Repurposed Drugs

Repurposing of drugs, or the use of prescription medicines for a disease or condition which have received official approval for a different disease or condition, is an attractive option for difficult-to-treat cancers. Such drugs have already been through safety and pharmacokinetic trials in humans, are already on the market, and may legally be prescribed for cancer treatment at the doctor’s discretion. In my opinion, repurposed drugs represent some of the most promising and readily available options for glioma therapy.

July 25, 2015
To join a discussion about the drugs described on this page, and about multi-agent approaches for brain tumors,visit the new blog community, called our brain tumor cocktails and stories.

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Page index
  • 13-cis retinoic acid (Accutane)
  • Alfacalcidol
  • Celecoxib (Celebrex)
  • Chloroquine
  • Cimetidine (Tagamet)
  • Dichloroacetate (DCA)
  • Levetiracetam (Keppra)
  • Inducing hypothyroxinemia with methimazole and thyroid hormone T3 (triiodothryonine)
  • Sodium phenylbutyrate (Buphenyl)
  • Valganciclovir (Valcyte)
  • Celecoxib (Celebrex) plus PDE5 inhibitor (sildenafil, tadalafil)
  • Disulfiram (Antabuse)
  • Fluoxetine (Prozac)
  • Metformin (Glucophage)
  • Minocycline
  • Mebendazole (Vermox)
  • Prazosin

Human evidence

The following drugs have shown some evidence of efficacy in human gliomas or other cancer types.

13-cis retinoic acid (isotretinoin, Accutane)

13-cis retinoic acid (trade name Accutane) is a vitamin A analog, commonly prescribed for the treatment of severe acne. Since the 1990s, it has also been tested and prescribed for glioma treatment in a number of clinical trials. The drug has activity as a cell differentiating agent, which does not kill the cell, but rather matures the cell and causes it to slow or cease proliferation. As a single agent in recurrent anaplastic glioma therapy, 13-cis retinoic acid has a moderate activity, with 40% of anaplastic astrocytoma patients showing a response or stable disease upon treatment with the drug [1]. A retrospective study of 85 recurrent glioblastoma patients treated with Accutane at MD Anderson, published in 2004, showed that 12% of patients responded with tumour shrinkage, and another 34% had disease stabilization with this treatment [45]. The benefits of 13-cis-retinoic acid have not been observed in combination with temozolomide. In a phase 2 trial for anaplastic gliomas, 13-cis retinoic acid was added to temozolomide therapy, but did not show significant improvement over treatment with TMZ alone [2]. Another phase 2 trial tested 13-cis-retinoic acid in combination with radiochemotherapy with TMZ, and again no significant benefit was observed [46].

September 20, 2014
Results of a randomized phase II trial for newly diagnosed glioblastoma were published online yesterday in Neuro-Oncology journal [62]. The trial tested the 7-day on, 7-day off TMZ schedule either alone or in doublet, triplet, or quadruplet combinations with isotretinoin (Accutane), celecoxib (Celebrex), and thalidomide. The only statistically significant effect was that adding isotretinoin to temozolomide therapy had a negative impact on survival. My general impression in reviewing the literature is that isotretinoin (Accutane) is best used as a maintenance therapy (after but not during chemotherapy). None of the other drugs or combinations showed any statistically significant effect, though due to the small number of patients in each group, large differences would have been required for statistical significance. The best median progression-free survival was in the temozolomide plus celecoxib group, with a median PFS of 13.4 months versus 10.5 months in the TMZ alone group. This was not statistically significant (hazard ratio=1, p=0.97), though perhaps with larger cohorts significance could be achieved. Overall, this trial shows that neither Accutane or thalidomide are beneficial combined with TMZ, though adding Celebrex may be. No MGMT analysis was available, which may confound interpretation of these results.
Abstract

Benefit versus risk: In a large retrospective study [45] performed on 85 recurrent GBM patients treated with Accutane monotherapy, 12% of patients had a response and 34% had disease stabilization with this therapy, for a total of 46% with apparent benefit. Only about 20% had durable benefit out to six months (PFS-6 was 19%). On the toxicity side, “grade 3 or 4 toxicity developed in 14 patients (16.5%), including 5 patients with hypercholesterolemia or hypertriglyceridemia (1 died of acute pancreatitis), 2 with rash, 7 with neutropenia or leukopenia, and 1 with retinal changes.” Additionally there have been reports of mood alterations, such as increased depression, in some patients taking Accutane for its approved indication (acne). In vitro, some GBM cell lines are inhibited by treatment with retinoids, while others are actually stimulated. For this reason, biomarkers are needed to help predict which patients will respond to retinoid treatment such as 13-cis retinoic acid, and all-trans retinoic acid.

