CUSP9* treatment protocol for recurrent glioblastoma: aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, ritonavir, sertraline augmenting continuous low dose temozolomide

Abstract

CUSP9 treatment protocol for recurrent glioblastoma was published one year ago. We now present a slight modification, designated CUSP9*. CUSP9* drugs--aprepitant, artesunate, auranofin, captopril, celecoxib, disulfiram, itraconazole, sertraline, ritonavir, are all widely approved by regulatory authorities, marketed for non-cancer indications. Each drug inhibits one or more important growth-enhancing pathways used by glioblastoma. By blocking survival paths, the aim is to render temozolomide, the current standard cytotoxic drug used in primary glioblastoma treatment, more effective. Although esthetically unpleasing to use so many drugs at once, the closely similar drugs of the original CUSP9 used together have been well-tolerated when given on a compassionate-use basis in the cases that have come to our attention so far. We expect similarly good tolerability for CUSP9*. The combined action of this suite of drugs blocks signaling at, or the activity of, AKT phosphorylation, aldehyde dehydrogenase, angiotensin converting enzyme, carbonic anhydrase -2,- 9, -12, cyclooxygenase-1 and -2, cathepsin B, Hedgehog, interleukin-6, 5-lipoxygenase, matrix metalloproteinase -2 and -9, mammalian target of rapamycin, neurokinin-1, p-gp efflux pump, thioredoxin reductase, tissue factor, 20 kDa translationally controlled tumor protein, and vascular endothelial growth factor. We believe that given the current prognosis after a glioblastoma has recurred, a trial of CUSP9* is warranted.

Fig. 1. In vitro activity of CUSP9 drugs compared to that of temozolomide alone

The cell-killing effects of CUSP9 without temozolomide versus temozolomide alone on glioblastoma cell lines in vitro. Two different glioblastoma cell lines were incubated with CUSP9 compounds without temozolomide (TMZ) or with TMZ alone at the respective concentrations commonly achievable in human plasma or cerebrospinal fluid (if the latter data were available). Control cells were treated with the corresponding amount of solvent only. Microphotographs were taken after 7 days of continuous exposure to CUSP9, TMZ, or solvent respectively. While glioblastoma cells grew rapidly under control conditions, all CUSP9 without TMZ-treated cells had died. In comparison, TMZ conferred a markedly weaker inhibition of cell growth.

Fig. 2

A satellite image of a river flowing into the Arctic Ocean, illustrating what we call the “Nile Distributary Problem” where multiple distributaries develop that can cross-cover, maintaining total flow should the flow at one distributary become blocked.