title: Toward a noncytotoxic glioblastoma therapy: blocking MCP-1 with the MTZ Regimen.
abstract: To improve the prognosis of glioblastoma, we developed an adjuvant treatment directed to a neglected aspect of glioblastoma growth, the contribution of nonmalignant monocyte lineage cells (MLCs) (monocyte, macrophage, microglia, dendritic cells) that infiltrated a main tumor mass. These nonmalignant cells contribute to glioblastoma growth and tumor homeostasis. MLCs comprise of approximately 10%-30% of glioblastoma by volume. After integration into the tumor mass, these become polarized toward an M2 immunosuppressive, pro-angiogenic phenotype that promotes continued tumor growth. Glioblastoma cells initiate and promote this process by synthesizing 13 kDa MCP-1 that attracts circulating monocytes to the tumor. Infiltrating monocytes, after polarizing toward an M2 phenotype, synthesize more MCP-1, forming an amplification loop. Three noncytotoxic drugs, an antibiotic - minocycline, an antihypertensive drug - telmisartan, and a bisphosphonate - zoledronic acid, have ancillary attributes of MCP-1 synthesis inhibition and could be re-purposed, singly or in combination, to inhibit or reverse MLC-mediated immunosuppression, angiogenesis, and other growth-enhancing aspects. Minocycline, telmisartan, and zoledronic acid - the MTZ Regimen - have low-toxicity profiles and could be added to standard radiotherapy and temozolomide. Re-purposing older drugs has advantages of established safety and low drug cost. Four core observations support this approach: 1) malignant glioblastoma cells require a reciprocal trophic relationship with nonmalignant macrophages or microglia to thrive; 2) glioblastoma cells secrete MCP-1 to start the cycle, attracting MLCs, which subsequently also secrete MCP-1 perpetuating the recruitment cycle; 3) increasing cytokine levels in the tumor environment generate further immunosuppression and tumor growth; and 4) MTZ regimen may impede MCP-1-driven processes, thereby interfering with glioblastoma growth.
authors.affiliation: Department of Internal Medicine, University of Kansas, Kansas City, KS, USA; Department of Neurosurgery, University of Kansas, Kansas City, KS, USA.
authors.forename: Michael E
authors.initials: ME
authors.lastname: Salacz
authors.affiliation: IIAIGC Study Center, Burlington, VT, USA.
authors.forename: Richard E
authors.initials: RE
authors.lastname: Kast
authors.affiliation: Health Research Institute, Research Center of Thalassemia and Hemoglobinopathy, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
authors.forename: Najmaldin
authors.initials: N
authors.lastname: Saki
authors.affiliation: Molecular Biology Laboratory, University Hospital Munich, Munich, Germany.
authors.forename: Ansgar
authors.initials: A
authors.lastname: Brüning
authors.affiliation: Department of Neurosurgery, University of Ulm, Ulm, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Karpel-Massler
authors.affiliation: Department of Neurosurgery, University of Ulm, Ulm, Germany.
authors.forename: Marc-Eric
authors.initials: ME
authors.lastname: Halatsch
keywords: cognition-sparing; high-grade glioma; immunosuppression; macrophage; microglia; monocyte