Alfacalcidol (1-alpha-hydroxycholecalciferol, One-Alpha)

Alfacalcidol is a synthetic vitamin D analog, available in Canada as the prescription drug One-Alpha (Leo Pharma), and is used to treat ailments related to vitamin D deficiency such as hypocalcemia, hypophosphatemia and rickets. While dietary or supplemental vitamin D3 may boost serum calcidiol (25-hydroxycholecalciferol), blood levels of the active vitamin D metabolite, calcitriol (1,25-dihydroxycholecalciferol) are tightly regulated. And while vitamin D3 requires two metabolic conversions, by the liver and kidney, alfacalcidol is directly converted to active calcitriol by the liver.

In glioma therapy, the likely mechanism of action is reported to be cell differentiation, as with retinoids. Only one small trial, with 10 glioblastoma patients and 1 anaplastic astrocytoma patient, has been carried out, with results published in 2001 [5]. The results from this trial were impressive, and it is puzzling why this trial was never followed up by a larger phase II trial. Patients in this trial were divided into two arms, one arm underwent CCNU and teniposide chemotherapy followed by alfacalcidol, and the other arm was given alfacalcidol during fotemustine chemotherapy. The median survival reported for patients in this trial was 21 months, well exceeding the 8-12 months median survival for glioblastomas from this era. Even more impressive, three patients (two glioblastomas and the one anaplastic astrocytoma) after several years on alfacalcidol alone, had a complete tumour disappearance and long-term survival of at least four and five years (for the two responding glioblastoma patients) and at least seven years for the responding anaplastic astrocytoma patient. These three were still alive without tumour progression at the time of study publication. As complete responses are rare in malignant gliomas, the fact that three of eleven patients (27%) had such a response is impressive.

Though three patients in this trial appeared to benefit from the alfacalcidol supplementation, there is some in vitro evidence showing that physiologic concentrations of calcitriol (hormonally active vitamin D3) may in some cases lead to increased cell proliferation in glioblastoma cell cultures. This mixed evidence is discussed on the Supplements page.

Benefit versus risk: In the small pilot trial described above [5], 3 of 11 (27%) patients had an objective response to treatment with alfacalcidol either during or following chemotherapy. In these 3, complete response (tumour disappearance) was observed after several years of alfacalcidol treatment. “There was no significant hypercalcemia, at the dose proposed, so that no interruption of the drug was necessary. No toxicity was observed on hepatic enzymes during the years of treatment”.

Celecoxib (Celebrex)

Celecoxib is a non-steroidal anti-inflammatory drug, commonly prescribed for inflammatory conditions such as arthritis. It selectively inhibits the COX-2 enzyme and limits the production of immunosuppressive, pro-invasive prostaglandins such as PGE2. In addition, it can inhibit cerebral edema. As discussed on the Immunotherapy page, celecoxib potentiated dendritic cell vaccination in a rat model of glioma.

In one published case study, a patient (who was himself a radiation oncologist) wishing to avoid the use of glucocorticoids (such as dexamethasone) to prevent brain edema during treatment, was instead given celecoxib, which successfully controlled edema for the duration of conventional treatment (radiation and temozolomide) [22].

Several studies have quantified the expression of the COX-2 enzyme in glioma tissue samples of various grades. In one of these studies [25], all 25 glioblastoma samples had COX-2 expression in over 25% of the cells. Likewise, all 10 anaplastic astrocytoma samples had COX-2 expression in over 25% of cells. 9 out of 15 (60%) of low grade gliomas had over 25% of cells expressing COX-2. A different study [26] had similar findings, with 97% (of 31) glioblastoma samples, 88% (of 25) anaplastic astrocytoma samples, and 60% (of 10) low grade astrocytoma samples having over 25% of cells positive for COX-2. This study also showed a poorer prognosis associated with high COX-2 expression. COX-2 was found predominantly expressed around areas of necrosis in the tumour, a feature most associated with glioblastomas.

Chloroquine

Chloroquine was introduced in the United States in the 1940s to treat malaria. Hydroxychloroquine has also been used for years as an anti-malarial. There have been two small clinical trials and one retrospective study published by Mexican researchers, detailing the benefits of adding chloroquine to standard therapy with radiation and intravenous BCNU (carmustine) for newly diagnosed glioblastomas [20]. In these small trials, chloroquine appeared to significantly increase the median survival compared to the control group. There are several potential modes of action by which chloroquine exerts its benefits in glioma therapy. It may act as an anti-mutagenic agent, or as an anti-autophagy agent in situations where autophagy is used by cancer cells as a survival mechanism.

Unfortunately, these results were not replicated in a recent phase I/II clinical trial of hydroxychloroquine added to standard radiation therapy and temozolomide in newly diagnosed glioblastoma [21]. At the maximum tolerated dose of 600 mg per day, autophagy inhibition was not consistently achieved, and there was no significant improvement in overall survival, with a median survival time of 15.6 months. There was no analysis of MGMT status included in this study.

A study [49] published in 2013 by researchers at Maastricht University in the Netherlands showed that EGFR-overexpressing U373 glioblastoma tumours, subcutaneously implanted in mice, were especially sensitive to intraperitoneal chloroquine injections.

