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Hey docs…..
- Thread starter 7.62willdo
- Start date
Today is the biopsy results along with mri results any questions I should ask????
What are my risks in having the treatment done. What will be the quality of life during and after treatment? What would you (the doctor) do if it was you or your loved one?
Those are questions I wish we had asked when my MiL went through something similar13 years ago.
Those are questions I wish we had asked when my MiL went through something similar13 years ago.
These are my greatest fears having the ability to make certain decisions that I my want to make taken away from me both physically and legaly
Are there teartments I may want to pick over others or avoid completely
What treatments have the best chance of success
What treatments have the best chance of success
Prayers brother and stay strong on both ends…
Hey, anyone have experience with brain tumors? Just found out it is in the area of the brain that regulates sleep. This is my only symptom so far, however no sleeps is awful and some reason they won’t prescribe anything for sleep.
Im off this weekend and let me see if anyone I work with knows a good neurosurgeon there.
Im sure there are more than a couple in Seattle area, but weeding through them to find a top notch one can suck.
Biopsy yet or just MRI results?
Have a friend and prior coworker from years back who has done amazing with alternative treatments.
Tom Brady diet. No alcohol. Some other stuff I can find out.
He was stage 3 bladder CA, in nodes and lung, did have resection of tumors, but NO radiation or chemo and is 2 yrs past their predicted with no sign on PET scan and more fit and going harder than most guys 1/2 his age (he is 67 now).
And prayers.
Im sure there are more than a couple in Seattle area, but weeding through them to find a top notch one can suck.
Biopsy yet or just MRI results?
Have a friend and prior coworker from years back who has done amazing with alternative treatments.
Tom Brady diet. No alcohol. Some other stuff I can find out.
He was stage 3 bladder CA, in nodes and lung, did have resection of tumors, but NO radiation or chemo and is 2 yrs past their predicted with no sign on PET scan and more fit and going harder than most guys 1/2 his age (he is 67 now).
And prayers.
It was late ‘90s interned lingo, or, “L33T speak” online gamers used to use for, “owned”.
I’m sorry you’re going through some shit. Please do NOT rub dirt in it. I honestly thought this thread was going to be something totally different when I posted that advice.
He is still waiting for staging and final path: glioblastoma / glial tumor on path. Been referred to good brain tumor center, but horrible backlog due to increasing numbers...
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That may be a bit misleading, reasons below.
This being the reason.
While one may find some information on say, "malignancies associated with Agent Orange," one will not find any usable data on Pediatric disorders.
After this came up I did some research, and it looks like mebendazole has the best results with brain tumors as it crosses the blood brain barrier the best of the benzidamoles.
Emerging Perspectives on the Antiparasitic Mebendazole as a Repurposed Drug for the Treatment of Brain Cancers
Daniela Meco, Writing – review & editing, Writing – original draft,1 Giorgio Attinà, Writing – review & editing,1 Stefano Mastrangelo, Writing – review & editing,1,2 Pierluigi Navarra, Writing – original draft,3 and Antonio Ruggiero, Conceptualization, Writing – original draft, Writing – review & editing1,2,*Barbara Mroczko, Academic Editor
Author information Article notes Copyright and License information PMC Disclaimer
Associated Data
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Abstract
Repurposing approved non-antitumor drugs is a promising and affordable strategy in drug discovery to identify new therapeutic uses different from the original medical indication that may help increase the number of possible, effective anticancer drugs. The use of drugs in ways other than their original FDA-approved indications could offer novel avenues such as bypassing the chemoresistance and recurrence seen with conventional therapy and treatment; moreover, it can offer a safe and economic strategy for combination therapy. Recent works have demonstrated the anticancer properties of the FDA-approved drug Mebendazole. This synthetic benzimidazole proved effective against a broad spectrum of intestinal Helminthiasis. Mebendazole can penetrate the blood–brain barrier and has been shown to inhibit the malignant progression of glioma by targeting signaling pathways related to cell proliferation, apoptosis, or invasion/migration, or by increasing the sensitivity of glioma cells to conventional chemotherapy or radiotherapy. Moreover, several preclinical models and ongoing clinical trials explore the efficacy of Mebendazole in multiple cancers, including acute myeloid leukemia, brain cancer, oropharyngeal squamous cell carcinoma, breast cancer, gastrointestinal cancer, lung carcinoma, adrenocortical carcinoma, prostate cancer, and head and neck cancer. The present review summarizes central literature regarding the anticancer effects of MBZ in cancer cell lines, animal tumor models, and clinical trials to suggest possible strategies for safe and economical combinations of anticancer therapies in brain cancer. Mebendazole might be an excellent candidate for the treatment of brain tumors because of its efficacy both when used as monotherapy and in combination as an enhancement to standard chemotherapeutics and radiotherapy, due to its effectiveness on tumor angiogenesis inhibition, cell cycle arrest, apoptosis induction, and targeting of critical pathways involved in cancer such as Hedgehog signaling. Therefore, attention to MBZ repurposing has recently increased because of its potential therapeutic versatility and significant clinical implications, such as reducing medical care costs and optimizing existing therapies. Using new treatments is essential, particularly when current therapeutics for patients with brain cancer fail.Keywords: Mebendazole, drug repurposing, antitumor therapy, brain cancer, benzimidazole
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1. Introduction
Cancer ranks as a leading cause of death and a significant barrier to increasing life expectancy in every country [1]. According to estimates from the World Health Organization (WHO) in 2019, cancer is the first or second leading cause of death before age 70 in 112 of 183 countries and ranks third or fourth in 23 countries [2]. Current tumor treatments usually consist of chemotherapy, radiotherapy, surgery, targeted therapy, immunotherapy, and endocrine therapy that can be used individually or in combination, depending on the stage and type of tumor and diagnosis. Several factors reduce the practical improvement of a cancer patient’s prognosis. Drug-untreatable targets, chemoresistance, tumor heterogeneity, and metastases formation are significant barriers to the effective cure of cancer patients. Despite intense preclinical and clinical research efforts, the survival rate of patients suffering from the most aggressive cancer types has not yet improved, mainly due to therapeutic failure. Moreover, nearly all anticancer medications currently on the market have serious adverse effects; therefore, new, safer anticancer drugs are desirable.However, developing new therapeutics has become increasingly difficult for pharmaceutical companies; indeed, the discovery and development of new drugs represent long and expensive processes with a low overall probability of success. At present, it takes about 10–15 years to develop a new drug [3], and despite all the effort, the success rate remains very low (around 2%) [4,5]. In recent years, the pool of newly discovered and Food and Drug Administration (FDA)-approved drugs has diminished [6], primarily due to the increasing cost of clinical trials [7]. From 2004 through 2012, the median price for a pharmaceutical clinical trial is around USD 2–3 billion. In this scenario, new approaches to drug use can reduce development time and offer novel and effective anticancer therapies. Compounds clinically used for non-cancer indications could lead to safe, affordable, and timely treatment options for patients with high medical needs.
In recent years, the concept of drug repurposing (also known as “drug repositioning”, “reprofiling”, or “retasking”) is gaining increasing attention as a strategy for identifying new therapeutic applications of existing drugs or those under investigation outside the scope of the original medical indication [8,9,10,11]. Many researchers have demonstrated that non-traditional antitumor drugs have distinct anticancer actions and represent a safe and promising treatment option. This strategy also provides an opportunity to develop innovative formulations, which may provide clinical benefits compared to older marketed drugs [12]. The benefits of this strategy are that the risk of failure is lower than the approach with newly developed drugs. The repurposed drug is sufficiently safe in preclinical models and humans. If early-stage trials are complete, it is less likely to fail, at least from a safety point of view, in subsequent efficacy trials. Another benefit of this strategy is that it can reduce the time frame for drug development because most preclinical testing, safety assessment, and in some cases, formulation development are already complete.
Consequently, less investment is needed, although this will vary greatly depending on the stage and development of the repurposing candidate [13,14]. The pharmacokinetic, pharmacodynamic, and toxicity profiles of approved medicines are well known, so the new users can more easily be translated into phase II and III clinical trials [15,16,17,18]. Moreover, drugs that have been on the market for several years are often relatively cheap compared to new medicinal products; furthermore, these medicines’ wide availability and affordability could facilitate clinical research and enable timely and affordable access for patients [19,20,21]. Finally, repurposed drugs may reveal new targets and pathways, suggesting further drug exploitation.
For this reason, there has been substantial interest in uncovering previously uncharacterized therapeutic properties among medications that the FDA has already approved. In this context, a relevant example of effective drug repurposing in cancer and advanced clinical trials is Mebendazole (MBZ). MBZ belongs to the anti-helminthic drugs category, including various chemical entities (like albendazole, parbendazole, fenbendazole, triclabendazole, oxibendazole, ricobendazole, and flubendazole) and has several distinct modes of action [22]. For decades, MBZ safely treated infections caused by parasitic worms (helminths) that colonize the human intestine, developed for treating veterinary parasites first and then for clinical application. The main reason for MBZ repurposing lies in its ability to inhibit both microtubule formation and glucose uptake; these aspects predetermine these compounds to possible cytostatic effects. In addition, several research groups investigated the repurposing of MBZ as a possible anticancer agent in oncology for its ability to interfere with several key oncogenic signal transduction pathways [23,24].
In this review, we highlight the potential anticancer effect of MBZ and its potential mechanistic actions on brain cancer. Several recent studies reported the anticancer effect of MBZ, with a wide range of pharmacological mechanisms against brain cancer, including proliferation inhibition, cell cycle arrest, apoptosis induction, angiogenesis inhibition, and targeting of several key oncogenic signal transduction pathways. In addition, we summarize the pharmacokinetic properties and side effects of MBZ, aiming to clarify the basic understanding and improve its use and potential in brain cancer therapy. Possible advantages, limitations, and additional perspectives are discussed and evaluated.
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2. Physiopathology of Glioma Development
Diffuse gliomas represent 80% of malignant brain tumors [25]. The standard classification of brain tumors by the World Health Organization (WHO, Geneva, Switzerland) is based on their mitotic activity, proliferation, and degree of necrosis; they are identified in four grades:- Grade I gliomas are low-grade benign lesions, such as pilocytic astrocytomas, that have limited proliferation and are frequent in children; however, they might acquire higher levels of malignancy. Surgical resection is a good therapeutic option in most cases.
- Grade II gliomas have low-grade but infiltrative lesions that tend to show higher recurrence after surgical resection.
- Grade III gliomas have intermediate- to high-grade lesions with atypia, higher mitotic activity, and evidence of malignancy. Patients with these tumors usually are prescribed additional radiation as well as chemotherapy.
- Grade IV tumors are high-grade malignant lesions with higher mitotic activity, microvascular proliferation, high necrosis, and the worst prognosis.
In 2016, CNS WHO released the latest update of tumor classification on the basis of the latest studies on molecular characterization [26]. Genomic sequencing efforts provided unprecedented insight into the genomic aberrations and cellular signaling mechanisms that drive these cancers, and discoveries from these efforts translated into novel diagnostic algorithms, biomarkers, and therapeutic strategies in neuro-oncology. These sequencing efforts helped revise WHO classification of nervous system tumors, and histologic and molecular parameters were incorporated into the diagnostic catalog [26,27]. Several diagnoses were restructured (diffuse gliomas, medulloblastomas, and embryonal tumors), and novel tumor entities were introduced. For this purpose, researchers at WHO used the datasets generated by The Cancer Genome Atlas (TCGA) and related gene expression and DNA methylation signatures with prognosis. Compared to the previous release, the principal change in the new classification is the relevant reorganization of diffuse gliomas, according to the IDH status, co-deletion of chromosome arms 1p and 19q, and MGMT methylation. The status of isocitrate dehydrogenase 1 and 2 (IDH1/2) enzymes are key reference genes for brain tumor classification. Mutations of IDH1 and IDH2 lead to a favorable outcome [28] and have more prolonged overall survival in comparison to those with IDH wild type. High-grade gliomas with IDH wild type have shorter overall survival, while low-grade gliomas display a poor glioblastoma (GBM)-like trajectory. The new diagnostic criterion for oligodendroglioma is the allelic loss of chromosomes 1p and 19q [29]. Although MGMT is not considered a valid predictive biomarker in diffuse gliomas, it is a prognostic biomarker (Figure 1) [30].
Figure 1
Diagnostic algorithm for diffuse gliomas, based on the WHO classification.
As for signaling pathways, brain tumors manifest aberrations in key cellular pathways that mediate cell growth and replication proliferation, survival, migration, and apoptosis, as observed in other cancers. These pathways are not linear sequences of enzymes but rather complex signaling pathways influenced by multiple growth factors. The Cancer Genome Atlas classified three main signaling pathways in gliomas’ pathogenesis: RTK/RAS/PI3K (receptor tyrosine kinase, RAS, phosphatidylinositol 3-kinase), p53, and retinoblastoma (RB); later, angiogenesis was added as an additional signaling pathway [26,31,32].
