Advances in Chemokine Signaling Pathways as Therapeutic Targets in Glioblastoma

Abstract

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.

Tumor-Associated Microglia/Macrophages as a Predictor for Survival in Glioblastoma and Temozolomide-Induced Changes in CXCR2 Signaling with New Resistance Overcoming Strategy by Combination Therapy

“…This finding matched the previously described TMZ-induced changes in the chemokine network, which could be identified as a mechanism to the development of therapy resistance [ 28 , 31 ]. Even if only a few effects of TMZ application were observed on CXCR2 signaling in matched patient samples, preclinical models showed the efficacy of combined approaches consisting of standard therapy and additionally targeting chemokine signaling axes [ 32 ]. Therefore, combining SB additionally with TMZ poses a promising therapeutic approach.…”

“…However, CXCL2 expression was significantly lower in recurrent tumors of the not standard (TMZ ≤3 ) group, while IL8 expression rose from 45% (standard) and 42% (not standard) in primary tumors to 61% and 74%, respectively, in recurrent tumors. The combination of TMZ with CXCR2-antagonization represented a new promising treatment approach in GBM based on the previous studies [ 25 , 26 , 28 , 32 , 40 , 51 , 52 , 53 ]. Here, we demonstrated a well-tolerated therapy regimen with an enhanced reduction of tumor volume and proliferation by adding SB to the TMZ treatment in a syngeneic orthotopic mouse model.…”

“…Thus, CXCR2 signaling represents a promising additional therapeutical target in GBM treatment to overcome TMZ-induced resistance, as single therapies often fail to target all tumor cells due to GBM heterogeneity [ 2 , 3 , 4 ]. Recent studies have also shown that combinational approaches exceed the efficacy of sole administration, especially when targeting chemokine signaling axes in addition to the standard of care therapy [ 32 ]. In this regard, we recently demonstrated an efficient CXCR2 antagonization with SB225002 (SB) with a significantly reduced tumor volume, decreased vessel density, and reduced TAM infiltration in an in vivo GL261 syngeneic mouse model [ 6 , 7 , 8 , 9 , 10 ].…”

Unraveling unique and common cell type-specific mechanisms in glioblastoma multiforme

“…The engagement of these signaling pathways with GBM has been extensively studied [45] , [46] , [47] , [48] , [49] , [50] , [51] , [52] . However, our analysis gives a holistic view of the mechanisms that are linked distinctively to the cell types and it unveils if the genes contributing to these molecular pathways are unique or common to the five cell types studied.…”

Brain tumours, brain metastases, and neuroinflammation: Insights from neuroimaging studies.

“…These immunosuppressive changes enabled by inflammatory mediators stimulate GBM cell proliferation, migration, angiogenesis, and resistance to treatment. For example, signaling mediated by CXCR3 and CCR2 receptors recruit tumor-promoting immune cells such as T cells and myeloidderived suppressor cells [16,[21][22][23][24][25][26][27][28]. In GBM cancer stem cells (CSCs), hypoxic tissue triggers expression of genes of the inflammatory reparative response [25,29].…”