Figure 1 Jutten 2013 Chloroquine EGFR+

EGFR-overexpressing GBM subcutaneous xenografts respond to chloroquine treatment with or without radiation

In vitro, U373 cells engineered to overexpress EGFR were more sensitive to chloroquine treatment than unaltered U373 glioblastoma cells. Other publications by this group showed an increased dependence of EGFR overexpressing cancer cells on autophagy, while chloroquine is a known autophagy inhibitor. Chloroquine may yet prove to be especially effective in EGFR-driven cancers. Many glioblastomas and IDH1 non-mutated astrocytomas have increased EGFR activity due to mutations and amplifications of the EGFR gene.

Cimetidine (Tagamet)

Cimetidine (trade name Tagamet) was introduced in the late 1970s and was a very popular drug in treating heartburn and peptic ulcers. Its mechanism of action is inhibition of histamine H2 receptors, which are linked to the production of gastric acid by parietal cells of the stomach. Though largely superseded by newer proton pump inhibitors for the treatment of gastric disorders, cimetidine is still available by prescription and over-the-counter.

See Re-educating the Immune System for a description of the immune effects of cimetidine.

An additional mechanism of cimetidine in glioma therapy is anti-migration [47]. In vitro, a low concentration of cimetidine (100 nM) significantly inhibited the distance of migration of 9L and U373 glioma cells by about 30% compared to controls at 36 hours. Notably, the lower cimetidine concentration was more effective than the higher concentration (100 nanomolar versus 1 micromolar). These low levels of cimetidine are clinically achievable, with 400 nM being recorded in human cerebrospinal fluid after 200 mg cimetidine three times daily plus 400 mg at night for six days (mean of 7 human subjects) [48].

Dichloroacetate (DCA)

DCA has been used since the 1980s for use in inborn disorders of mitochondrial function, often involving lactic acidosis. It is a small, simple molecule, akin to acetic acid, with chlorine atoms replacing some of the hydrogen. Its mode of action is to inhibit pyruvate dehydrogenase kinases (PDK), activate pyruvate dehydrogenase (PDH), and divert pyruvate away from glycolysis, towards oxidative respiration in the mitochondria. Essentially it reverses the signature metabolic remodelling of cancer cells, decreasing glycolysis and increasing normal aerobic respiration. The result is a decrease in proliferation and an increase in apoptosis (programmed cell death). The most noted side-effect in humans is a reversible peripheral neuropathy, which can be remedied by decreasing the dose.

One small clinical trial has tested the efficacy of the drug in glioblastoma patients [6]. Only 5 patients were included, both newly diagnosed and recurrent, with DCA added to standard radiation and temozolomide, or used alone. The most that we can say from such a small trial is that DCA appeared to have some effect, seen from analyzing tumour specimens from three patients, both before and after DCA treatment.

While DCA has a long history of use in humans, with limited side-effects, its use as a cancer therapy is still in the preliminary stages of testing. Many have opted to self-medicate with DCA, but clinical trials are needed to prove its efficacy. The University of Florida is conducting a phase I clinical trial of DCA for recurrent malignant brain tumours, with an estimated study completion date of March 2014. As explained on the Targeting Tumour Metabolism page, DCA targets a particular component of cancer cell metabolism (the conversion of pyruvate to lactate) widespread in glioblastoma tumours, but not in IDH1-mutant tumours. For a discussion of a particularly interesting study involving the combination of DCA with bevacizumab (Avastin) in a mouse glioblastoma model, see the Bevacizumab or Targeting Tumour Metabolism page.

Levetiracetam (Keppra)

Keppra is probably the most commonly used anti-seizure drug used for glioma and glioblastoma patients, who are at high risk for seizures. In addition to the anti-seizure effects of Keppra, the drug apparently also has chemosensitizing effects, perhaps through the inhibition of MGMT activity as shown in an in vitro study [55]. An abstract published by Korean researchers in 2013 showed the potential survival prolonging effects of Keppra when taken along with monthly temozolomide. This was a prospective, single arm study of 38 newly diagnosed GBM patients who took Keppra before monthly TMZ cycles. The exact drug scheduling was not stated in the abstract. Median overall survival was 25.7 months. A control group consisted of 42 patients taking valproic acid. The use of Keppra was a significant positive prognostic factor when all 80 patients were included in the multivariate analysis.

A larger study [56] was published by the Korean group in May 2015, consisting of 103 newly diagnosed GBM patients undergoing standard treatment. 58 of these patients took Keppra for at least 3 months during temozolomide chemotherapy. Patients taking Keppra had significantly improved progression-free and overall survival, in both univariate analysis and multivariate analysis adjusted for age, KPS, extent of resection, and MGMT methylation status. Similarly to the previous abstract, median overall survival in the group taking Keppra was 25.7 months, while median overall survival for those patients not taking Keppra was 16.7 months. There was no subgroup analysis to determine if the benefit of Keppra was mainly confined to those without methylation of the MGMT promoter.

