aprepitant and Brain-Neoplasms

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

CINV remains a distressing side effect experienced by glioma patients receiving multi-day temozolomide therapy, in spite of guideline-based antiemetic therapy with selective serotonin-receptor-antagonists. Antiemetic research with aprepitant has routinely excluded glioma patients. In this randomized open-label phase II study, use of a nonstandard 5-day regimen of aprepitant for glioma patients was investigated.. Patients were 61% male, 97% white, 48% with KPS > 90%, 60% non-smokers, mean age 54, 92% with low alcohol use, and 46% with a CINV history. The CC was 58.6% (Arm-A) and 54.5% (Arm-B). Acute-complete response (CR) rates, defined as CC on day 1 in Arm-A and -B, were 97.1% and 87.9%, respectively (p = 0.056). Treatment-related toxicities were mild or moderate in severity.. Aprepitant plus ondansetron may increase acute-CR, may have benefit regarding CINV's effect on QoL, and is safe for 5-day temozolomide compared to ondansetron. This study provides no evidence that aprepitant increases CC rate over ondansetron alone.

Topics: Adult; Aged; Antiemetics; Antineoplastic Agents; Aprepitant; Brain Neoplasms; Female; Glioma; Humans; Male; Middle Aged; Nausea; Ondansetron; Quality of Life; Temozolomide; Vomiting

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

Concomitant use of temozolomide (TMZ) and radiotherapy, which is the standard therapy for patients with high-grade glioma, involves a unique regimen with multiple-day, long-term administration. In a previous study, we showed not only higher incidence rates of chemotherapy-induced nausea and vomiting (CINV) during the overall study period, but also substantially higher incidence rates of moderate/severe nausea and particularly severe appetite suppression during the late phase of the treatment. Here, we prospectively evaluated the efficacy of a combination of palonosetron, aprepitant, and dexamethasone for CINV in patients treated with concomitant TMZ and radiotherapy. Twenty-one consecutive patients with newly diagnosed high-grade glioma were enrolled. CINV was recorded using a daily diary and included nausea assessment, emetic episodes, degree of appetite suppression, and use of antiemetic medication. The percentage of patients with a complete response in the overall period was 76.2%. The percentages of patients with no moderate/severe nausea were 90.5, 100, and 90.5% in the early phase, late phase, and overall period, respectively. Severe appetite suppression throughout the overall period completely disappeared. The combination of palonosetron, aprepitant, and dexamethasone was highly effective and well tolerated in patients treated with concomitant TMZ and radiotherapy. This combination of antiemetic therapy focused on delayed as well as acute CINV and may have the potential to overcome CINV associated with a multiple-day, long-term chemotherapy regimen.

Topics: Adult; Aged; Antiemetics; Antineoplastic Agents, Alkylating; Aprepitant; Brain Neoplasms; Dacarbazine; Dexamethasone; Drug Therapy, Combination; Female; Glioma; Humans; Isoquinolines; Male; Middle Aged; Morpholines; Nausea; Palonosetron; Prospective Studies; Quinuclidines; Serotonin Antagonists; Temozolomide; Vomiting

Radiation-induced nausea and vomiting (RINV) is one of the most distressing symptoms that adversely affects quality of life (QOL) as well as the ongoing management plan of cancer patients. Although there are protocols for management of chemotherapy induced nausea and vomiting (CINV) but such guidelines are still lacking for RINV. Various agents like 5-hydroxy tryptophan 3 (5-HT3) antagonist, dexamethasone, metoclopramide and haloperidol are used in clinical practice for RINV but the results are not very encouraging. Because of proposed similarity in the mechanism of nausea and vomiting following chemotherapy and radiotherapy, aprepitant, a substance P neurokinin 1 receptor antagonist can be an optimal agent for RINV on account of its unique pharmacological property. We report a case of metastatic carcinoma breast with bilateral cerebellar metastasis. She presented with complaints of headache and intractable nausea and vomiting. A single fraction whole brain radiotherapy (WBRT) was given for bilateral cerebellum metastasis which further precipitated her symptoms. The prophylactic and therapeutic efficacy of antiemetic used for RINV may be enhanced by adding aprepitant before starting radiotherapy in high risk cases as in ours.