The PI3K/AKT/mTOR signal transduction pathway and the Ras/MAPK pathway are hyperactivated in several cancer types, including glioblastoma, and play a key role in tumorigenesis by activating the tumor promoters and inhibiting the tumor suppressors. Several growth factors activate PI3K (e.g., human EGFR family and platelet-derived growth factor receptor (PDGFR) family growth factors). RTKs are frequently activated in malignant gliomas, such as EGFR gene amplification, which occurs in approximately 40% of patients with GBM, and PDGFRA gene amplification, which occurs in up to 16% of GBM [33,34,35,36]. At the same time, the EGFR variant (EGFRvIII) shows ligand-independent constitutive activation of the receptor. This deletion mutant is observed in approximately 30% to 50% of EGFR-amplified gliomas [37]. Downstream signaling from growth factor receptors can be activated by loss or mutation in the neurofibromatosis 1 gene (NF1), mutations in KRAS, mutations in PIK3CA (the gene for PI3K), and deletion or loss of heterozygosity of PTEN. PI3K participates in the phosphorylation of AKT and promotes cellular proliferation by inactivating cell cycle inhibitors and promoting cell cycle proteins. The PTEN tumor suppressor gene is inactivated in 40–50% exclusively in primary glioblastomas and usually inhibits the PI3K/Akt pathway [38].
The Tumor Protein p53 (TP53) tumor suppressor gene encodes a protein that regulates several cellular processes, including cell cycle arrest, the response of cells to DNA damage, senescence, apoptosis, and cell differentiation and neovascularization. The p53 cascade regulates over 2500 genes, 67 of which are involved in tumorigenesis [39,40,41,42]. After DNA damage, TP53 is activated and induces transcription factors to regulate the expression of downstream effector genes to determine cell fate. The p53 pathway is the most altered in sporadic glioma, with some aberration of p53 signaling found in 87% of tumors [38]. These aberrations are most prevalent in low-grade glioma of astrocytic lineage and secondary glioblastoma, often concurrent with IDH mutation [43]. Generally, P53 inactivation in glioblastoma occurs through amplification of MDM2 (mouse double-minute 2) (11%) or MDM4 (4%), deletion of ARF (55%), and mutations of p53 itself [4]. MDM2 is a primary negative regulator of the p53 pathway; it provides transcriptional inhibition by directly binding p53 and degrades p53 through its ligase activity [44].
RB is a tumor suppressor gene encoding the retinoblastoma susceptibility protein 1 (RB1). The Rb pathway is an important cell cycle regulator that inhibits the entry of cells through G1 into the S-phase of the cell cycle. The Rb pathway is implicated in the malignant progression of astrocytoma and is commonly altered in glioblastoma (79%). When phosphorylated by cyclin D, cyclin-dependent kinase 4 (CDK4), and CDK6, RB1 will be inactive, resulting in an unregulated progression through the cell cycle and tumor growth [45] (Figure 2).
Figure 2
Major signaling pathways involved in the pathogenesis of glioblastomas.
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3. Mebendazole: Chemical Structure and Pharmacokinetic Properties
Mebendazole (methyl 5-benzoyl-1H-benzimidazol-2-yl-carbamate) appeared in 1968 as an agent active against a wide range of broad-spectrum anthelmintics applied first to human subjects in 1971 [46]. Table 1 and Table 2 summarize the pharmacokinetic properties of MBZ. MBZ acts directly on luminal parasites in the gastrointestinal tract. First-pass metabolism of MBZ ensures that only about 20% of the oral dose reaches systemic circulation, with maximum plasma concentration reached 2–4 h post-administration. After the first pass in the intestinal wall and liver, the metabolites are active against parasites in internal organs and tissues [47,48]. MBZ is also extensively metabolized by the liver to amino and hydroxylated amino forms of the parent compound; nevertheless, the enzymes responsible have not been identified [49,50,51]. However, also P450 enzymes are involved in the process due to the documented inhibition with cimetidine [52]. The MBZ and its metabolites are excreted primarily in feces and about 2% in the urine [53]. MBZ induces the block of microtubule functions of parasites and mammalian cells through inhibition of polymerization of ß-tubulin into microtubules. The result is a loss of transport of secretory vesicles, a decrease in glucose uptake, and an increase in the use of stored glycogen [51,54].Table 1
Chemical properties of MBZ.Mebendazole: | Methyl 5-benzoyl-1H-benzimidazol-2-yl-carbamate |
|---|---|
Structure | 
|
Chemical formula | C16-H13-N3-O3 |
Weight | 295.293 g/mol |
CAS | 60254-95-7 |
Indication | oral administration |
Absorption | poor solubility and absorption |
Distribution | highly bound to plasma protein |
Metabolism | extensively hepatic first-pass |
Side effects | gastrointestinal upset, diarrhea, fever, abdominal |
discomfort, flatulence, hypersensitivity reactions | |
Excretion | bile and feces and ˂2% urine |
BBB permeability | Yes |
GI Absorption | High |
P-gp Substrate | No |
T1/2: elimination half-life | 3–6 h |
Table 2
Mean pharmacokinetic parameters of MBZ extracted from different studies.Author (Year) | Population | Formulation | Cmax (ng/mL) | AUC (ng.h/mL) | Tmax (h) | T1/2 (h) | MBZ Dose and Coadministration with Other Drugs | Ref | ||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
Brainthwaite (1982) | Patients (n.10) | tablet | 17.2–116.2 | 209.6 | 5.2 | | MBZ 10 mg/kg | [55] | ||||
Chronic treatment | 99.4–500.2 | 649.8 | 2 | MBZ 10 mg/kg | ||||||||
Dawson (1985) Edwards (1988) | Fasting volunteers (n.3) | oral intravenous | 91, 1–142 | 4.63 ± 1.80 2.27 ± 8.2 | 0.42 ± 0.12 | 0.93 ± 0.25 1.12 ± 0.24 | MBZ 1.18 µg of 3H-mebendazole | [47] | ||||
Corti (2009) | Healthy volunteers (n.8) Fasting | tablet | 31.0 ± 26.0 | 207.2 ± 157.6 | 2.1 ± 1 | 7.4 ± 2.2 | MBZ 1000 mg/day po on 3 days | [56] | ||||
tablet | 36.0 ± 22.8 | 228.9 ± 147 | 2.4 ± 1.7 | 9.3 ± 3.5 | MBZ 1000 mg/day po on 3 days + Short-term Ritovaris 200 mg po twice daily × 2 doses | |||||||
tablet | 11.5 ± 6.2 | 85.9 ± 53.2 | 2.1 ± 0.8 | 10.6 ± 8.6 | MBZ 1000 mg/day po on 3 days + Long-term Ritovaris 200 mg po twice daily × 7 doses | |||||||
Bekhti (1987) | Patients (n.8) with peptic ulcer and hydatid cysts | tablet | 55.7 ± 30.2 | | | | MBZ 1.5 g three times daily po × 30 days | [57] | ||||
82.3 ± 41.8 | MBZ 1.5 g three times daily po × 30 days + Cimetidine 400 mg three times daily po × 30 days | |||||||||||
Luder (1986) | Patients (n.10) with Echinococcus multilocularis or granulosus | tablet | HC | | | | MBZ 45–122 mg/kg/day po × 10 weeks + Cimetidine 1 G/day po × 10 weeks | [58] | ||||
NC | MBZ 45–122 mg/kg/day po × 10 weeks + Ursodeosycholic acid 500 mg/day | |||||||||||
Liu (2012) | Mouse | powder | 1.3 ± 0.42 | 11.6 ± 2.0 | 1.3 ± 0.6 | 12.0 ± 5.5 | MBZ-1% tragacanth po 25 mg/kg | [59] | ||||
3.3 ± 0.6 | 28.2 ± 2.5 | 1.7 ± 1.6 | 11.5 ± 6.2 | MBZ-Oleic Acid po 25 mg/kg | ||||||||
4.8 ± 0.6 | 19.8 ± 2.5 | 1 | 4.2 ± 1.0 | MBZ-Glycerol Trioleate po 25 mg/kg | ||||||||
4.4 ± 2.0 | 25.1 ± 4.4 | 1.5 ± 0.9 | 4.9 ± 1.7 | MBZ-Soybean oil po 25 mg/kg | ||||||||
Ren-Yuan Bai (2015) | MBZ polymorphs in mice (GL261 Glioma model) | tablet | Plasma | Brain | Plasma | Brain | Plasma | Brain | Plasma | Brain | | [53] |
379.3 | | 3052 | | 1 | | 3.23 | | MBZ Polimorph A | ||||
2778.3 | | 26474 | | 6 | | 3.18 | | MBZ Polimorph B | ||||
2553.3 | 2016 | 16039 | 13134 | 4 | 4 | 0.90 | 1.64 | MBZ Polimorph C |
AUC: area under the concentration-time curve; Cmax: maximum drug concentration; T1/2: elimination half-life; Tmax: time to reach Cmax; HC: higher concentration; NC: no change; N: sample size.
The World Health Organization (WHO)-recommended dose of MBZ is 40–50 mg/kg/day for at least 3–6 months and two years for cystic and alveolar echinococcosis, respectively [60]. The dosage varies according to the type of helminthic infection to treat. Pinworms are treated with a single 100 mg treatment, whereas roundworms or hookworms are treated with 100 mg twice daily for three days. In the case of long-term administration for treating human cystic and alveolar echinococcosis (also known as hydatid disease), the treatment is generally well tolerated. Still, the specific treatment for some patients must be discontinued. For example, in one open-labeled observational study, the patients treated with MBZ for alveolar echinococcosis (average: 24 months) experienced few adverse reactions, and in only three patients (of 17), the treatment was changed to albendazole due to intolerable side effects (reversible alopecia, psychological disturbance, and drop in performance) [61]. Side effects associated with low- to high-dose regimens include abdominal discomfort, flatulence, diarrhea, neutropenia, marrow aplasia, alopecia, allergic reaction, and elevations in transaminase levels [60]. However, drug withdrawal spontaneously reverses these relatively rare and mild adverse effects [23,62]. One of the most significant adverse effects is hepatotoxicity, although its incidence is infrequent; Tolomei et al. [63] have reported a case of severe hepatitis after 18 days of MBZ administration in a patient with Gilbert’s syndrome affected by pinworm infestation. After a standard dose of MDZ (2 × 100 mg/d for three days every week) and after short-term treatment, acute hepatitis manifested, with a serum level of ALT (alanine aminotransferase) higher than that observed for higher doses. Hepatic enzymes returned to normal over the following five weeks. Moreover, a case series report supports its safety in breastfeeding, where no evidence of MBZ-related toxicity in infants of lactating mothers has been observed [64]. MBZ is a teratogen in experimental rats if given in very high doses, although not in rabbits [31]. In human patients, MBZ is contraindicated during pregnancy [65]. However, long-term MBZ treatment (50 mg/kg daily for 9–18 months) was safe for children with hydatid disease [66]. The combination of MBZ (>500 mg) and metronidazole (>500 mg) is prohibited because severe and rare fatal adverse events such as Stevens–Johnson syndrome (or toxic epidermal necrosis) may occur. The risk increased with increasing doses of metronidazole but not MBZ, and there may be a synergistic interaction between MBZ and metronidazole [67].
Another well-known property of MBZ is its relative insolubility in water and most organic solvents. The absorption rate of oral MBZ in the human intestine is about 1–5% [51]. The low water solubility can cause a reduction in drug absorption that, combined with the rapid drug degradation, could result in an inadequate in vivo drug concentration and failure to achieve the therapeutic dose. Moreover, oscillation in the drug plasma levels results in unforeseeable levels of bioavailability. All these effects cause a reduction in MBZ’s potency in cancer therapy; thus, modifications enhancing its availability will determine its potential use in oncology. Several researchers suggested strategies to improve the poor aqueous MBZ and anticancer effects [59].
Alavi and Shahmabadi provide an overview of the strategies adopted to improve low bioavailability. To overcome these limitations, the authors proposed using nanocarrier-based formulations, pro-drug formulations, and solid dispersions (SDs) to improve drug solubility [68]. To overcome poor aqueous solubility, de la Torre-Iglesias et al. [69] have prepared re-dispersible microparticles (RDM) containing MBZ for improved oral bioavailability and therapeutic activity using low doses of MBZ (5 mg/kg). These formulations could optimize anthelmintic efficacy and enhance MBZ concentrations in muscle and cysts. This aspect is crucial for inoperable or disseminated cases of hydatidosis or neuro-cysticercosis.
Furthermore, low doses of MBZ lead to low toxicity in humans. Münst et al. [70] have demonstrated that bioavailability may significantly improve by coadministration with a high-fat meal. Plasma concentrations remained at 17 nmol/L in three fasting volunteers treated with 1.5 g doses. Instead, when the treated volunteers had a standard breakfast, the plasma concentration rose to 91,112 and 142 nmol/L within 2 to 4 h. In another clinical study, Braithwaite et al. [55] showed that MBZ plasma concentration-time profiles differed considerably between patients after oral administration of MBZ. The authors monitored the plasma concentrations of MBZ and its metabolites in twelve patients after receiving 10 mg/kg, in subjects receiving their first dose of MBZ, and in subjects with chronic treatment. The elimination half-lives ranged from 2.8–9.0 h; the peak plasma concentrations ranged from 17.7 to 116.2 ng/mL for subjects receiving their initial dose and from 99.4 to 500.2 ng/mg for subjects on chronic treatment. Studies reported by Alavi et al. [68] showed that the plasma AUCTs for the main metabolites of MBZ (methyl 5-(α-hydroxybenzyl)-2-benzimidazole carbamate and 2-amino-5 benzoylbenzimidazole) were about five times larger than the plasma MBZ AUCT found in patients on chronic therapy, confirming that the gastrointestinal tract poorly absorbs MBZ.
