A conceptually new treatment approach for relapsed glioblastoma: coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care

Abstract

To improve prognosis in recurrent glioblastoma we developed a treatment protocol based on a combination of drugs not traditionally thought of as cytotoxic chemotherapy agents but that have a robust history of being well-tolerated and are already marketed and used for other non-cancer indications. Focus was on adding drugs which met these criteria: a) were pharmacologically well characterized, b) had low likelihood of adding to patient side effect burden, c) had evidence for interfering with a recognized, well-characterized growth promoting element of glioblastoma, and d) were coordinated, as an ensemble had reasonable likelihood of concerted activity against key biological features of glioblastoma growth. We found nine drugs meeting these criteria and propose adding them to continuous low dose temozolomide, a currently accepted treatment for relapsed glioblastoma, in patients with recurrent disease after primary treatment with the Stupp Protocol. The nine adjuvant drug regimen, Coordinated Undermining of Survival Paths, CUSP9, then are aprepitant, artesunate, auranofin, captopril, copper gluconate, disulfiram, ketoconazole, nelfinavir, sertraline, to be added to continuous low dose temozolomide. We discuss each drug in turn and the specific rationale for use- how each drug is expected to retard glioblastoma growth and undermine glioblastoma's compensatory mechanisms engaged during temozolomide treatment. The risks of pharmacological interactions and why we believe this drug mix will increase both quality of life and overall survival are reviewed.

Figure 1. Schema showing relationship between CCR5 and neurokinin receptor (NK-1R) signaling operative in glioblastoma

Note three points: (a) NK-1R signaling can augment CCR5 signaling by converting less active plain CCR5 to the more active serine phosphorylated CCR5, (b) NK-1R and CCR5 can cross-cover for each other, both independently can activating ERK1 / 2 and (c) expected synergy between aprepitant and maraviroc in blocking this aspect of glioblastoma growth promotion. Maraviroc is a newly approved blocking drug at the CCR5 cytokine receptor.

Figure 2. Schema showing several places where artesunate, auranofin, and disulfiram act to increase intracellular oxidative stress

induced apoptosis protein; ROS = reactive oxygen species; TRX-2 = thioredoxin reductase; HIF-1 = hypoxia induced factor-1; ATIA = anti-TNF-alpha-induced apoptosis; PTP = mitochondrial outer membrane permeability transition pore.

Figure 4. Diagram of another aspect of disulfiram + ritonavir of potential benefit to glioblastoma treatment effectiveness

Caspase-1 is synonymous with ICE, interleukin-1 converting enzyme. The diagram lists ritonavir. It remains unproven if nelfinavir will function similarly, although every indication so far is that it will.

Figure 5. Schema indicating how HSP90, and hence its inhibition by nelfinavir (NFV) sit at several crossroads previously documented as crucial for glioblastoma growth

Note that CUSP9 is expected to inhibit the compensatory survival-enhancing response to temozolomide by two paths. A) as indicated in this Figure via nelfinavir dampening of AKT function, and B] by the NFkB degradative actions of disulfiram. Maintainance of a good NFkB pool is one of the crucial elements in glioblastoma hardiness [314].

Figure 6

A. Schema showing auranofin shifting of intracellular redox towards an oxidizing state by diminishing regeneration of reduced thioredoxin. B. Schema showing related path by which thioredoxin reductase inhibition increases intracellular hydrogen peroxide (H₂O₂). Particular importance of NADPH regeneration from NADP+ in glioblastoma metabolism and growth is reviewed in ref. 313.