Glioblastoma: synergy of growth promotion between CCL5 and NK-1R can be thwarted by blocking CCL5 with miraviroc, an FDA approved anti-HIV drug and blocking NK-1R with aprepitant, an FDA approved anti-nausea drug.
BACKGROUND
Two receptor signaling pathways that are commonly active in facilitating glioblastoma growth and invasion- that of CCR5 and neurokinin (NK)-1R- have small molecule inhibitors that are FDA approved and marketed to treat other conditions. The anti-HIV drug, maraviroc, inhibits human CCR5's ligand from binding, and hence blocks CCR5 stimulation. The anti-nausea drug aprepitant blocks substance P signaling at NK-1R.


OBJECTIVE
We propose on the basis of molecular insights that a combination of the two drugs is likely to be useful in the treatment of glioblastoma.


CONCLUSIONS
After stimulation by their respective ligands both CCR5 and NK-1R, through intermediaries, phosphorylate and thereby activate ERK1/2, triggering in turn migratory and mitotic events. Neurokinin-1R second messenger signaling also happens to serine phosphorylate CCR5. Phosphorylated CCR5 exhibits amplified activity after agonist ligation. Therefore, aprepitant and maraviroc combined treatment is expected to exert synergestic inhibition of growth enhancing signaling in glioblastoma. Inhibiting an amplifier is equivalent to amplifying an inhibitor. Since the two suggested drugs are non-cytotoxic they are envisioned as adjunctive treatments to current standard temozolomide, radiation, and bevacizumab, all to be used after debulking primary resection.


CONCLUSIONS
Our analysis makes the case for a well-designed trial of the proposed combination in the treatment of glioblastoma.
Department of Psychiatry, University of Vermont, Burlington, VT 05401, USA. rekast@email.com
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Kast
D019380:Anti-HIV Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000932:Antiemetics / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D000077608:Aprepitant; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D017277:Drug Approval; D004347:Drug Interactions; D005909:Glioblastoma / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D000077592:Maraviroc; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009025:Morpholines / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D064729:Neurokinin-1 Receptor Antagonists; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D014230:Triazoles / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D014481:United States; D014486:United States Food and Drug Administration
D019380:Anti-HIV Agents; D000932:Antiemetics; D000970:Antineoplastic Agents; D065100:CCR5 Receptor Antagonists; D003510:Cyclohexanes; D009025:Morpholines; D064729:Neurokinin-1 Receptor Antagonists; D014230:Triazoles; D000077608:Aprepitant; D048052:Mitogen-Activated Protein Kinase 3; D000077592:Maraviroc