In patients on chronic MBZ therapy, MBZ concentrations found in both liver tissue and parasite tissue were significantly higher than in adipose tissue. While the MBZ concentration in liver was higher, that in other tissues was lower than the plasma Cmax detected for each patient. To reduce the wide inter- and intra-individual variation in systemic availability of MBZ, the drug should be taken with food. For intravenous administration, no guidelines can be provided because there are no data on the pharmacokinetics of MBZ after intravenous infusion. Bekhti et al. [57] and Luder et al. [58] proved that MBZ produces pharmacodynamic effects possibly exaggerated by pharmacokinetic interactions with other agents. In that paper, they showed that cimetidine increases plasma levels of the MBZ (maximum serum levels rose from 55.7 ± 30.2 ng/mL [0.19 ± 0.10 μM] to 82.3 ± 41.8 ng/mL [0.28 ± 0.14 μM], on 1.5 g of MBZ following chronic dosing of cimetidine at 400 mg three times a day for 30 days). The available evidence suggests that the increase in Cmax of MBZ, caused by concurrent use of cimetidine, would influence the therapeutic actions of MBZ, probably due to inhibition of hepatic first-pass cytochrome P450-mediated metabolism of the MBZ. However, what remains unclear is whether such an increase in Cmax would predispose a patient to adverse effects. Due to such an interaction, clinicians should closely monitor patients receiving this combination for signs of adverse effects of MBZ and choose alternative agents when possible. In addition, Corti et al. [56] investigated the effect of ritonavir (protease inhibitor of the CYP3A system) on the pharmacokinetics of MBZ under single-dose and steady-state conditions. They observed that the pharmacokinetic parameters of MBZ did not change in the short-term administration of ritonavir. In contrast, long-term administration of ritonavir resulted in significant changes in MBZ disposition, with a substantial decrease in AUC and Cmax. In addition, three polymorphs, A, B, and C, of MBZ exist, showing different solubility, toxicity, and therapeutic effects in anthelmintic applications [71,72,73]. Ren-Yuan Bai et al. [74] determined the pharmacokinetics of MBZ-A, B, and C and their concentrations in the brain and brain tumor distribution after oral MBZ administration on GL261 tumor-bearing mice. They suggest that MBZ-C is the most efficacious polymorph in brain tumor therapy with limited toxicity. Moreover, they demonstrated that the combination of Mebendazole-C with elacridar (P-glycoprotein inhibitor) could significantly improve the efficacy for future Phase I clinical trials of high-grade glioma and medulloblastoma. The high intra- and inter-patient variability may be essential to evaluate the response of MBZ as a potential anticancer therapy. Therefore, further research should elucidate the pharmacokinetic and dynamic profiles of upcoming formulations. To this end, monitoring the levels of MBZ and its metabolites should become standard practice in clinical treatments. Currently, preclinical evidence shows that chronic and high-dose schedules achieve plasma levels in the range required for clinical activity.
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4. Preclinical Evidence of Mebendazole in Brain Cancer—In Vitro and In Vivo
Anthelmintic drugs have gained attention in the last two decades as potential anticancer agents due to their interactivity with microtubules [23,24,75,76]. In particular, a wide range of cancer cells and animal models showed the possible effect of MBZ in inhibiting tumor cell growth through its ability to inhibit tubulin polymerization, leading to a lethal effect in rapidly dividing cells. The potential effect of MBZ in inhibiting cancer cell growth has been described in thyroid [77], gastrointestinal [78], breast [79], prostate [80], pancreatic [81], ovarian [82], colorectal [83,84], melanoma [85], head and neck [86], leukemia [87], and bile duct cancer [88]. Moreover, MBZ can modulate various cancer-associated pathways, including MAPK14, MEK-ERK, C-MYC, USP5/c-Maf, TNIK, XIAP, ELK/SRF, NFKB, MYC/MAX, E2F/DP1, TGF/SMAD, AP1, and STAT1/2, dependent on the specific cancer model (Figure 3) [23,24]. In addition, MBZ is relatively non-toxic for normal cells, whereas it increases its specific sensitivity in cancer cells. Regarding brain cancer, several studies (Table 3) demonstrated the antitumor properties of MBZ. In 2011, routine animal studies unexpectedly showed that fenbendazole (a benzimidazole anthelmintic used to treat pinworm infection) inhibited brain tumor engraftment. Based on this hint, Ren-Yuan Bai et al. [89] proved that MBZ offers an auspicious opportunity for the clinical application of GBM; their research with in vitro and in vivo experiments with benzimidazoles identified for the first time MBZ as the most promising drug for GBM therapy. In detail, they observed that MBZ induced apoptosis in GBM cell lines. The IC50 was 0.24 μM in the GL261 mouse glioma line and 0.1 μM in the 060919 human GBM. In vitro activity was also correlated with significant inhibition of tubulin polymerization at 0.1 µM. They also proved that MBZ significantly extended mean survival to 65 days, compared with 48 days for the control group in syngeneic and xenograft orthotopic mouse glioma models. Moreover, they showed that the combination of MBZ plus temozolomide (TMZ) extends survival further than TMZ alone in the GL261 mouse model. Other diverse mechanisms of MBZ in CNS tumors have been proposed. In particular, Ren LW et al. [90] have suggested that all benzimidazole compounds (flubendazole, Mebendazole, fenbendazole) could inhibit the proliferation and metastasis of GBM cells regulating cell migration, cell cycle, programmed cell death, and other biological processes. Furthermore, MBZ inhibited the migration and invasion of GBM cells and regulated the expression of crucial (epithelial-to-mesenchymal transition) EMT markers, showing that MBZ could inhibit the metastasis of GBM. It also dose-dependently arrested the cell cycle at the G2/M phase of GBM cells through the P53/P21/cyclin B1 pathway.
Figure 3
Anticancer effects and mechanisms of action of MBZ in different cancers. ↑ upregulation/activation; ↓ downregulation/inhibition.
Table 3
The most relevant molecular properties of MBZ in preclinical studies.Cancer Type | Cell Lines | Model Used | Molecular Targets | Efficacy | IC50 or Doses | Combination with Other Drugs | Ref |
|---|---|---|---|---|---|---|---|
Glioblastom | 060919 | In vitro | Inhibit tubulin polymerization | ↓ Cell viability | 0.11 μM | | [57] |
In vivo orthotopic mouse models | Apoptosis | ↑ Survival: 48 d CT: 65 d MBZ | | | |||
Glioma | GL261 | In vitro | | ↓ Cell viability | 0.24 µM | | |
In vivo orthotopic mouse models | | ↑ Survival: 30 d CT: 49 d MBZ ↑ Survival: 29 d CT: 41 d TMZ: 50 d MBZ + TMZ | | Temozolomide | |||
Glioma | GL261 | In vivo orthotopic mouse models | Inhibit tubulin polymerization | ↑ Survival (MBZ tablets from different suppliers) 29 days CT; 34 days in S2015; 50 days in S2017; 42 days in medley; 44 days in Janssen | 50 mg/kg | | [53] |
Medulloblastoma | GL261 D425 | In vivo orthotopic mouse models | | ↑ Survival with elacridar | | Elacridar (P-glycoprotein inhibitor) | |
Glioma | GL261 | In vitro | MBZ sensitizes GL261 cells to IR | ↓ Cell viability | 35 nM | IR (ionizing radiation) | [79] |
Glioblastoma | GBM14 glioma cells | | MBZ sensitizes GBM14 cells to IR | ↓ Cell viability | | IR (ionizing radiation) | |
Glioblastoma | U87-MG | In vitro | Inhibited migration and invasion | ↓ Cell viability | 0.21 μmol/L | | [58] |
U251-MG | | Arrest the cell cycle at the G2/M phase | ↓ Cell viability | 0.25 μmol/L | |||
Glioblastoma | GL261 | In vitro | Tubulin disruption | ↓ Cell viability | 160 nM | | [71] |
In vivo orthotopic mouse models | | ↓ Tumor growth ↑ Survival: CT 10 d; 50 MBZ 14 d; 100 MBZ 16.5 d No effect with vincristine | 50 mg/kg 100 mg/kg | ||||
Medulloblastoma | HUVEC | In vitro | ↓VEGFR2 kinase activity, CD31 | | 1–10 µM 4.3 µM | | [74] |
D425 | In vivo orthotopic mouse models | | ↓ Tumor growth ↑ Survival: CT 21 d; MBZ 48 d | 50 mg/kg | |||
| PTCH Mutant allograft MB | | ↑ Survival: CT 12 d; MBZ 30 d | 50 mg/kg | |||
| PTCH Mutant D477G allograft MB | | ↑ Survival: CT 12 d; MBZ 30 d | 50 mg/kg | |||
Medulloblastoma | Daoy | In vitro | Inhibits hedgehog Signaling pathway ↓ GLI1 | ↓ Cell viability and colony formation | 516 nmol/L | | [76] |
Daoy | In vivo orthotopic mouse models | ↓ GLI1 and PTCH2 | ↓ Tumor growth and hedgehog signaling ↑ Survival: CT 75 d; MBZ 113 d | 50 mg/kg | |||
Medulloblastoma | D425 SHH SHH- vismodegib-resistant | In vivo orthotopic mouse models | inhibition of VEGFR2 kinase activity | ↑ Survival: CT 21 d; MBZ 48 d | 50 mg/kg | | [77] |
Meningioma | KT21MG1 IOMMLE AC-1 SF4068 SF6717, SF1335 SF1335 + YAP | In vitro | Apoptosis induction, angiogenesis Inhibitor | ↓ Cell viability and colony formation | 0.39 μM 0.39 μM 0.342 μM 0.42 μM 0.372 μM 0.262 μM | | [78] |
KT21MG1 | In vivo orthotopic mouse models | ↓ Tumor, Ki67, CD31 ↑ Survival cleaved caspase 3 | ↑ Survival: CT 19 d; MBZ 30 d; radiation 33.5 D; MBZ + R 39 d | 50 mg/kg | Radiation | ||
Glioblastoma | U87 A172 U251 U138 C6 (murine) | In vitro | Low expression of FGFR3 and AKT2 was especially sensitive to T + V + M. | ↓ Cell viability | 500 nM | 50 µM TMZ 5 nM VBL | [80] |
| | ↓↓↓ Cell viability | T + V + M | | |||
Glioblastoma | U87 U87vIII T98G U251 | In vitro | MBZ inhibits ABL1, ERK2/MAPK1, and MAPK14/p38a in vitro, with particularly high potency against MAPK14/p38a | ↓↓↓Cell viability | 2.1 μM 288 nM | | [81] |
The greatest challenge facing any CNS-targeted drug discovery program is the effective penetration of the blood–brain barrier (BBB). The limited ability of cancer therapeutics to accumulate in the tumor is the major obstacle to improving brain cancer therapy [91]. It is estimated that only ~2% of small-molecule drugs can effectively cross the BBB. MBZ’s small size (295 Daltons) and lipophilic property favor brain penetration. Depending on crystallization conditions, MBZ can form three different polymorphs, A, B, and C, which display significant differences in bioavailability. Ren-Yuan Bai et al. [74] studied MBZ’s brain penetration and pharmacokinetics and the therapeutic differences of the three polymorphic forms (A, B, C) on intracranial murine GL261 glioma allografts and human medulloblastoma D425 xenografts. The authors determined that MBZ-A showed low blood and brain concentrations and no antitumoral efficacy; however, MBZ-B and MBZ-C are therapeutically favorable for brain tumor therapy. Polymorph C demonstrated the highest penetration capability in the brain tissue and tumor. Furthermore, combination therapy of elacridar (P-glycoprotein (P-gp) inhibitor) and MBZ-C increased the survival in GL261 syngeneic glioma and D425 xenograft medulloblastoma models. In addition, De Witt M et al. [92] examined the mechanisms of tumor cell-killing of MBZ and cell viability compared with those of vincristine on GL261 glioblastoma cells. They demonstrated that MBZ and vincristine have similar inhibitory effects on cell viability and microtubule polymerization. They also compared the therapeutic efficacies and toxicities of MBZ and vincristine in the GL261-C57BL/6 syngeneic orthotopic mouse model, showing that MBZ is more effective than vincristine and provides significant survival.
Recently, Dakshanamurthy and colleagues [93] applied a computational proteo-chemometric method to a library of FDA-approved compounds and identified MBZ as a potential inhibitor of vascular endothelial growth factor receptor 2 (VEGFR2), which suggested a possible role of MBZ in interfering with tumor angiogenesis. VEGF is an essential pathway in angiogenesis-related glioma pathology; in glioblastoma, VEGF is upregulated and therefore induces angiogenesis with consequent production of dysfunctional and immature vessels, associated with significant edema and destruction of the BBB [94]. For this reason, therapeutic inhibition of VEGFR-2 action has a significant impact on restricting cancer growth. Numerous studies confirm that MBZ can suppress the autophosphorylation of VEGFR-2 kinase by competing with ATP. In this context, Ren-Yuan Bai et al. [95] tested the drug on a panel of eight medulloblastoma cell lines, obtaining IC50 for cell growth of 0.13–1 µM. They found that MBZ also inhibited vascular endothelial growth factor receptor 2 (VEGFR2) autophosphorylation at 1–10µM, while it cultured HUVECs with an IC50 of 4.3 µM. They demonstrated that MBZ selectively exhibited tumor angiogenesis but not normal brain vasculatures in orthotopic medulloblastoma models and interfered with VEGFR2 activity in multiple models. MBZ was able to prolong the median survival from 21 days to 48 days in the D425 xenograft medulloblastoma. Analysis of tumor sections from treated mice revealed a significant reduction of tumor angiogenesis, while the microvessel density in the normal brain parenchyma was unaffected.
