Use of FDA approved methamphetamine to allow adjunctive use of methylnaltrexone to mediate core anti-growth factor signaling effects in glioblastoma.

Methylnaltrexone (MNTX) was recently FDA approved to treat opiate induced constipation. It happens to also indirectly reduce Src activity. Src is a 54 kDa tyrosine kinase, crucial in signaling of, and link between, vascular endothelial growth factor (VEGF), and epidermal growth factor (EGF). Glioblastomas use both EGF and VEGF signaling to enhance growth and neo-angiogenesis. Stem cell sub-fractions of glioblastomas are enriched for high VEGF synthesizing cells so this is a particularly valuable adjunctive target during cytotoxic treatment with drugs like temozolomide. MNTX does not cross the blood-brain barrier (BBB). Methamphetamine (MA) temporarily opens the BBB and therefore may allow methylnaltrexone entry into glioblastoma tissue. MA is FDA approved, marketed to treat attention problems in children. MA-MNTX combination should be tested as glioblastoma treatment adjunct. Temozolomide CSF levels are 10-20% of blood levels. Thus MA may also allow greater brain tissue temozolomide levels yet with lower systemic exposure.