed to be promising to overcome CXCR2-mediated resistance.

Objective To investigate the influence of pyridoxamine on the pre- iferation of rat vascular smooth muscle cells induced by Angiotensin (A)in vitro and its mechanism. Methods Primary VSMCs were cultivated from the thoracic aortas of spontaneously hypertensive rats, and which from the 3th to 5th generation at exponential phase of growth were selected for the experiments and induced by A (10⁻⁷ mol/l). The proliferation of VSMCs after intervention with pyridoxamine (0.1, 1 and 10 mmol/l) was determined by MTT. The levels of advanced glycation end-products in cellular supernatant was determined by enzyme-linked immunosorbent assay (ELISA) and the intracellular level of reactive oxygen species (ROS) was detected by f1ow cytometry. The mRNA expressions of RAGE, NF-κB-P65, NADPH oxidaseP47phox were detected by Real-time PCR. Results The proliferation of VSMCs induced by A was inhibited by pyridoxamine in dependent-concentration manner (0.1, 1 and 10 mmol/l). The cellular supernatant AGEs level in pyridoxamine (1 mmol/l, P1) and pyridoxamine (10 mmol/l, P10) group was significantly lower (p<0.001) as compared with A group. It was decreased more in P10 group than that in P1 group (p<0.001); the intracellular ROS level significantly was decreased in P1and P10 group as compared with that in A group (p<0.001), and less in P10 group than that in P1 group (p<0.001); Compared with A group, The mRNA expressions of advanced glycation end-products receptor (RAGE), NF-κB-P65, NADPH oxidaseP47phox and MMP-9 mRNA in P1 and P10 group all were significantly lower (p<0.01), and they were much decreased in P10 group than that in P1 group (p<0.01). Conclusions The pyridoxamine inhibits the proliferation of VSMCs induced by A in dependent-concentration manner, and the potential mechanism of which pyridoxamine may reduce the expressions of RAGE by NF-κB pathway signals and inhibiting AGEs expressing and oxidative stress.

CFTR modulator therapy has unprecedented positive effects on people with CF (pwCF). However, immunogenic reactions to CFTR modulator therapy may lead to drug discontinuation. We aimed to identify pwCF, intolerant to CFTR modulator therapy due to suspected immunogenic adverse events (iAE). This survey assessed the types of reaction (e.g. rash, liver injury, drug fever) including reactions after re-exposure and was completed by ECFS CTN Centers. Response rate to the survey was 74 %. 89 CF centers treating approximately 12000 to 17500 pwCF in 28 countries participated and 75 (84 %) CF centers reported discontinuation of CFTR modulator therapy. 37 (41.1 %) of CF centers reported iAE affecting 200 (1.1 - 1.7 %) pwCF. Detailed information about iAEs was provided for 41 of 200 (20.5 % of affected) pwCF. Of the iAEs reported in detail 33/41 (80.5 %) were associated with elexacaftor/tezacaftor/ivacaftor modulator therapy, 6 (14.6 %) with lumacaftor/ivacaftor and 2 (4.9 %) with tezacaftor/ivacaftor. 72 % of pwCF with iAE were re-exposed to CFTR modulator therapy. 32 % of re-exposed pwCF reported a second iAE. Rash and elevated liver enzymes were most frequently reported iAEs. iAE were mostly transient. Drug allergy to CFTR modulator therapy was rare, but highly relevant for individual pwCF.