A growing body of evidence suggests that activated Hedgehog (Hh) signaling is preclinically responsive to MBZ. Some studies indicate that the aberrant activation of Hh signaling leads to tumor cell growth, proliferation, and invasion. Therefore, the development of therapy targeting Hh signaling is an attractive and validated therapeutic strategy for treating a wide range of cancers [96]. Larsen et al. [97] found that MBZ is a potent inhibitor of the Hh signaling cascade in human medulloblastoma cultured cell lines and decreased GLI1 expression with an IC50 of 516 nM. Cell proliferation was inhibited at a concentration as low as 100 nM, and viability was significantly impaired at one µM. In the same paper, the authors suggested that MBZ treatment prevented the primary cilium formation. This microtubule-based organelle functions as a signaling hub for Hh pathway activation, decreasing the expression of downstream Hh pathway effectors and the proliferation and survival of human medulloblastoma cells with constitutive Hh activation. The activity of MBZ in vivo was then assessed in a DAOY intracranial mouse xenograft. Treatment significantly increased survival from 75 days in the control group to 94 days in the group administered MBZ 25 mg/kg and 113 days in the 50 mg/kg group. Along this same line, the study by Bodhinayake et al. [98] highlighted that using orthotopic models of medulloblastoma (a genetic model of the sonic hedgehog (SHH)allograft, SHH vismodegib-resistant, and D425 implanted into cerebellum) the MBZ treatment induced markedly extended survival of 150%, 100%, and 129%, respectively.
MBZ can also sensitize cancer cells to conventional therapy, such as chemotherapeutics and radiation, enhancing their combined antitumor potential, confirming that MBZ may be useful as an adjuvant therapeutic combined with traditional chemotherapy. Skibinski et al. [99] demonstrated that MBZ administration alone or combined with radiation effectively extended survival in preclinical models of malignant meningioma for the first time. The human meningioma cell lines treated with MBZ alone had IC50 values in the 0.26–0.42 μM range, similar to those observed in medulloblastoma and glioblastoma. The authors also described a synergistic effect when combining MBZ therapy with radiation in an intracranial mouse model of malignant meningioma. This combination increased median survival and delayed tumor growth by inducing apoptosis via the caspase-3/7 pathway, decreasing cell proliferation and reducing levels of the angiogenesis marker CD31. Another study observed significant improvement in the radiosensitization of glioma cells (GL261 and GBM14) after MBZ treatment. Markowitz et al. [100] treated GL261 and GBM14 glioma cells with MBZ 3–9 h post-IR; this experiment demonstrated that MBZ could sensitize cancer cells to IR independently of the induction of mitotic arrest.
Several studies have shown that MBZ and TMZ coadministration led to a synergic response by glioblastoma cells, with an increase in mortality both in sensitive and resistant cells to TMZ. Glioblastoma patients, whose tumors expressed low FGFR3 and AKT2, responded poorly to TMZ. Kipper et al. [101] suggested that the triple combination of Temozolomide, Vinblastine, and Mebendazole (TVM) may be a considerable therapeutic alternative for the TMZ-tolerant gliomas that harbor low expression of FGFR3/AKT2. All cell lines showed an increase in Notch3 expression after TVM treatment.
In a recent study, Ariey-Bonnet et al. [102] confirmed that MBZ decreased the viability of glioblastoma cells in vitro. Moreover, for the first time, they found that the cytotoxic activity of the MBZ is significantly correlated with its ability to inhibit MAPK14 kinase activity in vitro, which relates to poor prognosis in GBM patients, increased tumor invasiveness, and aggressive phenotype [103,104]. This study suggests that targeting MAPK14 with MBZ is a promising strategy to enhance chemotherapy efficacy against GBM cancer.
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5. Clinical Evidence of Antitumoral Properties of Mebendazole
Clinical trials can help clarify the availability of MBZ as adjuvant and neoadjuvant therapeutics for cancer treatments. Six complete or recruiting clinical trials investigating the anticancer effect of MBZ, alone or in combination with other drugs, are currently registered at clinicaltrials.gov and are listed in Table 4.Table 4
Clinical trials of MBZ in cancer patients.Title | Phase | Conditions | Intervention/ Treatment | Institution | Study/Results | Status |
|---|---|---|---|---|---|---|
Study of Mebendazole in Newly Diagnosed High-Grade Glioma Patients Receiving Temozolomide NCT N. NCT01729260 | Phase 1 | Newly diagnosed high-grade glioma (WHO Grade III or IV) | Mebendazole: 500 mg chewable tablets with meals three times every day on a 28-day cycle | The Johns Hopkins Hospital Baltimore, Maryland, United States, 21287 | No results Available | Study Start Date: 2012 Study Completion Date: 2021 Completed |
Phase I Study of Mebendazole Therapy for Recurrent/Progressive Pediatric Brain Tumors NCT N. NCT02644291 | Phase 1 | Medulloblastoma Astrocytoma, Grade III Glioblastoma Anaplastic Astrocytoma Brain Stem Neoplasms, Malignant Oligodendroblastoma Anaplastic Oligodendroglioma Malignant Glioma | Mebendazole: 500 mg tablets, three divided doses with meals | Johns Hopkins All Children’s Hospital, Saint Petersburg, Florida, United States, 33701 Johns Hopkins University School of Medicine Baltimore, Maryland, United States, 21231 | No results Available | Study Start Date: 2016 Study Completion Date: June 2022 Completed |
A Phase I Study of Mebendazole for the Treatment of Pediatric Gliomas Phase I: determine if MBZ is tolerated when used in combination with the current three-drug regimen. Phase II: evaluate the efficacy of this regimen. NCT N. NCT01837862 | Phase 1 Phase 2 | Pilomyxoid Astrocytoma Pilocytic Astrocytoma Glioma, Astrocytic Optic Nerve Glioma Pleomorphic Xanthoastrocytoma Glioblastoma Multforme Anaplastic Astrocytoma Gliosarcoma Diffuse Intrinsic Pontine Glioma (DIPG) Low-grade Glioma Brainstem Glioma | Mebendazole: 50 mg/kg/day, 100 mg/kg/day, or 200 mg/kg/day p.o. and b.d. for 70 weeks for Low-grade Glioma (in combination with vincristine, carboplatin, and temozolomide) and 48 weeks for High-grade Glioma/Pontine Glioma (in combination with bevacizumab and irinotecan) | Cohen Children’s Medical Center of New York Recruiting New Hyde Park, New York, United States, 11040 | No results Available | Study Start Date: 2013 Estimated Primary Completion Date: April 2024 Estimated Study Completion Date: April 2025 Recruiting |
A Clinical Safety and Efficacy Study of Mebendazole on GI Cancer or Cancer of Unknown Origin NCT N. NCT03628079 | Phase 1 Phase 2 | Cancer of the Gastrointestinal Tract Cancer of Unknown Origin | ReposMBZ Capsules 50 mg, 100 mg, 200 mg Pharmacokinetics analysis | Dept of Oncology, University Hospital, Uppsala, Sweden, 75185 | No Results Available | Study Start Date: 2018 Study Completion Date: 2019 Terminated |
Clinical Study Evaluating Mebendazole as Adjuvant Therapy in Patients with Colorectal Cancer NCT N. NCT03925662 | Phase 3 | Colorectal Cancer | Folfox with Avastin only Folfox with Avastin with Mebendazole | Sherief Abd-Elsalam, Tanta University | No Results Available | Study Start Date 2019 Study Completion Date: 2028 Recruiting |
Study of the Safety, Tolerability, and Efficacy of Metabolic Combination Treatments on Cancer (METRICS) NCT N. NCT02201381 | Phase 3 | Cancer Overall Survival | Oral Mebendazole 100 mg p.o. and uid, for the study duration Oral atorvastatin up to 80 mg uid Oral metformin up to 1000 mg uid Oral doxycycline 100 mg uid | Care Oncology Clinic London, United Kingdom, W1G 9PP | | Study Start Date: May 2022 Study Completion Date: 2027 Withdrawn (Prospective recruitment not possible) |
Mebendazole Monotherapy and Long-Term Disease Control I Metastatic Adrenocortical carcinoma. 2011 | Clinical Study | 48-year-old man with adrenocortical carcinoma | Mebendazole: 100 mg twice daily for 19 months | University of Michigan | Metastases regressed, and the disease remained stable Well tolerated, and the associated adverse effects are minor | |
Drug repositioning from bench to bedside: Tumor remission by the anthelmintic drug Mebendazole in refractory metastatic colon cancer. 2013 | Clinical Study | 74-year-old man with metastatic colon cancer | Repositioning drugs for use in advanced colon cancer Mebendazole: 100 mg twice a day b.d. for six weeks | Uppsala University, Sweden | Complete remission of the metastases in the lungs and lymph nodes and a good partial remission in the liver No adverse effects from the treatment | |
In 2011, Dobrosotskaya et al. [105] published the first clinical case report on MBZ as a cancer treatment in a human patient. He described a 35-year-old woman affected by metastatic adrenocortical carcinoma (right adrenal gland and multiple liver metastases) who showed tumor progression after repeated surgeries, radiation, and chemotherapy treatments. After administering MBZ 100 mg orally twice daily for 19 months, they observed prolonged tumor response, as the liver metastases initially regressed and remained stable for 19 months. In contrast to the morbidity observed with other treatments, MBZ was well tolerated and greatly improved the patient’s quality of life. This study also demonstrated reduced angiogenesis in the tumor treated with MBZ, which may result from diminished tumor growth. However, 24 months after the beginning of oral MBZ, a scan showed disease progression, and everolimus was added to the MBZ but without additional benefit in disease control.
Nyger and Larsson [106] reported that MBZ induced remission of lung and lymph node metastases and a partial remission of liver metastases in a patient with refractory colon cancer. The authors considered the case of a 74-year-old patient affected by metastatic colon cancer in progression at multiple sites (lungs, abdominal lymph nodes, and liver), following two lines of chemotherapy (with capecitabine, oxaliplatin, and bevacizumab, and then capecitabine and irinotecan). They had no other standard treatment options, so they started a treatment based on an oral dose of MBZ of 100 mg twice daily. After six weeks of monotherapy of MBZ treatment, the patient showed near-complete remission of the metastases in the lungs and lymph nodes and a good partial remission in the liver after the computerized tomography evaluation. The liver enzymes AST (serum aspartate aminotransferase) and ALT were found to be elevated from five to seven times, so MBZ was temporarily stopped and reintroduced at half dose. Liver enzymes slowly decreased, and the patient reported no adverse effects from MBZ; moreover, the disease remained stable. After ceasing treatment for about three months, the patient developed brain metastases treated with radiotherapy, followed by evidence of disease in the lymph nodes.
A phase I clinical study started in 2013 and was completed in 2021 at John Hopkins Hospital; the goal was to determine the maximum tolerated dose (MTD) of MBZ in combination with TMZ after surgery and the standard radiation and TMZ treatment in patients with newly diagnosed malignant gliomas. The outcome supports that oral MBZ can be used safely in high doses in combination with TMZ (http://clinicaltrials.gov/ct2/show/NCT01729260, accessed on 24 October 2022). In this study, 24 patients (18 glioblastomas and six anaplastic gliomas) received MBZ in combination with adjuvant TMZ after completing concurrent radiation plus TMZ. The primary aim was to determine the maximum tolerated dose of MBZ with TMZ and whether this combined regimen could slow tumor progression. Dose-escalation levels were 25, 50, 100, and 200 mg/kg/day of oral Mebendazole. A total of 15 patients were enrolled at the highest dose studied with 200 mg/kg/day. This dosing is based on a previous study of 37 children treated for hydatid disease with 100–200 mg/kg/day of MBZ without serious side effects [51]. Although the 200 mg/kg/day dose level encountered late toxicity, it is not considered MTD, as none of the AEs (those requiring hospitalization or resulting in death) were attributable to MBZ. However, there are considerations as to why levels less than 200 mg/kg/day might be preferable. The most common side effect was the reversible elevation of liver enzymes. In conclusion, the authors affirm that further clinical evaluation of MBZ in patients with high-grade gliomas is warranted to evaluate better this regimen’s potential benefit.
Currently, a clinical trial phase I/II investigates the anticancer effects of MBZ in combination with standard-of-care agents for recurrent pediatric brain cancers that are not responding to standard therapies (http://clinicaltrials.gov/ct2/show/NCT02644291). The patients for this experimental trial were aged 1 to 21 years with a diagnosis of medulloblastoma, or high-grade glioma (pediatric glioblastoma, anaplastic astrocytoma, and diffuse intrinsic pontine glioma), where the tumor has resumed growth or continued to grow despite standard medical therapy. The study patients will be divided into two groups (low-grade glioma and high-grade/pontine glioma) to determine the maximally tolerated dose of MBZ.
