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.

Glioma associated microglia/macrophages, a potential pharmacological target to promote antitumor inflammatory immune response in the treatment of glioblastoma

“…The drugs were instead effective in combination with temozolomide, significantly increasing mice survival [27] . Interestingly, it has been shown that the production of MCP-1 by glioma cells can be efficiently reduced by non-cytotoxic drugs, including the antibiotic minocycline, the angiotensin II receptor inhibitor telmisartan and the bisphosphonate zolendronic acid [40] . These drugs have a good BBB penetration and will be tested in combination as an ancillary therapy to improve the outcome of currently approved cytotoxic regimens.…”

Effects of tumor grade and dexamethasone on myeloid cells in patients with glioma

“…40,44,45 These studies have led to the proposal of MCP-1 blockade as a treatment for GBM. 46,47 A detailed examination of human gliomas demonstrated that MCP-3, not MCP-1 correlates with myeloid cell accumulation in glioblastoma, 48 calling into question the utility of MCP-1 inhibition in preventing TAM infiltration.…”

Blocking epithelial-to-mesenchymal transition in glioblastoma with a sextet of repurposed drugs: the EIS regimen

“…Similarly, in hepatocellular carcinoma TGF-beta synthesized and released by tumor infiltrating monocytes, drives the proper carcinoma cells’ EMT [ 119 ]. A parallel relationship between monocyte lineage cells and malignant phenotype has been described in GB as well [ 120 ].…”