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.

Repurposing itraconazole for the treatment of cancer

“…Ovarian clear cell carcinoma, one of the more aggressive disease subtypes, has been identified to have increased expression of these efflux pumps, thereby preventing the accumulation of cytotoxic agents within the malignant cells (43). In vitro studies confirm that itraconazole inhibits the efflux pump, thus reversing resistance (10,14,19,20). This has also been observed in resistant leukaemia and human embryonic kidney cells (21,22).…”

“…Drugs demonstrated to block the Hedgehog pathway include vismodegib (GDC-0449), sonidegib (LDE-225) and cyclopamine (39). These drugs are known to act by binding to and antagonising the function of SMO (4,11,14). Itraconazole similarly inhibits the Hedgehog pathway by acting directly on SMO but, unlike other drugs, it binds to a different site on the SMO protein (4,11).…”

“…Itraconazole can therefore be used in combination with or, in cases of drug resistance, as an alternative to other Hedgehog pathway inhibitors (4). When other signalling pathways facilitate neoplastic growth, tumours may survive even in the presence of Hedgehog pathway inhibition, and therefore, a combination of drugs acting on multiple pathways may be required (14).…”

“…It has been revealed in vitro to reverse multi-drug resistance in numerous types of malignancies (9). In ovarian and breast cancer, drug resistance to chemotherapy is associated with permeability glycoprotein (also termed p-glycoprotein), multidrug resistance protein 1 and ATP-binding cassette sub-family B member 1 (14,18). This is an efflux pump present on cell membranes that reduces intracellular drug concentrations, conferring cellular resistance to genotoxic therapies (42).…”

Small-Molecule Screens: A Gateway to Cancer Therapeutic Agents with Case Studies of Food and Drug Administration–Approved Drugs

“…Auranofin was subsequently advanced to a phase II clinical study in CLL patients (Shen et al, 2013). Recently, auranofin was included in the CUSP9* treatment protocol for a revolutionary glioblastoma trial consisting of a nine-drug cocktail (Kast et al, 2014). This trial was targeted to inhibit multiple escape pathways to enable the effectiveness of temozolomide, the current standard of care for primary glioblastoma.…”