Patients on the low-grade arm will receive treatment with seven 10-week cycles of carboplatin, vincristine, temozolomide, and MBZ. In comparison, patients on the high-grade glioma/pontine glioma arm will receive treatment with twelve 28-day cycles of bevacizumab, irinotecan, and MBZ. In addition, to determine the safety and efficacy of these combinations, MBZ (50 mg/kg/day, 100 mg/kg/day, or 200 mg/kg/day) will be given orally twice daily throughout treatment (70 weeks for low-grade glioma patients, 48 weeks for high-grade glioma/pontine glioma patients).
The second clinical trial is a phase I and II pilot study of MBZ in combination with vincristine, carboplatin, and temozolomide for pediatric patients with low-grade gliomas at Cohen Children’s Medical Centre of New York (http://clinicaltrials.gov/ct2/show/NCT01837862). Patients with low-grade gliomas will receive a regimen of MBZ in combination with vincristine, carboplatin, and temozolomide. In contrast, patients with high-grade gliomas and diffuse intrinsic pontine gliomas will receive a regimen of MBZ in combination with bevacizumab and irinotecan. MBZ doses will be escalated from the initial dose level of 50 mg/kg/day to a second dose of 100 mg/kg/day and a third of 200 mg/kg/day, each divided twice daily. A standard “3 + 3” design will be used for determining dose escalation. The primary objective of the Phase I part of the trial is to determine if MBZ is tolerated when used in combination with the current three-drug regimen. After determining the maximally tolerated dose for each group, the study will continue to evaluate the efficacy of this regimen. The study will be corrected for the maximally tolerated dose for each group; it will be used in the remainder of the study. Phase II aims to include the time of progression-free status in patients and their overall survival. Currently, the study is recruiting participants, and the estimated study completion date is April 2025.
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6. Conclusions
The repurposing of drugs not initially developed for cancer treatment is an ongoing research activity in many countries worldwide. The recognition that drug repositioning is an excellent opportunity to expedite anticancer therapies to the clinic in oncology represents a solution to the exorbitant cost of discovering new drugs and has the substantial advantages of cheaper, faster, and safer preclinical and clinical validation protocols. The consolidated knowledge of preclinical and clinical data on pharmacokinetics, side effects, and regimens may accelerate approval. Moreover, repurposing such compounds in oncology may also elude the detrimental impacts of conventional cancer chemotherapeutics, which may produce adverse effects that negatively affect patients’ quality of life [107,108,109,110,111].MBZ is attractive as an anticancer therapy because it can cross the blood–brain barrier permeability with a low-toxicity profile. Toxicity is particularly low in children compared to other microtubule inhibitors such as vincristine and paclitaxel. Despite its poor oral bioavailability, available preclinical studies demonstrated that MBZ reaches plasmatic and tissue concentrations sufficient to activate antineoplastic activity in vitro. Additional clinical investigations will clarify this issue.
Many research groups have investigated MBZ as a tubulin polymerization inhibitor and strongly recommend its clinical use as a replacement for vincristine for treating brain tumors [92]. In addition, many studies demonstrated its capability in reducing angiogenesis, arresting the cell cycle, and targeting several key oncogenic signal transduction pathways. Therefore, MBZ’s ability to hit multiple targets can improve the efficacy of anticancer therapy and help overcome acquired resistance to conventional chemotherapy.
One of the most relevant MBZ properties is that it exerts cancer cell-specific selectivity inducing minimal cytotoxicity in normal cells while inducing high cytotoxicity in tumor cells, showing a favorable therapeutic index for in vivo applications [89,100,101]. Finally, MBZ can inhibit endothelial cells and tumor angiogenesis by inhibiting VEGF receptor 2. Many studies demonstrated the anti-angiogenic effect of MBZ in medulloblastoma preclinical mouse models and its encouraging impact on overall survival [95,98].
Although MBZ has several advantages, researchers must address some challenges before its successful use for clinical purposes. Potential limitations for successfully repositioning MBZ in oncology relate to its physicochemical properties, route of administration, and poor bioavailability with significant individual pharmacokinetic variability [51,55,70].
Furthermore, achieving sufficient efficacy of repurposed MBZ for cancer therapy may require treatment at higher doses and for more extended periods than the conventional prescription, resulting in unexpected side effects. Researchers are investigating diverse formulation strategies and fatty meals to improve oral absorption and reach therapeutic blood levels to increase drug solubility and dissolution rate. For this reason, further studies should focus on the poor aqueous solubility and systemic availability of MBZ because its improvement may enhance anti-tumorigenesis and prolong overall survival.
Although MBZ has already been under phase II/III clinical trials for cancer therapy, there are still too few experimental studies in the clinical setting for translating the preclinical study knowledge to the patient context. However, the few available experimental studies confirm the sufficient safety and efficacy of MBZ in tumor patients. MBZ has prolonged patient survival and improved patient outcomes in some clinical trials, supporting its application’s feasibility in a clinical setting. A few case reports demonstrated that patients with metastatic late-stage cancers responded to MBZ, showing reduced metastasis and stabilized disease. Ongoing clinical trials will clarify the potential use of MBZ in brain cancer treatments.
In summary, the available data indicate that the repositioning of MBZ in treating brain cancer is promising and may represent a low-cost and fast route for expanding approved drugs for better brain cancer therapy. In the future, MBZ could be an alternative drug for treating TMZ-sensitive GBM patients alone or in combination with TMZ. Further studies are needed to confirm the potential use of MBZ in patients with TMZ-resistant GBM.
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Funding Statement
This work was supported by Fondazione per l’Oncologia Pediatrica (FOP).Go to:
Author Contributions
Conceptualization, A.R.; writing—original draft preparation, A.R., P.N. and D.M.; writing—review and editing, A.R., G.A., S.M. and D.M. All authors have read and agreed to the published version of the manuscript.Go to:
Institutional Review Board Statement
Not applicable.Go to:
Informed Consent Statement
Not applicable.Go to:
Data Availability Statement
Not applicable.Go to:
Conflicts of Interest
The authors declare no conflict of interest.Go to:
Footnotes
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References
1. Xia C., Dong X., Li H., Cao M., Sun D., He S., Yang F., Yan X., Zhang S., Li N., et al. Cancer statistics in China and United States, 2022: Profiles, trends, and determinants. Chin. Med. J. 2022;9:584–590. doi: 10.1097/CM9.0000000000002108. [PMC free article] [PubMed] [CrossRef] [Google Scholar]2. World Health Organization (WHO) Global Health Estimates 2020: Deaths by Cause, Age, Sex, by Country and by Region, 2000–2019. [(accessed on 11 December 2020)]; Available online: https://www.who.int/data/gho/data/t...-health-estimates/ghe-leading-causes-of-death
3. Sertkaya A., Wong H.H., Jessup A., Beleche T. Key cost drivers of pharmaceutical clinical trials in the United States. Clin. Trials. 2016;13:117–126. doi: 10.1177/1740774515625964.[PubMed] [CrossRef] [Google Scholar]
4. Yeu Y., Yoon Y., Park S. Protein localization vector propagation: A method for improving the accuracy of drug repositioning. Mol. Biosyst. 2015;11:2096–2102. doi: 10.1039/C5MB00306G.[PubMed] [CrossRef] [Google Scholar]
5. Pammolli F., Magazzini L., Riccaboni M. The productivity crisis in pharmaceutical R&D. Nat. Rev. Drug Discov. 2011;10:428–438. [PubMed] [Google Scholar]
6. Scannell J.W., Blanckley A., Boldon H., Warrington B. Diagnosing the decline in pharmaceutical R&D efficiency. Nat. Rev. Drug. Discov. 2012;11:191–200. [PubMed] [Google Scholar]
7. Collier R. Rapidly rising clinical trial costs worry researchers. CMAJ. 2009;180:277–278. doi: 10.1503/cmaj.082041. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
8. Pushpakom S., Iorio F., Eyers P.A., Escott K.J., Hopper S., Wells A., Doig A., Guilliams T., Latimer J., McNamee C., et al. Drug repurposing: Progress, challenges and recommendations. Nat. Rev. Drug Discov. 2019;18:41–58. doi: 10.1038/nrd.2018.168. [PubMed] [CrossRef] [Google Scholar]
9. Ashburn T.T., Thor K.B. Drug repositioning: Identifying and developing new uses for existing drugs. Nat. Rev. Drug Discov. 2004;3:673–683. doi: 10.1038/nrd1468. [PubMed] [CrossRef] [Google Scholar]
10. Wurth R., Thellung S., Bajetto A., Mazzanti M., Florio T., Barbieri F. Drug-repositioning opportunities for cancer therapy: Novel molecular targets for known compounds. Drug Discov. Today. 2016;21:190–199. doi: 10.1016/j.drudis.2015.09.017. [PubMed] [CrossRef] [Google Scholar]
11. Schcolnik-Cabrera A., Juárez-López D., Duenas-Gonzalez A. Perspectives on Drug Repurposing. Curr. Med. Chem. 2021;28:2085–2099. doi: 10.2174/0929867327666200831141337. [PubMed] [CrossRef] [Google Scholar]
12. Smith R.B. Repositioned drugs: Integrating intellectual property and regulatory strategies. Drug Discov. Today Ther. Strateg. 2011;8:131–137. doi: 10.1016/j.ddstr.2011.06.008. [CrossRef] [Google Scholar]
13. Breckenridge A., Jacob R. Overcoming the legal and regulatory barriers to drug repurposing. Nat. Rev. Drug Discov. 2018;18:1–2. doi: 10.1038/nrd.2018.92. [PubMed] [CrossRef] [Google Scholar]
14. Nosengo N. Can you teach old drugs new tricks? Nature. 2016;534:314–316. doi: 10.1038/534314a. [PubMed] [CrossRef] [Google Scholar]
15. Bertolini F., Sukhatme V.P., Bouche G. Drug repurposing in oncology--patient and health systems opportunities. Nat. Rev. Clin. Oncol. 2015;12:732–742. doi: 10.1038/nrclinonc.2015.169.[PubMed] [CrossRef] [Google Scholar]
16. Munj S.A., Taz T.A., Arslanturk S., Heath E.I. Biomarker-driven drug repurposing on biologically similar cancers with DNA-repair deficiencies. Front. Genet. 2022;13:1015531. doi: 10.3389/fgene.2022.1015531. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
17. Kato S., Moulder S.L., Ueno N.T., Wheler J.J., Meric-Bernstam F., Kurzrock R., Janku F. Challenges and perspective of drug repurposing strategies in early phase clinical trials. Oncoscience. 2015;2:576–580. doi: 10.18632/oncoscience.173. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
18. Gupta S.C., Sung B., Prasad S., Webb L.J., Aggarwal B.B. Cancer drug discovery by repurposing: Teaching new tricks to old dogs. Trends Pharmacol. Sci. 2013;34:508–517. doi: 10.1016/j.tips.2013.06.005. [PubMed] [CrossRef] [Google Scholar]
19. Bloom B.E. The trials and tribulations of repurposing metformin and other generic drugs for tuberculosis. Pharm. Pat. Anal. 2016;5:101–105. doi: 10.4155/ppa.15.45. [PubMed] [CrossRef] [Google Scholar]
20. Bloom B.E. Creating new economic incentives for repurposing generic drugs for unsolved diseases using social finance. ASSAY Drug Dev. Technol. 2015;13:606–611. doi: 10.1089/adt.2015.29015.beddrrr. [PubMed] [CrossRef] [Google Scholar]
21. Verbaanderd C., Rooman I., Meheus L., Huys I. On-label or off-label? Overcoming regulatory and financial barriers to bring repurposed medicines to cancer patients. Front. Pharmacol. 2020;10:1664. doi: 10.3389/fphar.2019.01664. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
22. Chai J.Y., Jung B.K., Hong S.J. Albendazole and Mebendazole as Antiparasitic and Anticancer Agents: An Update. Korean J. Parasitol. 2021;59:189–225. doi: 10.3347/kjp.2021.59.3.189. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