Inducing hypothyroxinemia with methimazole and thyroid hormone T3 (triiodothryonine)

As far back as 1988, Aleck Hercbergs has been exploring the relationship between thyroid hormones and cancer, and specifically how hypothyroidism (or underactive thyroid function) is associated with better outcomes in various cancers. More recently, a specific mechanism for these observations was uncovered with the discovery of receptors for thyroid hormones on integrin αVβ3, a pro-invasive, pro-angiogenic receptor found in abundance in some cancers including glioblastoma. Furthermore it was found that thyroid hormone T4 (thyroxine) is a far more potent inducer of tumor cell proliferation than T3 (triiodothyronine).

In a study [52] published in 2015 by Hercbergs and colleagues, 23 stage IV or recurrent, progressive solid cancer patients, including four glioblastoma patients and one brainstem glioma, were treated by inducing “hypothyroxinemia”, which means lowering thyroid hormone T4 (thyroxine) levels. Patients who were taking T4 for pre-existing hypothyroidism were abruptly switched over to T3. In these patients, circulating free thyroxine (FT4) levels decreased to below the lower limit of the reference range by week 7 after the start of T3 treatment. The other group of patients were given methimazole to suppress T4 production by the thyroid gland. T3 was also given to suppress thyroid-stimulating hormone (TSH) and avoid symptoms of hypothyroidism. Doses of methimazole and T3 are given on page 2 of the study.

Looking at the five glioma patients, actual survival from the start of the T4-depleting therapy far exceeded the expected survival in all cases. Patient 1 was a 68-year old GBM patient with a KPS of 40 and an expected survival of 2 months, who survived for 8 months. Three additional GBM patients with an expected survival of 10 months lived for 36 and 48 months beyond the start of T4-depleting therapy and the third was still alive at 16 months. Finally, the brainstem glioma patient with an expected survival of 12 months was still alive at 33 months. Safety was good, with no clear instance of methimazole toxicity.

In a different study [53], integrin αVβ3, which mediates the effects of T4 hormone on cancer cells, was found in abundance on glioblastoma cells and vasculature. Far less integrin αVβ3 was found on five grade 2 astrocytoma samples. Therefore the T4-depleting therapy is likely more effective for glioblastoma patients than low grade gliomas.

As of January 2016, a phase 2 trial is set to open in Israel to test the strategy described above in newly diagnosed glioblastoma, in combination with standard treatments.
NCT02654041

Sodium phenylbutyrate

Sodium phenylacetate and sodium phenylbutyrate (Buphenyl) are both FDA approved drugs used clinically for treatment of hyperammonemia and urea cycle disorders. Both drugs have also been tested in cancer trials as cell differentiating agents. Phenylbutyrate is largely converted to phenylacetate after ingestion, which then reacts with glutamine in the liver and kidney to form phenylacetylglutamine, which is excreted in the urine. One of the effects is a lowering of circulating glutamine levels [34]. Due to this ability, phenylacetate was proposed as an anticancer drug as far back as 1971 [35]. Phenylbutyrate is considered a prodrug of phenylacetate.

There are several clinical advantages of sodium phenylbuyrate over sodium phenylacetate: less toxicity, higher lipophilicity (expected to increase its delivery to target tissues), and lack of the offensive smell of phenylacetate, making oral ingestion of the odorless phenylbutyrate more tolerable [36]. In glioma trials, phenylacetate has been delivered intravenously, while phenylbutyrate is taken orally.

In a phase II trial of intravenous phenylacetate for recurrent malignant glioma (80% were glioblastoma cases), medium time to progression was only 2 months, partial response rate was 7.5%, and disease stabilization rate was 17.5%. Phenylacetate at the tested dosing schedule was concluded to be ineffective in this patient population [37].

A phase I trial [38] of oral sodium phenylbutyrate for recurrent malignant glioma (74% were glioblastoma cases) similarly showed little activity for the majority of patients, with 13 of 19 (68%) having neither response nor disease stabilization. However, of the four anaplastic astrocytoma patients included in the response assessment, one had disease stabilization and one had a remarkable complete response after nine months of phenylbutyrate therapy. A case report of this patient (a 44 year old female with an astrocytoma of the left anterior corpus callosum) was published in 2002, and from this we learn that the response was durable, lasting at least 4 years [39]. The phenylbutyrate dosage was reduced from 18 grams per day to 9 grams after the first month due to side-effects (nausea, headache, dizziness) and was later reduced further to 4.5 grams per day. At the time of publication the patient was still displaying significant clinical improvement, was seizure-free with a KPS (Karnofsky Performance Score) of 100%. The mechanism of action in this case is unknown, though eight potential mechanisms are listed in the study, including depletion of intracellular glutamine. Another mechanism of sodium phenylbutyrate is the inhibition of histone deacetylase (HDAC). It has been tested as an epigenetic cancer therapy in this regard.