Topics: Antiemetics; Aprepitant; Brain Neoplasms; Female; Humans; Middle Aged; Morpholines; Nausea; Palliative Care; Tomography, X-Ray Computed; Vomiting

The neuropeptide substance P (SP) has been implicated in the disruption of the blood-brain barrier (BBB) and development of cerebral edema in acute brain injury. Cerebral edema accumulates rapidly around brain tumors and has been linked to several tumor-associated deficits. Currently, the standard treatment for peritumoral edema is the corticosteroid dexamethasone, prolonged use of which is associated with a number of deleterious side effects. As SP is reported to increase in many cancer types, this study examined whether SP plays a role in the genesis of brain peritumoral edema. A-375 human melanoma cells were injected into the right striatum of male Balb/c nude mice to induce brain tumor growth, with culture medium injected in animals serving as controls. At 2, 3 or 4 weeks following tumor cell inoculation, non-treated animals were perfusion fixed for immunohistochemical detection of Albumin, SP and NK1 receptor. A further subgroup of animals was treated with a daily injection of the NK1 antagonist Emend (3 mg/kg), dexamethasone (8 mg/kg) or saline vehicle at 3 weeks post-inoculation. Animals were sacrificed a week later to determine BBB permeability using Evan's Blue and brain water content. Non-treated animals demonstrated a significant increase in albumin, SP and NK1 receptor immunoreactivity in the peritumoral area as well as increased perivascular staining in the surrounding brain tissue. Brain water content and BBB permeability was significantly increased in tumor-inoculated animals when compared to controls (p<0.05). Treatment with Emend and dexamethasone reduced BBB permeability and brain water content when compared to vehicle-treated tumor-inoculated mice. The increase in peritumoral staining for both SP and the NK1 receptor, coupled with the reduction in brain water content and BBB permeability seen following treatment with the NK1 antagonist Emend, suggests that SP plays a role in the genesis of peritumoral edema, and thus warrants further investigation as a potential anti-edematous treatment.

Topics: Animals; Aprepitant; Blood-Brain Barrier; Brain Edema; Brain Neoplasms; Disease Models, Animal; Humans; Male; Mice; Morpholines; Neurokinin-1 Receptor Antagonists; Permeability; Receptors, Neurokinin-1; Substance P

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

Emend, an NK1 antagonist, and dexamethasone are used to treat complications associated with metastatic brain tumours and their treatment. It has been suggested that these agents exert anticancer effects apart from their current use. The effects of the NK1 antagonists, Emend and N-acetyl-L-tryptophan, and dexamethasone on tumour growth were investigated in vitro and in vivo at clinically relevant doses. For animal experiments, a stereotaxic injection model of Walker 256 rat breast carcinoma cells into the striatum of Wistar rats was used. Emend treatment led to a decrease in tumour cell viability in vitro, although this effect was not replicated by N-acetyl-L-tryptophan. Dexamethasone did not decrease tumour cell viability in vitro but decreased tumour volume in vivo, likely to be through a reduction in tumour oedema, as indicated by the increase in tumour cell density. None of the agents investigated altered tumour cell replication or apoptosis in vivo. Inoculated animals showed increased glial fibrillary acidic protein and ionized calcium-binding adapter molecule 1 immunoreactivity indicative of astrocytes and microglia in the peritumoral area, whereas treatment with Emend and dexamethasone reduced the labelling for both glial cells. These results do not support the hypothesis that NK1 antagonists or dexamethasone exert a cytotoxic action on tumour cells, although these conclusions may be specific to this model and cell line.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Aprepitant; Astrocytes; Brain Edema; Brain Neoplasms; Calcium-Binding Proteins; Carcinoma; Cell Line, Tumor; Corpus Striatum; Dexamethasone; Drug Screening Assays, Antitumor; Female; Glial Fibrillary Acidic Protein; Humans; In Vitro Techniques; Male; Mammary Neoplasms, Experimental; Microfilament Proteins; Microglia; Models, Biological; Morpholines; Neoplasm Proteins; Neurokinin-1 Receptor Antagonists; Random Allocation; Rats; Rats, Wistar; Receptors, Neurokinin-1; Tryptophan; Tumor Burden; Tumor Microenvironment