23. Guerini A.E., Triggiani L., Maddalo M., Bonù M.L., Frassine F., Baiguini A., Alghisi A., Tomasini D., Borghetti P., Pasinetti N., et al. Mebendazole as a candidate for drug repurposing in oncology: An extensive review of current literature. Cancers. 2019;11:1284. doi: 10.3390/cancers11091284. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
24. Son D.S., Lee E.S., Adunyah S.E. The antitumor potentials of benzimidazole anthelmintics as repurposing drugs. Immun. Netw. 2020;20:29. doi: 10.4110/in.2020.20.e29. [PMC free article][PubMed] [CrossRef] [Google Scholar]
25. Bray F., Ferlay J., Soerjomataram I., Siegel R.L., Torre L.A., Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 2018;68:394–424. doi: 10.3322/caac.21492. [PubMed] [CrossRef] [Google Scholar]
26. Louis D.N., Ohgaki H., Wiestler O.D., Cavenee W.K. World Health Organization Classification of Tumours of the Central Nervous System. 4th ed. International Agency for Research on Cancer; Lyon, France: 2016. [Google Scholar]
27. Louis D.N., Perry A., Wesseling P., Brat D.J., Cree I.A., Figarella-Branger D., Hawkins C., Ng H.K., Pfister S.M., Reifenberger G., et al. The 2021 WHO Classification of Tumors of the Central Nervous System: A summary. Neuro-Oncol. 2021;2:1231–1251. doi: 10.1093/neuonc/noab106.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
28. Hartmann C., Hentschel B., Wick W., Capper D., Felsberg J., Simon M., Westphal M., Schackert G., Meyermann R., Pietsch T., et al. Patients with IDH1 wild-type anaplastic astrocytomas exhibit worse prognosis than IDH1-mutated glioblastomas, and IDH1 mutation status accounts for the unfavorable prognostic effect of higher age: Implications for classification of gliomas. Acta Neuropathol. 2010;120:707–718. doi: 10.1007/s00401-010-0781-z. [PubMed] [CrossRef] [Google Scholar]
29. Giannini C., Burger P.C., Berkey B.A., Cairncross J.G., Jenkins R.B., Mehta M., Curran W.J., Aldape K. Anaplastic oligodendroglial tumors: Refining the correlation among histopathology, 1p 19q deletion and clinical outcome in Intergroup Radiation Therapy Oncology Group Trial 9402. Brain Pathol. 2008;18:360–369. doi: 10.1111/j.1750-3639.2008.00129.x. [PMC free article][PubMed] [CrossRef] [Google Scholar]
30. Perez-Larraya J.G., Ducray F., Chinot O., Catry-Thomas I., Taillandier L., Guillamo J.-S., Campello C., Monjour A., Cartalat-Carel S., Barrie M., et al. Temozolomide in elderly patients with newly diagnosed glioblastoma and poor performance status: An ANOCEF phase II trial. J. Clin. Oncol. 2011;29:3050–3055. doi: 10.1200/JCO.2011.34.8086. [PubMed] [CrossRef] [Google Scholar]
31. Louis D.N., Perry A., Burger P., Ellison D.W., Reifenberger G., von Deimling A., Aldape K., Brat D., Collins V.P., Eberhart C., et al. International Society of Neuropathology-Haarlem consensus guidelines for nervous system tumor classification and grading. Brain Pathol. 2014;24:429–435. doi: 10.1111/bpa.12171. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
32. Wang H., Xu T., Jiang Y., Xu H., Yan Y., Fu D., Chen J. The challenges and the promise of molecular targeted therapy in malignant gliomas. Neoplasia. 2015;17:239–255. doi: 10.1016/j.neo.2015.02.002. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
33. Hatanpa K.J., Burma S., Zhao D., Habib A.A. Epidermal growth factor receptor in glioma: Signal transduction, neuropathology, imaging, and radioresistance. Neoplasia. 2010;12:675–684. doi: 10.1593/neo.10688. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
34. Nazarenko I., Hede S.M., He X., Hedren A., Thompson J., Lindstrom M.S., Nister M. PDGF and PDGF receptors in glioma. Upsala J. Med Sci. 2012;117:99–112. doi: 10.3109/03009734.2012.665097. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
35. Tilak M., Holborn J., New L.A., Lalonde J., Jones N. Receptor Tyrosine Kinase Signaling and Targeting in Glioblastoma Multiforme. Int. J. Mol. Sci. 2021;12:1831. doi: 10.3390/ijms22041831. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
36. Yip S., Iafrate A.J., Louis D.N. Molecular diagnostic testing in malignant gliomas: A practical update on predictive markers. J. Neuropathol. Exp. Neurol. 2008;67:1–15. doi: 10.1097/nen.0b013e31815f65fb. [PubMed] [CrossRef] [Google Scholar]
37. Sugawa N., Ekstrand A.J., James C.D., Collins V.P. Identical splicing of aberrant epidermal growth factor receptor transcripts from amplified rearranged genes in human glioblastomas. Proc. Natl. Acad. Sci. USA. 1990;87:8602–8606. doi: 10.1073/pnas.87.21.8602. [PMC free article][PubMed] [CrossRef] [Google Scholar]
38. Mao H., LeBrun D., Yang J., Zhu V.F., Li M. Deregulated signaling pathways in glioblastoma multiforme: Molecular mechanisms and therapeutic targets. Cancer Investig. 2012;30:48–56. doi: 10.3109/07357907.2011.630050. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
39. Duffy M.J., Synnott N.C., Crown J. Mutant p53 as a target for cancer treatment. Eur. J. Cancer. 2017;83:258–265. doi: 10.1016/j.ejca.2017.06.023. [PubMed] [CrossRef] [Google Scholar]
40. Karsy M., Neil J.A., Guan J., Mahan M.A., Colman H., Jensen R.L. A practical review of prognostic correlations of molecular biomarkers in glioblastoma. Neurosurg. Focus. 2015;38:E4. doi: 10.3171/2015.1.FOCUS14755. [PubMed] [CrossRef] [Google Scholar]
41. Huse J.T., Holland E.C. Targeting brain cancer: Advances in the molecular pathology of malignant glioma and medulloblastoma. Nat. Rev. Cancer. 2010;10:19–331. doi: 10.1038/nrc2818. [PubMed] [CrossRef] [Google Scholar]
42. Brennan C.W., Verhaak R.G.W., McKenna A., Campos B., Noushmehr H., Salama S.R., Zheng S., Chakravarty D., Sanborn J.Z., Berman S.H., et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155:462–477. doi: 10.1016/j.cell.2013.09.034. [PMC free article][PubMed] [CrossRef] [Google Scholar]
43. Ohgaki H., Kleihues P. Genetic pathways to primary and secondary glioblastoma. Am. J. Pathol. 2007;170:1445–1453. doi: 10.2353/ajpath.2007.070011. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
44. Haupt Y., Maya R., Kazaz A., Oren M. Mdm2 promotes the rapid degradation of p53. Nature. 1997;387:296–299. doi: 10.1038/387296a0. [PubMed] [CrossRef] [Google Scholar]
45. Dick F.A., Rubin S.M. Molecular mechanisms underlying RB protein function. Nat. Rev. Mol. Cell Biol. 2013;14:297–306. doi: 10.1038/nrm3567. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
46. Brugmans J.P., Theinpont D.C., Wijngaarden I.V., Vanparijs O.F., Schuermans V.L., Lauwers H.L. Mebendazole in enterobiasis. Radiochemical and pilot clinical study in 1278 subjects. JAMA. 1971;217:313–316. doi: 10.1001/jama.1971.03190030039008. [PubMed] [CrossRef] [Google Scholar]
47. Dawson M., Braithwaite P.A., Roberts M.A., Watson T.R. The pharmacokinetics and bioavailability of a tracer dose of (3H)-mebendazole in man. Br. J. Clin. Pharmacol. 1985;19:79–86. doi: 10.1111/j.1365-2125.1985.tb02616.x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
48. Witassek F., Burkhardt B., Eckhardt J., Bircher J. Chemotherapy of alveolar echinococcosis; comparison of plasma Mebendazole concentrations in animals and man. Eur. J. Clin. Pharmacol. 1981;20:427–433. doi: 10.1007/BF00542095. [PubMed] [CrossRef] [Google Scholar]
49. Dollery C.T. Therapeutic Drugs. 2nd ed. Volume 2. Churchill Livingstone; Edinburgh, UK: 1999. Mebendazole; pp. M12–M15. [Google Scholar]
50. EMEA-European Medicines Evaluation Agency . Mebendazole Summary Report by CVMP.EMEA; London, UK: 1999. EMEA/MRL/625/99-Final. [Google Scholar]
51. Edwards G., Brechenridge A.M. Clinical pharmacokinetics of anthelmintic drugs. Clin. Pharmacokinet. 1988;15:67–93. doi: 10.2165/00003088-198815020-00001. [PubMed] [CrossRef] [Google Scholar]
52. Pawluk S.A., Roles C.A., Wilby K.J., Ensom M.H. A review of pharmacokinetic drug-drug interactions with the anthelmintic medications albendazole and mebendazole. Clin. Pharmacokinet. 2015;54:371–383. doi: 10.1007/s40262-015-0243-9. [PubMed] [CrossRef] [Google Scholar]
53. Dayan A.D. Albendazole, mebendazole and praziquantel. Review of non-clinical toxicity and pharmacokinetics. Acta Trop. 2003;86:141–159. doi: 10.1016/S0001-706X(03)00031-7.[PubMed] [CrossRef] [Google Scholar]
54. Hamilton G., Rath B. Repurposing of anthelminthics as anticancer drugs. Oncomedicine. 2017;2:142–149. doi: 10.7150/oncm.20563. [CrossRef] [Google Scholar]
55. Braithwaite P.A., Roberts M.S., Allan R.J., Watson T.R. Clinical pharmacokinetics of high dose mebendazole in patients treated for cystic hydatid disease. Eur. J. Clin. Pharmacol. 1982;22:161–169. doi: 10.1007/BF00542462. [PubMed] [CrossRef] [Google Scholar]
56. Corti N., Heck A., Rentsch K., Zingg W., Jetter A., Stieger B., Pauli-Magnus C. Effect of ritonavir on the pharmacokinetics of the benzimidazoles albendazole and Mebendazole: An interaction study in healthy volunteers. Eur. J. Clin. Pharmacol. 2009;65:999–1006. doi: 10.1007/s00228-009-0683-y. [PubMed] [CrossRef] [Google Scholar]
57. Bekhti A., Pirotte J. Cimetidine increases serum mebendazole concentrations. Implications for treatment of hepatic hydatid cysts. Br. J. Clin. Pharmacol. 1987;24:390–392. [PMC free article][PubMed] [Google Scholar]
58. Luder P.J., Siffert B., Witassek F., Meister F., Bircher J. Treatment of hydatid disease with high oral doses of Mebendazole. Eur. J. Clin. Pharmacol. 1986;31:443–448. doi: 10.1007/BF00613522. [PubMed] [CrossRef] [Google Scholar]
59. Liu C.-S., Zhang H.-B., Jiang B., Yao J.-M., Tao Y., Xue J., Wen A.-D. Enhanced bioavailability and cysticidal effect of three mebendazole-oil preparations in mice infected with secondary cysts of Echinococcus granulosus. Parasitol. Res. 2012;111:1205–1211. doi: 10.1007/s00436-012-2954-2. [PubMed] [CrossRef] [Google Scholar]
60. Pantziarka P., Bouche G., Meheus L., Sukhatme V., Sukhatme V.P. Repurposing Drugs in Oncology (ReDO)-mebendazole as an anti-cancer agent. Ecancermedicalscience. 2014;8:443. doi: 10.3332/ecancer.2014.485. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
61. Reuter S., Jensen B., Buttenschoen K., Kratzer W., Kern P. Benzimidazoles in the treatment of alveolar echinococcosis: A comparative study and review of theliterature. J. Antimicrob. Chemother. 2000;46:451–456. doi: 10.1093/jac/46.3.451. [PubMed] [CrossRef] [Google Scholar]
62. Yangco B.G., Klein T.W., Deresinski S.C., Vickery A.C., Craig C.P. Flubendazole andmebendazole in the treatment of trichuriasis and other helminthiases. Clin. Ther. 1981;4:285–290. [PubMed] [Google Scholar]
63. Tolomeo M., Colomba C., Meli M., Cascio A. Hepatotoxicity caused by Mebendazole in a patient with Gilbert’s syndrome. J. Clin. Pharm. Ther. 2019;44:985–987. doi: 10.1111/jcpt.13033.[PubMed] [CrossRef] [Google Scholar]
64. Karra N., Cohen R., Berlin M., Dinavitser N., Koren G., Berkovitch M. Safety of mebendazole use during lactation: A case series report. Drugs R D. 2016;16:251–254. doi: 10.1007/s40268-016-0142-z. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
65. De Silva N., Guyatt H., Bundy D. Anthelmintics. A comparative review of their clinical pharmacology. Drugs. 1997;53:769–788. doi: 10.2165/00003495-199753050-00004. [PubMed] [CrossRef] [Google Scholar]
66. Göçmen A., Toppare M.F., Kiper N. Treatment of hydatid disease in childhood with Mebendazole. Eur. Respir. J. 1993;6:253–257. doi: 10.1183/09031936.93.06020253. [PubMed] [CrossRef] [Google Scholar]
67. Chen K.T., Twu S.J., Chang H.J., Lin R.S. Outbreak of Stevens-Johnson syndrome/toxic epidermal necrolysis associated with mebendazole and metronidazole use among Filipino laborers in Taiwan. Am. J. Public Health. 2003;93:489–492. doi: 10.2105/AJPH.93.3.489. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
68. Alavi S.E., Ebrahimi Shahmabadi H. Anthelmintics for drug repurposing: Opportunities and challenges. Saudi Pharm. J. 2021;29:434–445. doi: 10.1016/j.jsps.2021.04.004. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
69. De la Torre-Iglesias P.M., García-Rodriguez J.J., Torrado G., Torrado S., Torrado-Santiago S., Bolás-Fernández F. Enhanced bioavailability and anthelmintic efficacy of Mebendazole in redispersible microparticles with low-substituted hydroxypropylcellulose. Drug Des. Dev. Ther. 2014;18:1467–1479. [PMC free article] [PubMed] [Google Scholar]
70. Münst G.J., Karlaganis G., Bircher J. Plasma concentrations of Mebendazole during treatment of echinococcosis. Eur. J. Clin. Pharmacol. 1980;17:375–378. doi: 10.1007/BF00558451.[PubMed] [CrossRef] [Google Scholar]