Incidentally, the expensive “antineoplastons” marketed by the controversial Dr. Stanislaw Burzynski are composed of compounds such as phenylacetic acid and phenylacetylglutamine [40]. A more economical alternative to antineoplastons might be simple sodium phenylbutyrate.

Valganciclovir (Valcyte)

Valcyte is an antiviral drug used to treat cytomegalovirus (CMV) related disease. Recent studies have shown that virtually all glioblastoma as well as a high proportion of lower grade glioma tumours are infected with CMV, which confers a poorer prognosis [7, 8].

Is Valcyte a useful therapy for glioma patients?

A phase II clinical trial –the VIGAS trial– randomized 22 newly diagnosed glioblastoma patients into a Valcyte arm, and 20 patients into a placebo arm [14]. All 42 patients received standard radiochemotherapy with temozolomide. All patients had at least 90% resection of their tumours and Valcyte treatement “was started when there was no evidence of progressive disease” [15]. 68% of the patients in the Valcyte arm had complete resections, while only 35% of patients in the placebo arm had complete resections. Median progression-free survival and median overall survival were similar between the two arms. For the Valcyte arm, median progression-free survival was 5.6 months and median overall survival was 17.9 months. For the placebo arm, median progression-free survival was 5.5 months and median overall survival was 17.4 months. The differences in these two outcomes were statistically insignificant, though there was a trend toward decreased tumour growth rates in the Valcyte arm. Of note, at the time of tumour progression or at the six-month mark, patients in both the placebo arm and the Valcyte arm were offered the choice to continue or begin Valcyte treatment, when the randomization codes were still sealed. In other words, at tumour progression or at the six-month mark, patients made a decision to receive or not receive open-label Valcyte without knowing whether they had been in the placebo or Valcyte arm. Though the overall survival data is confounded by this crossover at six months, median progression-free survival was less than six months in both arms, excluding treatment crossover as a confounding factor. In this small randomized trial, Valcyte treatment made no significant difference to the median progression-free survival outcome.

This trial was conceived as a “hypothesis-generating” trial with the primary endpoint being “differences in tumor volume between treatment and placebo groups at 3 and 6 months after surgery, as assessed by neuroimaging”. Because the primary endpoint was tumor volume at 3 and 6 months, rather than survival or progression-free survival (the usual endpoints in randomized brain tumour trials), treatment crossover was allowed at six months and also “a power calculation of sample size was not performed”. Most randomized trials include a calculation of sample size to ensure that there are enough patients in each arm to detect differences in outcome between the arms with a sufficient degree of “power”. This trial, with only about 20 patients in each arm, was “underpowered” compared to the standards of most randomized trials. While there was a trend towards reduced tumour volume in the Valcyte arm at both 3 and 6 months (3.31 cubic centimeters in the Valcyte group versus 13.75 cubic centimeters in the placebo group at six months), the trial was not sufficiently powered to render these differences statistically significant. Furthermore, there was no comparison of MGMT methylation status between the two arms, an important prognostic factor in any trial that includes therapy with alkylating agents such as temozolomide.

The investigators of the VIGAS trial later published a retrospective study of 50 glioblastoma patients treated with Valcyte at Karolinska University in Sweden [8]. This analysis included the 22 patients from the Valcyte arm from the VIGAS trial, and 28 additional patients receiving Valcyte for compassionate use, 8 of whom were taken from the placebo group of the VIGAS trial. The median overall survival of the 50 patients was 25 months. 62% of patients lived to at least two years. 40 patients who were able to stay on Valcyte for at least 6 months had a median overall survival of 30.1 months and a two-year survival rate of 70%. Most impressively, 25 patients who continued to take Valcyte beyond the six month mark had a median overall survival of 56.4 months and a 2-year survival rate of 90%.

This retrospective study has been criticized by several eminent figures in the neuro-oncology community, such as Wolfgang Wick and Michael Weller, [16, 17] who point out that the authors of the retrospective study created a “long-term benefiting subgroup of patients” by “selecting for patients with valganciclovir exposure of > 6 months”. The commentators feel that the retrospective study is biased and “deliberately enriched for favorable outcome” [16]. Their crucial point is that the randomized trial showed little statistically significant benefit to the addition of Valcyte, while the retrospective study was biased in its analysis, as patients who maintain stable disease for 6 months or more, and therefore are able to continue with Valcyte treatment, may have had superior prognostic features regardless of their treatment with Valcyte.

The March 2014 edition of Neuro-Oncology contains an invited Point/Counterpoint between Wolfgang Wick and Michael Platten on one side of the issue, and Charles Cobbs on the other side. Wick and Platten again argue that the randomized trial done by the Karolinska Institute showed no significant benefit of adding Valcyte to standard therapy. They further argue that there is contradictory evidence concerning cytomegalovirus presence in gliomas and that its role in gliomagenesis or in glioma progression is not yet clear. Their position is that there is currently “no proof of biological efficacy of valganciclovir as an anti-glioma agent and it should thus not be used outside of clinical trials.”

