An Update on Glioblastoma Biology, Genetics, and Current Therapies: Novel Inhibitors of the G Protein-Coupled Receptor CCR5

Abstract

The mechanisms governing therapeutic resistance of the most aggressive and lethal primary brain tumor in adults, glioblastoma, have increasingly focused on tumor stem cells. These cells, protected by the periarteriolar hypoxic GSC niche, contribute to the poor efficacy of standard of care treatment of glioblastoma. Integrated proteogenomic and metabolomic analyses of glioblastoma tissues and single cells have revealed insights into the complex heterogeneity of glioblastoma and stromal cells, comprising its tumor microenvironment (TME). An additional factor, which isdriving poor therapy response is the distinct genetic drivers in each patient’s tumor, providing the rationale for a more individualized or personalized approach to treatment. We recently reported that the G protein-coupled receptor CCR5, which contributes to stem cell expansion in other cancers, is overexpressed in glioblastoma cells. Overexpression of the CCR5 ligand CCL5 (RANTES) in glioblastoma completes a potential autocrine activation loop to promote tumor proliferation and invasion. CCL5 was not expressed in glioblastoma stem cells, suggesting a need for paracrine activation of CCR5 signaling by the stromal cells. TME-associated immune cells, such as resident microglia, infiltrating macrophages, T cells, and mesenchymal stem cells, possibly release CCR5 ligands, providing heterologous signaling between stromal and glioblastoma stem cells. Herein, we review current therapies for glioblastoma, the role of CCR5 in other cancers, and the potential role for CCR5 inhibitors in the treatment of glioblastoma.

Bombesin Receptor Family Activation and CNS/Neural Tumors: Review of Evidence Supporting Possible Role for Novel Targeted Therapy

“…In gliomas, one study in U-87MG glioma cells ( 160 ) reported both GRPR and NMBR mRNA were present; however, GRP mRNA was not found, leading the authors to suggest that the GRP effect on growth of this glioma cell line was likely mediated by a paracrine mechanism. This result is somewhat surprising, both because autocrine growth, a mechanism of activation, is present in so many other tumors and also because in gliomas, autocrine mechanisms are reported for a number of other glioma growth factors, including the G-protein coupled receptor CCR5 [with its ligand CCL5 (RANTES) present in glioma cells] ( 289 ), TGFbeta1 ( 290 ), bone morphogenetic proteins (BMP4) ( 291 ), PDGF ( 292 ), and dopamine ( 293 ). In contrast, in neuroblastomas, numerous studies support an autocrine role for Bn-related peptides in BnR activation.…”

Chaperone-Mediated Autophagy in Pericytes: A Key Target for the Development of New Treatments against Glioblastoma Progression

“…GB is one of the few cancers in which conventional therapies, i.e., surgery, radiotherapy, and pharmacotherapy with temozolomide (TMZ), do not increase survival of the patients [ 64 ]. As previously discussed, GB has a very heterogeneous niche, which provides therapeutic resistance and limits the availability of effective therapies.…”

“…As previously discussed, GB has a very heterogeneous niche, which provides therapeutic resistance and limits the availability of effective therapies. The current chemotherapeutic for GB is usually TMZ, which is used in combination with irradiation to prevent resistance [ 64 ]. Interestingly, TMZ seems to induce expression of LAMP-2A and, therefore, CMA activity in human tumors [ 65 ], which might explain why tumor cells become resistant and PCs are, at least in part, responsible for the increased resistance [ 66 ].…”

“…Interestingly, TMZ seems to induce expression of LAMP-2A and, therefore, CMA activity in human tumors [ 65 ], which might explain why tumor cells become resistant and PCs are, at least in part, responsible for the increased resistance [ 66 ]. As dose intensification fails to boost effectiveness, this treatment only prolongs the median survival of patients for 20 months after diagnosis [ 64 ]. Other alternative approaches focused on CAR-T- [ 67 ] and NK cell-targeted therapies [ 68 ] or target-specific mutations and tumor metabolism [ 64 ] are still under study [ 36 ].…”

Cytotoxicity Effect of Quinoin, Type 1 Ribosome-Inactivating Protein from Quinoa Seeds, on Glioblastoma Cells

“…In addition, type 1 RIPs, such as trichosanthin from Trichosanthes kirilowii [18,19] and saporin from Saponaria officinalis [20,21], display remarkable cytotoxicity against glioblastoma cell lines, which increases by linking them to specific conjugates [22]. This cytotoxicity is of interest, considering that glioblastoma is a highly aggressive brain tumor, in which malignant cells escape apoptosis by being resistant to radiotherapy and chemotherapy and unresponsive to drugs by rapidly inactivating or reducing intracellular drug concentrations or increasing the rate of DNA repair [23].…”