aprepitant and Glioblastoma

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.

Topics: Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Artemisinins; Auranofin; Brain Neoplasms; Captopril; Dacarbazine; Disulfiram; Glioblastoma; Gluconates; Humans; Ketoconazole; Morpholines; Nelfinavir; Neoplasm Recurrence, Local; Sertraline; Succinates; Temozolomide

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.. 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.. 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.. Our analysis makes the case for a well-designed trial of the proposed combination in the treatment of glioblastoma.

Topics: Anti-HIV Agents; Antiemetics; Antineoplastic Agents; Aprepitant; CCR5 Receptor Antagonists; Cyclohexanes; Drug Approval; Drug Interactions; Glioblastoma; Humans; Maraviroc; Mitogen-Activated Protein Kinase 3; Morpholines; Neurokinin-1 Receptor Antagonists; Phosphorylation; Signal Transduction; Triazoles; United States; United States Food and Drug Administration

Although there is no doubt regarding the involvement of oxidative stress in the development of glioblastoma, many questions remained unanswered about signaling cascades that regulate the redox status. Given the importance of the substance P (SP)/neurokinin 1 receptor (NK1R) system in different cancers, it was of particular interest to evaluate whether the stimulation of this cascade in glioblastoma-derived U87 cells is associated with the induction of oxidative stress. Our results showed that SP-mediated activation of NK1R not only increased the intracellular levels of malondialdehyde (MDA) and reactive oxygen species (ROS) but also reduced the concentration of thiol in U87 cells. We also found that upon SP addition, there was a significant reduction in the cells' total antioxidant capacity (TAC), revealing that the SP/NK1R axis may be involved in the regulation of oxidative stress in glioblastoma cells. The significant role of SP/NK1R in triggering oxidative stress in glioblastoma has become more evident when we found that the abrogation of the axis using aprepitant reduced cell survival, probably through exerting antioxidant effects. The results showed that both MDA and ROS concentrations were significantly reduced in the presence of aprepitant, and the number of antioxidant components of the redox system increased. Overall, these findings suggest that aprepitant might exert its anticancer effect on U87 cells through shifting the balance of oxidant and antioxidant components of the redox system.

Topics: Antioxidants; Aprepitant; Cell Line, Tumor; Glioblastoma; Humans; Neurokinin-1 Receptor Antagonists; Oxidation-Reduction; Reactive Oxygen Species; Receptors, Neurokinin-1; Substance P

Constructed from a theoretical framework, the coordinated undermining of survival paths in glioblastoma (GBM) is a combination of nine drugs approved for non-oncological indications (CUSP9; aprepitant, auranofin, captopril, celecoxib, disulfiram, itraconazole, minocycline, quetiapine, and sertraline) combined with temozolomide (TMZ). The availability of these drugs outside of specialized treatment centers has led patients to embark on combination treatments without systematic follow-up. However, no experimental data on efficacy using the CUSP9 strategy in GBM have been reported.. Using patient-derived glioblastoma stem cell (GSC) cultures from 15 GBM patients, we described stem cell properties of individual cultures, determined the dose-response relationships of the drugs in the CUSP9, and assessed the efficacy the CUSP9 combination with TMZ in concentrations clinically achievable. The efficacy was evaluated by cell viability, cytotoxicity, and sphere-forming assays in both primary and recurrent GSC cultures.. We found that CUSP9 with TMZ induced a combination effect compared to the drugs individually (p < 0.0001). Evaluated by cell viability and cytotoxicity, 50% of the GSC cultures displayed a high sensitivity to the drug combination. In clinical plasma concentrations, the effect of the CUSP9 with TMZ was superior to TMZ monotherapy (p < 0.001). The Wnt-signaling pathway has been shown important in GSC, and CUSP9 significantly reduces Wnt-activity.. Adding experimental data to the theoretical rationale of CUSP9, our results demonstrate that the CUSP9 treatment strategy can induce a combination effect in both treatment-naïve and pretreated GSC cultures; however, predicting response in individual cultures will require further profiling of GSCs.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Auranofin; Brain Neoplasms; Captopril; Celecoxib; Disulfiram; Dose-Response Relationship, Drug; Drug Screening Assays, Antitumor; Female; Glioblastoma; Humans; Itraconazole; Mice; Mice, SCID; Minocycline; Neoplastic Stem Cells; Quetiapine Fumarate; Reproducibility of Results; Sertraline; Signal Transduction; Temozolomide; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

In the effort to find better treatments for glioblastoma we tested several currently marketed non-chemotherapy drugs for their ability to enhance the standard cytotoxic drug currently used to treat glioblastoma- temozolomide. We tested four antiviral drugs- acyclovir, cidofovir, maraviroc, ritonavir, and an anti-emetic, aprepitant. We found no cytotoxicity of cidofovir and discussed possible reasons for discrepancy from previous findings of others. We also found no cytotoxicity from acyclovir or maraviroc also in contradistinction to predictions. Cytotoxicity to glioma cell line GAMG for temozolomide alone was 14%, aprepitant alone 7%, ritonavir alone 14%, while temozolomide + aprepitant was 19%, temozolomide + ritonavir 34%, ritonavir + aprepitant 64 %, and all three, temozolomide + ritonavir + aprepitant 78%. We conclude that a remarkable synergy exists between aprepitant and ritonavir. Given the long clinical experience with these two well-tolerated drugs in treating non-cancer conditions, and the current median survival of glioblastoma of 2 years, a trial is warranted of adding these two simple drugs to current standard treatment with temozolomide.

Topics: Antiemetics; Antineoplastic Agents, Alkylating; Apoptosis; Aprepitant; Brain Neoplasms; Cell Proliferation; Dacarbazine; Glioblastoma; HIV Protease Inhibitors; Humans; Immunoenzyme Techniques; Morpholines; Ritonavir; Temozolomide; Tumor Cells, Cultured

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.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Artemisinins; Artesunate; Auranofin; Brain Neoplasms; Captopril; Celecoxib; Dacarbazine; Disulfiram; Glioblastoma; Humans; Itraconazole; Molecular Targeted Therapy; Morpholines; Neoplasm Recurrence, Local; Pyrazoles; Ritonavir; Sertraline; Signal Transduction; Sulfonamides; Temozolomide; Treatment Outcome

Topics: Antiemetics; Aprepitant; Cerebellar Diseases; Cerebellar Neoplasms; Glioblastoma; Humans; Morpholines; United States; United States Food and Drug Administration