Charles Cobbs published the first evidence of cytomegalovirus proteins in glioblastoma tissue in 2002. As a counterpoint to the argument of Wick and Platten, Cobbs makes several interesting points. He agrees with Wick and Platten that class 1 evidence for the efficacy of Valcyte as an anti-glioma agent is missing, but makes several arguments in favor of further prospective trials. He points out that the median survival data from the prospective trial is flawed because after six months patients in the control group were allowed to cross over into the Valcyte group, which pontentially blurred any survival benefit of the drug. He states that out of 50 patients who received Valcyte and were included in the later retrospective analysis (published in the New England Journal of Medicine), the likelihood of the top 25 longest survivors having a median survival of 56 months is low, even if these patients were “cherry picked” for good prognosis. This long survival in the top 25 survivors he takes to be an indication of Valcyte efficacy. Cobbs further goes on to say that even though the role of cytomegalovirus in glioma is not yet clear, Valcyte should continue to be studied for several reasons: it is well tolerated and has minimal risk; and it may have anti-cancer activity apart from its activity against cytomegalovirus. He argues that historically, the clinical utility of many drugs have been observed prior to a clear understanding of their mechanism. For all these reasons, further trials with Valcyte for glioma patients should proceed.

April 18, 2014
The Valcyte controversy has now spread to the International Journal of Cancer with a pair of letters published online in December 2013, recently republished in the July 1 2014 edition of the journal [18, 19]. In the first of these International Journal of Cancer letters [18], Liu and Hu propose that the supposed survival benefit in the glioblastoma patients undergoing Valcyte treatment for longer than six months may be due to “immortal time bias”. This is to say that if a treatment group is defined as having received the treatment for a given span of time, in this case six months, then this six month period is “immortal time”, during which time an event, in this case death, cannot have occured in order for a patient to be included in this time-defined group. Any patient receiving treatment who dies or stops treatment due to disease progression before six months is not included in the group. Therefore the minimum six-month treatment group is enriched in patients with an inherently more positive prognosis. Liu and Hu cite a study demonstrating that 40% of studies containing survival analyses with a time-dependent factor were susceptible to immortal time bias. They conclude by suggesting a re-analysis of the data from the Valcyte study using statistical methods preventing this form of bias.

In response to this letter [19], Soderberg-Naucler et al, of the Karolinska Institute in Sweden, (authors of both the randomized Valcyte trial for glioblastoma and the subsequent retrospective study published in the New England Journal of Medicine) claim that after adjusting for the “immortal time bias” using statistical methods, a highly statistically significant Valcyte effect still remains. They explain the small impact of immortal time bias by noting that the period of “immortal time” (six months) was small in relation to the total follow-up time. They conclude that immortal time bias does not explain the long survival of glioblastoma patients undergoing long-term Valcyte treatment, and that a properly designed randomized trial should begin as soon as possible.

Clearly, a properly designed prospective clinical trial is needed to settle the Valcyte dispute. Valcyte clinical use is currently reserved for treatment of cytomegalovirus retinitis in AIDS patients and for prevention of CMV disease in solid organ transplant patients. Cost of the drug is in the range of $3000 per month.

Rodent evidence

Celecoxib (Celebrex) plus PDE5 inhibitor (sildenafil, tadalafil)

The therapeutic effects of Celebrex as a COX-2 inibitor and Viagra (sildenafil) as an agent which can increase the permeability of the blood-tumour barrier have previously been discussed. A preclinical study [27] published in Ocotober 2014 by researchers at Virginia Commonwealth University shows that a combination of these two agents has greater than additive (ie synergistic) therapeutic effects on multiple tumour types in vitro and in vivo.

A semi-established human glioblastoma cell line (GBM6) was implanted in the brains of athymic mice. At day 14 after implantation, control mice were treated with vehicle, and three additional groups were treated orally with either sildenafil, celecoxib, fingolimod, or all three drugs combined for 14 days. Tumour growth at various time points was monitored by luciferase activity. The results are visually shown in figure S3U. Mice in the untreated control groups had died by day 28 while mice treated with combined sildenafil and celecoxib had stable tumours which had not grown throughout the study at day 28. Mice treated with combined sildenafil, celecoxib and fingolimod had significant shrinkage of their tumours. However, as fingolimod is used clinically in multiple sclerosis as an immunosuppressant which acts by sequestering lymphocytes in lymph nodes, this drug should also be tested in a syngeneic immunocompetent model to ensure that its immunosuppressant activity does not outweigh its anti-glioma activity. The oral dose of sildenafil used in this study equates to a dose that is about half the starting dose used clinically. Combinations of these same drugs were also tested in mammary cancer xenograft models. Similar to the in vitro data, the combination of oral celecoxib and sildenafil was significantly more effective than either drug alone.