71. Rodriguez-Caabeiro F., Criado-Fornelio A., Jimenez-Gonzalez A., Guzman L., Igual A., Perez A., Pujol M. Experimental chemotherapy and toxicity in mice of three Mebendazole polymorphic forms. Chemotherapy. 1987;33:266–271. doi: 10.1159/000238506. [PubMed] [CrossRef] [Google Scholar]
72. Swanepoel E., Liebenberg W., de Villiers M.M. Quality evaluation of generic drugs by dissolution test: Changing the USP dissolution medium to distinguish between active and non-active Mebendazole polymorphs. Eur. J. Pharm. Biopharm. 2003;55:345–349. doi: 10.1016/S0939-6411(03)00004-3. [PubMed] [CrossRef] [Google Scholar]
73. Charoenlarp P., Waikagul J., Muennoo C., Srinophakun S., Kitayaporn D. Efficacy of single-dose Mebendazole, polymorphic forms A and C, in the treatment of hookworm and Trichuris infections. Southeast Asian J. Trop. Med. Public Health. 1993;24:712–716. [PubMed] [Google Scholar]
74. Bai R.Y., Staedtke V., Wanjiku T., Rudek M.A., Joshi A., Gallia G.L., Riggins G.J. Brain Penetration and Efficacy of Different Mebendazole Polymorphs in a Mouse Brain Tumor Model. Clin. Cancer Res. 2015;21:3462–3470. doi: 10.1158/1078-0432.CCR-14-2681. [PMC free article][PubMed] [CrossRef] [Google Scholar]
75. Armando R.G., Mengual Gómez D.L., Gomez D.E. New drugs are not enough drug repositioning in oncology: An update. Int. J. Oncol. 2020;56:651–684. doi: 10.3892/ijo.2020.4966. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
76. Nath J., Paul R., Ghosh S.K., Paul J., Singha B., Debnath N. Drug repurposing andrelabeling for cancer therapy: Emerging benzimidazole antihelminthics with potent anticancer effects. Life Sci. 2020;1:118189. doi: 10.1016/j.lfs.2020.118189. [PubMed] [CrossRef] [Google Scholar]
77. Williamson T., Mendes T.B., Joe N., Cerutti J.M., Riggins G.J. Mebendazole inhibits tumor growth and prevents lung metastasis in models of advanced thyroid cancer. Endocr. Relat. Cancer. 2020;27:123–136. doi: 10.1530/ERC-19-0341. [PubMed] [CrossRef] [Google Scholar]
78. Mansoori S., Fryknäs M., Alvfors C., Loskog A., Larsson R., Nygren P. A phase 2a clinical study on the safety and efficacy of individualized dosed Mebendazole in patients with advanced gastrointestinal cancer. Sci. Rep. 2021;26:8981. doi: 10.1038/s41598-021-88433-y. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
79. Choi H.S., Ko Y.S., Jin H., Kang K.M., Ha I.B., Jeong H., Song H.N., Kim H.J., Jeong B.K. Anticancer Effect of Benzimidazole Derivatives, Especially Mebendazole, on Triple-Negative Breast Cancer (TNBC) and Radiotherapy-Resistant TNBC In Vivo and In Vitro. Molecules. 2021;24:5118. doi: 10.3390/molecules26175118. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
80. Rushworth L.K., Hewit K., Munnings-Tomes S., Somani S., James D., Shanks E., Dufès C., Straube A., Patel R., Leung H.Y. Repurposing screen identifies Mebendazole as a clinical candidate to synergise with docetaxel for prostate cancer treatment. Br. J. Cancer. 2020;122:517–527. doi: 10.1038/s41416-019-0681-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
81. Williamson T., de Abreu M.C., Trembath D.G., Brayton C., Kang B., Mendes T.B., de Assumpção P.P., Cerutti J.M., Riggins G.J. Mebendazole disrupts stromal desmoplasia and tumorigenesis in two models of pancreatic cancer. Oncotarget. 2021;6:1326–1338. doi: 10.18632/oncotarget.28014. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
82. Elayapillai S., Ramraj S., Benbrook D.M., Bieniasz M., Wang L., Pathuri G., Isingizwe Z.R., Kennedy A.L., Zhao Y.D., Lightfoot S., et al. Potential and mechanism of Mebendazole for treatment and maintenance of ovarian cancer. Gynecol. Oncol. 2021;160:302–311. doi: 10.1016/j.ygyno.2020.10.010. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
83. Hegazy S.K., El-Azab G.A., Zakaria F., Mostafa M.F., El-Ghoneimy R.A. Mebendazole; from an antiparasitic drug to a promising candidate for drug repurposing in colorectal cancer. Life Sci. 2022;15:120536. doi: 10.1016/j.lfs.2022.120536. [PubMed] [CrossRef] [Google Scholar]
84. Petersen J.S.S.M., Baird S.K. Treatment of breast and colon cancer cell lines with anti-helmintic benzimidazoles mebendazole or albendazole results in selective apoptotic cell death. J. Cancer Res. Clin. Oncol. 2021;147:2945–2953. doi: 10.1007/s00432-021-03698-0. [PubMed] [CrossRef] [Google Scholar]
85. Simbulan-Rosenthal C.M., Dakshanamurthy S., Gaur A., Chen Y.S., Fang H.B., Abdussamad M., Zhou H., Zapas J., Calvert V., Petricoin E.F., et al. The repurposed anthelmintic Mebendazole in combination with trametinib suppresses refractory NRASQ61K melanoma. Oncotarget. 2017;21:12576–12595. doi: 10.18632/oncotarget.14990. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
86. Zhang F., Li Y., Zhang H., Huang E., Gao L., Luo W., Wei Q., Fan J., Song D., Liao J., et al. Anthelmintic mebendazole enhances cisplatin’s effect on suppressing cell proliferation and promotes differentiation of head and neck squamous cell carcinoma (HNSCC) Oncotarget. 2017;21:12968–12982. doi: 10.18632/oncotarget.14673. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
87. Freisleben F., Modemann F., Muschhammer J., Stamm H., Brauneck F., Krispien A., Bokemeyer C., Kirschner K.N., Wellbrock J., Fiedler W. Mebendazole Mediates Proteasomal Degradation of GLI Transcription Factors in Acute Myeloid Leukemia. Int. J. Mol. Sci. 2021;22:10670. doi: 10.3390/ijms221910670. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
88. Sawanyawisuth K., Williamson T., Wongkham S., Riggins G.J. Effect of the antiparasitic drug Menbendaziole on cholangiocarcinoma growth. Southeast Asian J. Trop. Med. Public Health. 2014;45:1264–1270. [PubMed] [Google Scholar]
89. Bai R.Y., Staedtke V., Aprhys C.M., Gallia G.L., Riggins G.J. Antiparasitic Mebendazole shows survival benefit in 2 preclinical models of glioblastoma multiforme. Neuro-Oncol. 2011;13:974–982. doi: 10.1093/neuonc/nor077. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
90. Ren L.W., Li W., Zheng X.J., Liu J.Y., Yang Y.H., Li S., Zhang S., Fu W.Q., Xiao B., Wang J.H., et al. Author Correction: Benzimidazoles induce concurrent apoptosis and pyroptosis of human glioblastoma cells via arresting cell cycle. Acta Pharmacol. Sin. 2022;15:194–208. doi: 10.1038/s41401-021-00752-y. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
91. Pardridge W.M. The blood-brain barrier: Bottleneck in brain drug development. NeuroRx. 2005;2:3–14. doi: 10.1602/neurorx.2.1.3. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
92. De Witt M., Gamble A., Hanson D., Markowitz D., Powell C., Al Dimassi S., Atlas M., Boockvar J., Ruggieri R., Symons M. Repurposing mebendazole as a replacement for vincristine for the treatment of brain tumors. Mol. Med. 2017;23:50–56. doi: 10.2119/molmed.2017.00011.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
93. Dakshanamurthy S., Issa N.T., Assefnia S., Seshasayee A., Peters O.J., Madhavan S., Uren A., Brown M.L., Byers S.W. Predicting new indications for approved drugs using a proteochemometric method. J. Med. Chem. 2012;55:6832–6848. doi: 10.1021/jm300576q. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
94. Ahir B.K., Engelhard H.H., Lakka S.S. Tumor Development and Angiogenesis in Adult Brain Tumor: Glioblastoma. Mol. Neurobiol. 2020;57:2461–2478. doi: 10.1007/s12035-020-01892-8.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
95. Bai R.Y., Staedtke V., Rudin C.M., Bunz F., Riggins G.J. Effective treatment of diverse medulloblastoma models with Mebendazole and its impact on tumor angiogenesis. Neuro-Oncol. 2015;17:545–554. doi: 10.1093/neuonc/nou234. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
96. Skoda A.M., Simovic D., Karin V., Kardum V., Vranic S., Serman L. The role of the Hedgehog signaling pathway in cancer: A comprehensive review. Bosn. J. Basic Med. Sci. 2018;20:8–20. doi: 10.17305/bjbms.2018.2756. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
97. Larsen A.R., Bai R.-Y., Chung J.H., Borodovsky A., Rudin C.M., Riggins G.J., Bunz F. Repurposing the antihelmintic Mebendazole as a hedgehog inhibitor. Mol. Cancer Ther. 2015;14:3–13. doi: 10.1158/1535-7163.MCT-14-0755-T. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
98. Bodhinayake I., Symons M., Boockvar J.A. Repurposing mebendazole for the treatment of medulloblastoma. Neurosurgery. 2015;76:N15–N16. doi: 10.1227/01.neu.0000460594.93803.cb.[PubMed] [CrossRef] [Google Scholar]
99. Skibinski C.G., Williamson T., Riggins G.J. Mebendazole and radiation in combination increase survival through anticancer mechanisms in an intracranial rodent model of malignant meningioma. J. Neurooncol. 2018;140:529–538. doi: 10.1007/s11060-018-03009-7. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
100. Markowitz D., Ha G., Ruggieri R., Symons M. Microtubule-targeting agents can sensitize cancer cells to ionizing radiation by an interphase-based mechanism. Onco Targets Ther. 2017;24:5633–5642. doi: 10.2147/OTT.S143096. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
101. Kipper F.C., Silva A.O., Marc A.L., Confortin G., Junqueira A.V., Neto E.P., Lenz G. Vinblastine and antihelmintic Mebendazole potentiate temozolomide in resistant gliomas. Investig. New Drugs. 2018;36:323–331. doi: 10.1007/s10637-017-0503-7. [PubMed] [CrossRef] [Google Scholar]
102. Ariey-Bonnet J., Carrasco K., Le Grand M., Hoffer L., Betzi S., Feracci M., Tsvetkov P., Devred F., Collette Y., Morelli X., et al. In silico molecular target prediction unveils mebendazole as a potent MAPK14 inhibitor. Mol. Oncol. 2020;14:3083–3099. doi: 10.1002/1878-0261.12810.[PMC free article] [PubMed] [CrossRef] [Google Scholar]
103. Demuth T., Reavie L.B., Rennert J.L., Nakada M., Nakada S., Hoelzinger D.B., Beaudry C.E., Henrichs A.N., Anderson E.M., Berens M.E. MAP-ing glioma invasion: Mitogen-activated protein kinase kinase 3 and p38 drive glioma invasion and progression and predict patient survival. Mol. Cancer Ther. 2007;6:1212–1222. doi: 10.1158/1535-7163.MCT-06-0711.[PubMed] [CrossRef] [Google Scholar]
104. Ben-Hamo R., Efroni S. Gene expression and network-based analysis reveals a novel role for has-miR-9 and drug control over the p38 network in glioblastoma multiforme progression. Genome Med. 2011;3:77. doi: 10.1186/gm293. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
105. Dobrosotskaya I.Y., Hammer G.D., Schteingart D.E., Maturen K.E., Worden F.P. Mebendazole monotherapy and long-term disease control in metastatic adrenocortical carcinoma. Endocr. Pract. 2011;17:59–62. doi: 10.4158/EP10390.CR. [PubMed] [CrossRef] [Google Scholar]
106. Nygren P., Larsson R. Drug repositioning from bench to bedside: Tumour remission by the antihelmintic drug mebendazole in refractory metastatic colon cancer. Acta Oncol. 2014;53:427–428. doi: 10.3109/0284186X.2013.844359. [PubMed] [CrossRef] [Google Scholar]
107. Trisciuzzi M.T.S., Riccardi R., Piccardi M., Iarossi G., Buzzonetti L., Dickmann A., Colosimo C., Ruggiero A., Di Rocco C., Falsini B. A fast visual evoked potential method for functional assessment and follow-up of childhood optic gliomas. Clin. Neurophysiol. 2004;115:217–226. doi: 10.1016/S1388-2457(03)00282-7. [PubMed] [CrossRef] [Google Scholar]
108. Ruggiero A., Rizzo D., Trombatore G., Maurizi P., Riccardi R. The ability of mannitol to decrease cisplatin-induced nephrotoxicity in children: Real or not? Cancer Chemother. Pharmacol. 2016;77:19–26. doi: 10.1007/s00280-015-2913-6. [PubMed] [CrossRef] [Google Scholar]
109. Walker M., Brown J., Brown K., Gregor A., Whittle I., Grant R. Practical problems with the collection and interpretation of serial quality of life assessments in patients with malignant glioma. J. Neurooncol. 2003;63:179–186. doi: 10.1023/A:1023900802254. [PubMed] [CrossRef] [Google Scholar]
110. Ruggiero A., Rizzo D., Catalano M., Coccia P., Triarico S., Attiná G. Acute chemotherapy-induced nausea and vomiting in children with cancer: Still waiting for a common consensus on treatment. J. Int. Med. Res. 2018;46:2149–2156. doi: 10.1177/0300060518765324. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
111. Henriksson R., Asklund T., Poulsen H.S. Impact of therapy on quality of life, neurocognitive function and their correlates in glioblastoma multiforme: A review. J. Neurooncol. 2011;104:639–646. doi: 10.1007/s11060-011-0565-x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]
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Mebendazole in recurrent glioblastoma: Results of a phase 2 randomized study.