In conclusion, this study shows that a low oral dose of sildenafil plus celecoxib achieves synergistic tumour stabilization in an orthotopic glioblastoma model using athymic (immunocompromised) mice. The triple combination involving fingolimod should be tested in an immunocompetent model before application to humans, as its immunosuppressant activity could potentially outweigh the anti-tumour activity. The triple combination with all-trans retinoic acid also looked very promising in vitro, though this combination wasn’t tested in vivo. The relatively low risk use of sildenafil and celecoxib make this combination a very promising and available therapy for tumours of various types, as seen in this study [27].

See Re-Educating the Immune System for use of PDE5 inhibitors (sildenafil, tadalafil etc.) in reducing cancer-induced immunosuppression.

Disulfiram (Antabuse)

The drug disulfiram (Antabuse) has been in clinical use since the 1940s, mainly to discourage alcohol abuse, as consuming alcohol while on this drug leads to some very unpleasant side-effects. It is currently in two clinical trials for glioma therapy due to a multitude of anti-cancer and anti-glioma actions, including aldehyde dehydrogenase (ALDH) inhibition, proteasome (and consequently NF-KB) inhibition, MGMT and P-glycoprotein inhibition, polo-like kinase inhibition, and inhibition of the two matrix metalloproteinases, MMP-2 and MMP-9, which are critical for cell invasion. It must be noted however, that most of the favorable evidence in terms of glioma therapy thus far comes from in vitro laboratory studies.

In vitro, disulfiram is one of the most effective agents for targeting glioma stem cells. In a high-throughput screen of 2000 compounds being tested against glioblastoma stem cells, disulfiram emerged as the most promising candidate for further testing [30]. In this study, its effects were attributed to its inhibition of the ubiquitin-proteasome pathway, as mentioned above.

In a separate study, low concentrations of disulfiram were highly toxic to glioblastoma cells, while not affecting normal human astrocytes. Furthermore, disulfiram was highly effective in cell lines which were unaffected by temozolomide, and in one test the two drugs were synergistic, inhibiting proliferation and self-renewal of glioma cells by 50% at concentrations which had no effect as single agents. In this study, the efficacy of disulfiram was attributed to its action as a polo-like kinase 1 inhibitor [31].

November 5, 2014
Though the limiting factor in the efficacy of disulfiram for brain tumour treatment is likely its marginal ability to cross the blood-brain barrier, a mouse study published in November 2014 in Neuro-Oncology demonstrates that enough of the drug can accumulate in the brain to have an effect on xenografted tumours growing there. In this study [44], nude mice were intacranially injected with patient-derived brain tumour initiating cells (BTIC) from atypical teratoid/rhabdoid tumors. 7 days after implantation, some of the mice were treated with intraperitoneally injected disulfiram at an appropriate dosage for 3 weeks (tumour volume analysis), or 5 weeks (survival analysis). The tumour cells used in this study had high expression of aldehyde dehydrogenase (ALDH), a finding that is confirmed in cancer stem cell studies for other cancers, including glioblastoma. ALDH is the primary recognized clinical target of disulfiram.

Several weeks of disulfiram treatment significantly inhibited tumour volume and proliferation (lowered Ki-67 index), and reduced the percentage of ALDH positive tumour cells. Caspase-3, a marker of apoptosis, was significantly increased in the disulfiram-treated tumours. In the survival analysis, disulfiram led to a modestly increased survival compared with the untreated control group. Though the effects on mouse survival were not dramatic, this study provides preclinical proof that disulfiram can enter the brain in sufficient quantity to have an effect on tumour growth. This is the first published study using disulfiram to treat xenografted tumours in animal brains at clinically relevant doses.

June 27, 2015
According to a recent study [58] one of the main cellular targets of disulfiram therapy, aldehyde dehydrogenase (ALDH), is particularly prevalent in “classical” type glioblastomas expressing EGFR.

August 10, 2015
A Chinese study [59] just published online in Cancer Letters shows that in a U87 GBM orthotopic mouse model, mice given intravenous disulfiram alone had only minor therapeutic benefits, while the mice given intravenous disulfiram plus copper (by stomach) had significantly increased therapeutic benefit, including reduced microvessel density and tumor volume (see figure 8).

There has been considerable debate whether additional copper beyond what is already in the stomach or bloodstream is required to potentiate the anti-cancer effect of disulfiram. Several mouse studies including the one above have shown that orally delivered copper in mice increases the therapeutic effects of disulfiram. Please note that the addition of copper likely also increases the risk of unwanted side-effects such as peripheral neuropathy [60].

The following paragraph was written for the 2016 edition of Treatment Options for Glioblastoma and Other Gliomas, published annually on the VirtualTrials.com website.