Authors: Nandini Sharrel Menon, Abhishek Chatterjee, Raees Tonse, Amit Choudhary, Abhishek Mahajan, AmeyaPuranik, Epari Sridhar, … SHOW ALL …, and Vijay Maruti PatilAUTHORS INFO & AFFILIATIONSPublication: Journal of Clinical Oncology
Volume 40, Number 16_suppl
https://doi.org/10.1200/JCO.2022.40.16_suppl.2029
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Volume 40, Number 16_suppl
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Abstract
2029Background: Recurrent glioblastoma (GBM) has dismal outcomes and limited treatment options. Mebendazole (MBZ) is an anti-helminthic drug with in-vivo and in-vitro activity against glioma cell lines and has been demonstrated to be well tolerated in combination with lomustine (CCNU) and temozolomide (TMZ). In this phase 2 study, we sought to determine whether the addition of MBZ to CCNU or TMZ would improve overall survival (OS) in recurrent GBM. Methods: Adult patients with ECOG PS 0-3, with recurrent glioblastoma who were not eligible for re-radiation, were randomized 1:1 between CCNU-MBZ (n = 44) and TMZ-MBZ (n = 44). The primary endpoint was OS at 9 months, selected to reflect the BELOB trial. A 9-month OS of 55% or more in any arm was hypothesized to warrant further evaluation and a value below 35% was too low to warrant further investigation. Results: At 17.4 months, 68 events for OS analysis had occurred. The 9-month overall survival was 36.6% (95%CI 22.3-51) and 45% (95%CI 29.6-59.2) in the TMZ-MBZ and CCNU-MBZ arms respectively. ECOG PS was the only independent prognostic factor impacting OS (HR-0.478 95%CI 0.268-0.851; P = 0.012). Twenty-three patients (28.6%) enrolled had an ECOG PS 2-3 with inferior outcomes (median OS-5.67, HR-2.092 95%CI 1.175-3.731). Analysis restricted to ECOG PS 0-1 (n = 65) patients revealed a 9-month OS of 39.6% (95% CI 22.4-56.3) and 57.9% (95% CI 38.7-73) in TMZ-MBZ and CCNU-MBZ arms respectively. Grade 3-5 adverse events were seen in 8 (18.6%; n = 43) and 4 (9.5%; n = 42) patients in the TMZ-MBZ and CCNU-MBZ arms respectively. Conclusions: The addition of MBZ to TMZ or CCNU failed to achieve the pre-set benchmark of 55% 9-month OS. This was probably due to 28.6% of patients with poor PS of 2-3. In patients with ECOG PS 0-1, CCNU-MBZ had a 9 month OS of 57.9% and needs to be evaluated further. Clinical trial information: CTRI/2018/01/011542.
Phase I Study of Mebendazole Therapy for Recurrent/Progressive Pediatric Brain Tumors
ClinicalTrials.gov ID NCT02644291Sponsor Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Information provided by Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins (Responsible Party)
Last Update Posted 2022-06-23
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Study Overview
Brief SummaryThis is a safety (Phase 1) trial using mebendazole for recurrent pediatric brain cancers that include medulloblastoma and high grade glioma, that are no longing responding to standard therapies. The drug mebendazole is an oral drug in a chewable 500 mg orange flavored tablet. It is already approved to treat parasitic infections. The purpose of this study is to determine the safety and side effects for increasing doses of mebendazole, followed by the treatment of an additional 12 patients at the best tolerated dose.
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Detailed Description
The primary objectives of this study are to determine the maximum tolerated dose (MTD) of oral mebendazole in patients with recurrent/progressive pediatric brain tumors and to confirm the tolerance of the MTD of oral mebendazole by assessing tolerance in a dose expansion cohort. Secondary Objectives of the study include to determine the safety, tolerability and toxicity of mebendazole in this patient population, determine the plasma levels of mebendazole in this patient population and Determine progression-free and overall survival of mebendazole in an extended cohort of patients with treatment refractory pediatric brain cancer.
Mebendazole (MBZ) is a drug developed to treat human helminthic disease and is FDA-approved for the treatment of roundworm, common hookworm, American hookworm, pinworm and whipworm. MBZ use is well documented and frequently used in tropical countries at higher doses for the rarer parasitic infections of the brain.
We have shown efficacy in preclinical laboratory models of high grade glioma and medulloblastoma. Mebendazole therapy demonstrated safety in a phase I clinical trial for adults with high grade gliomas such as glioblastoma. This trial completed the maximum approved enrollment of 24 patients treated with mebendazole, with high doses consistent with dosing published for severe parasitic infections.
Laboratory studies indicate that mebendazole enters the brain and brain tumors at concentrations that may be effective for a combination of anti-cancer mechanisms. In animal models of brain cancer evidence suggest that mebendazole can prevent cell proliferation by interfering with tubulin formation, and it may prevent the formation of new abnormal blood vessels that feed tumor growth.
The patients for this experimental trial are those between the age of 1 to 21 with the diagnosis of medulloblastoma, or high grade glioma, where the tumor has resumed growth or continued to grow despite standard medical therapy. High grade glioma are those with a World Health Organization (WHO) grade of III or IV. It includes diagnosis of pediatric glioblastoma, anaplastic astrocytoma, and diffuse intrinsic pontine glioma. Patients who have failed other forms of experimental therapy may also be eligible for this trial.
Mebendazole is provided at no cost in the form of a chewable 500 mg tablets, recommended to be taken three times daily with meals or food. The pill can be chewed after meals, or ground up to be mixed with food or drink. It has a mild orange flavor that is similar in consistency to an antacid tablet.
Although side effects are rare and the vast majority are reversible, they include stomach upset, decreased blood count, and elevated liver enzymes due to inflammation.
The main additional procedure beyond taking this drug, is that patients are requested to consent to up to three additional blood draws to check the blood (serum) levels of the drug to ensure it is being absorbed at sufficient doses.
Patients can continue to receive the drug as long as in the attending physicians opinion the therapy is not causing any severe side effects, and there is no clear indication that the patient will not respond to mebendazole therapy. Patients can withdraw from this trial at any time for any reason, and may be eligible for other experimental therapies afterwards.
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Official Title
Phase I Study of Mebendazole Therapy for Recurrent/Progressive Pediatric Brain Tumors
Conditions
Medulloblastoma
Astrocytoma, Grade III
Glioblastoma
Anaplastic Astrocytoma
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Intervention / Treatment
- Drug: Mebendazole
- J15211
- IRB00072999 ( Other Identifier ) (OTHER: JHMIRB)
2016-05
Primary Completion (Actual)
2022-06-09
Study Completion (Actual)
2022-06-09
Enrollment (Actual)
16
Study Type
Interventional
Phase
Phase 1
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I generally consider it a very bad idea to write publicly about sensitive medical information.
My recommendation is engage your doctor(s), not a gun forum, for advice, but don't treat them as all knowing and get a second or third opinion if necessary.
My recommendation is engage your doctor(s), not a gun forum, for advice, but don't treat them as all knowing and get a second or third opinion if necessary.
@UKDslayer
Well Done!!!!
And I definitely hope that the information given in this thread, helps the OP.
et al
Well Done!!!!
And I definitely hope that the information given in this thread, helps the OP.
et al
1. Maybe you don't understand the mistrust the general public now has for many of its physicians?
2. Maybe the OP has been referred to a reputable brain tumor center, but has to wait for 30 days due to certain increases in said brain tumors from an unspeakable "medical intervention" applied to the populace?
Man, Wildo… I hope this is a false positive or benign …
You is great people here! Not deserving!
We are ALL pulling for ya, buddy!!!
Sirhr
You is great people here! Not deserving!
We are ALL pulling for ya, buddy!!!
Sirhr
I also qm a Pure blood for lol the good it did me
Wasn't talking about you. The OP is as well. The problem is a larger number of people now have this problem then did five years ago, and along with "population changes'' receiving care, the system to manage these patients is overwhelmed.
I've been blessed to know this community over the years - almost two decades now, and I would trust many people here over total strangers at least for opinions or direction, not to mention support.
Hello to all who have read or reacted to this thread. Frankly I don’t even know if this will get to anywhere.. so here goes..
It is here with great sadness, I am informing the people of this page in group, that my husband, Eric Kroon has passed away. His brain tumor ruptured on Friday. He spoke of people on this site highly, and he thought of you all to be friends of his. He would have wanted me to update you. And it may be down the road I may reach out to this page, to help me with some questions about some of his possessions that I will no longer need. Thank you, Lani Kroon
It is here with great sadness, I am informing the people of this page in group, that my husband, Eric Kroon has passed away. His brain tumor ruptured on Friday. He spoke of people on this site highly, and he thought of you all to be friends of his. He would have wanted me to update you. And it may be down the road I may reach out to this page, to help me with some questions about some of his possessions that I will no longer need. Thank you, Lani Kroon
Oh my.
our deepest condolences for your loss.
Is there anything you need?
We will keep you and your family our prayers.
our deepest condolences for your loss.
Is there anything you need?
We will keep you and your family our prayers.
I think I speak for most here when I say our sincere condolences.
Oh Lani, So sorry to hear that. Condolences and prayers for you.Hello to all who have read or reacted to this thread. Frankly I don’t even know if this will get to anywhere.. so here goes..
It is here with great sadness, I am informing the people of this page in group, that my husband, Eric Kroon has passed away. His brain tumor ruptured on Friday. He spoke of people on this site highly, and he thought of you all to be friends of his. He would have wanted me to update you. And it may be down the road I may reach out to this page, to help me with some questions about some of his possessions that I will no longer need. Thank you, Lani Kroon
Deepest condolences Lani, from all of us here on the Hide. He will be missed.Hello to all who have read or reacted to this thread. Frankly I don’t even know if this will get to anywhere.. so here goes..
It is here with great sadness, I am informing the people of this page in group, that my husband, Eric Kroon has passed away. His brain tumor ruptured on Friday. He spoke of people on this site highly, and he thought of you all to be friends of his. He would have wanted me to update you. And it may be down the road I may reach out to this page, to help me with some questions about some of his possessions that I will no longer need. Thank you, Lani Kroon
- Nov 3, 2010
- 9,697
- 20,385
Fuck I checked in to see if he was doing ok. God damn it so much, this is horrible news. Deepest condolences.
a member since '03
another good one gone too soon.
condolences for your loss Lani.
another good one gone too soon.
condolences for your loss Lani.
I am so sorry for your loss Lani. My deepest condolences. I got on to this thread to check how he was doing and didn’t expect to see this. Prayers for you and your family. I kept him in my prayers every night.
Words are never quite enough.
You and your family will remain in my prayers.
You and your family will remain in my prayers.
@7.62willdo Lani. Sorry for your loss. Been keeping you and him in prayers since the 6th. You will see him on the other side.
Definitely not the update I was hoping to hear.
So sorry, Lani.
So sorry, Lani.
Lani... yes, you are in the right place. And it is with greatest sadness that we mourn a great man and a great member of our community.Hello to all who have read or reacted to this thread. Frankly I don’t even know if this will get to anywhere.. so here goes..
It is here with great sadness, I am informing the people of this page in group, that my husband, Eric Kroon has passed away. His brain tumor ruptured on Friday. He spoke of people on this site highly, and he thought of you all to be friends of his. He would have wanted me to update you. And it may be down the road I may reach out to this page, to help me with some questions about some of his possessions that I will no longer need. Thank you, Lani Kroon
Thank you for letting us know. And words cannot begin to make up for your loss.
In greatest respect...
Sirhr and a huge part of our community!
Sorry to hear about that Lani. Just a few months I was talking to Eric and realized my kid is dating one of your relatives. Eric said you were related to Cotton from Neah Bay.
Ms Lani we are very sad to hear about Eric losing this battle.It is here with great sadness, I am informing the people of this page in group, that my husband, Eric Kroon has passed away. His brain tumor ruptured on Friday. He spoke of people on this site highly, and he thought of you all to be friends of his. He would have wanted me to update you. And it may be down the road I may reach out to this page, to help me with some questions about some of his possessions that I will no longer need. Thank you, Lani Kroon
Our hearts go out to you as well as all the rest of Eric's family and friends. I will be praying for your strength, peace and healing. Thank you for taking the time to find this forum and let us know this terrible news.
Be well.
So sorry to hear this, but he was spared the long drawn out suffering and he's no longer hurting. I know that's little comfort to you rt now but later on it may be of more help. I lost my son 5 months ago and the knowledge that he is now with his Lord and Savior has been the most comforting thing my wife and I have had to fall back on. You are in my prayers.Hello to all who have read or reacted to this thread. Frankly I don’t even know if this will get to anywhere.. so here goes..
It is here with great sadness, I am informing the people of this page in group, that my husband, Eric Kroon has passed away. His brain tumor ruptured on Friday. He spoke of people on this site highly, and he thought of you all to be friends of his. He would have wanted me to update you. And it may be down the road I may reach out to this page, to help me with some questions about some of his possessions that I will no longer need. Thank you, Lani Kroon
This sucks. My deepest condolences, we will be praying for you family and friends.