Disulfiram is currently being tested in a phase I pharmacodynamics trial at Washington University, St. Louis, Missouri. This trial consists of two arms: in one arm patients are given one of two disulfiram doses (500 mg or 1000 mg) daily beginning in conjunction with monthly cycles of temozolomide; in the second arm 6 mg of copper gluconate is given in combination with disulfiram plus temozolomide. Results for the first arm (disulfiram and temozolomide without copper) were published in the Journal of Neuro-Oncology in early 2016 [64]. Twelve patients were evaluated: seven on a dose of 500 mg disulfiram per day, and five patients on 1000 mg per day. Two of seven patients in the 500 mg cohort discontinued disulfiram after 55 and 80 days due to delirium and peripheral motor neuropathy. Two of five patients in the 1000 mg per day cohort suffered from grade 3 delirium after 15 days on disulfiram, and the maximum tolerated dose of disulfiram in combination with adjuvant temozolomide was determined as 500 mg per day. The pharmacodynamic endpoint of the trial was proteasome inhibition and minor decreases in proteasome activity were detected in the whole blood of patients at week 4 (average 5% inhibition for 500 mg dose and average 11% inhibition for 1000 mg dose). At the time of the analysis, 9 of the 12 patients had experienced disease progression. Results for the arm of the trial receiving copper gluconate in addition to disulfiram have not yet been reported.

Fluoxetine (Prozac)

Fluoxetine, more commonly known by the trade name Prozac, was the first selective serotonin reuptake inhibitor (SSRI), approved by the FDA in December 1987 for major depressive disorder. Potential side-effects of fluoxetine include nausea, insomnia, drowsiness, anorexia, anxiety, nervousness, weakness and tremors, and sexual dysfunction.

The most dramatic evidence in favor of fluoxetine as a potential therapy for glioblastoma was a mouse study published in December 2014 in the online journal Oncotarget, by a Taiwanese research group [51]. In this study, high concentrations (~25-30 micromolar) of fluoxetine caused apoptosis in several human glioblastoma cell lines through a mechanism involving binding to GluR1 (glutamate receptor 1, a subunit of the AMPA glutamate receptor), rapid influx of calcium ions into the cells, damage to mitochondrial membranes, and the release of apoptotic factors leading to cell death. However, it’s unclear whether such a mechanism is operative in vivo, as only submicromolar concentrations of unbound drug are found in blood plasma or brain. More impressive is the effect of fluoxetine on glioblastoma xenografts implanted in mouse brains. One week after implantation of either U87 or GBM8401 human glioblastoma cells into the mouse brains, the mice were then treated with low oral daily doses of fluoxetine, or intraperitoneal doses of temozolomide. Tumour size was monitored by luciferase activity. In both U87 and GBM8401 models, fluoxetine treatment controlled tumour growth, with small stable tumours at day 26 in the U87 model. In the GBM8401 model, average tumour size increased until day 12, but shrank from day 12-18 as the drug treatment started to take effect.

Fluoxetine GBM mouse study Figure 6

Upon examination of mouse brain slices, large amounts of cleaved caspase-3 (a marker of apoptotic cell death) were found in the tumour region of fluoxetine-treated mice, with only weak signals in normal brain, showing a preferential killing of tumour cells. The mouse dose of fluoxetine used in this study (10 mg/kg per day) gives plasma levels in mice similar to the plasma levels in humans with long term dosing at 20 mg per day.

Further support for the use of fluoxetine is provided in a Chinese study published online in September 2015, which shows that fluoxetine can inhibit protein expression of MGMT and sensitize resistant GBM tumors to TMZ chemotherapy in mice. This study is discussed on the Temozolomide page.

Metformin (Glucophage)

Metformin is very commonly used to control hyperglycemia in type II diabetes. Metformin’s site of action is in the cell mitochondria, where it disrupts cell respiration, specifically by inhibiting respiratory complex I. Metformin acts to lower blood glucose levels by creating a situation of energy stress in the liver and thereby suppressing the process of gluconeogenesis (the manufacture of new glucose by the liver). Insulin levels are in turn lowered. Metformin also has direct antineoplastic action, observed in vitro. However, these effects seen in the lab often require concentrations of metformin in the millimolar range, well in excess of levels achievable in the body. Therefore, the anti-cancer action of metformin may be mostly due to the its indirect glucose and insulin lowering ability.

New research (February 2015) also shows profound tumour inhibition in mouse studies, dependent on activation of CD8+ tumour infiltrating lympocytes. For more discussion of these immunomodulatory effects of metformin, see the Re-educating the Immune System page.

MD Anderson Cancer Center is currently conducting a Phase I trial with temozolomide plus the drugs metformin, memantine, and mefloquine, either singly or in combination, for newly diagnosed glioblastoma. The estimated primary completion date of this trial is September 2015.

Minocycline

As described on Targeting Tumour-Associated Macrophages/ Microglia, minocycline is a synthetic tetracycline antibiotic. Several in vivo studies have shown activity against intracranial gliomas in mice, especially by targeting the microglial production of pro-invasive molecules.

In the first of these studies [41], syngeneic GL261 mouse glioma cells were implanted in the brains of mice, and then minocyline was applied to the drinking water beginning either immediately after glioma cell implantation, or on day 7 after implantation. Minocycline treatment continued for 2 weeks in both experiments. When tumour volumes were measured after 2 weeks of minocycline treatment, treated mice harboured significantly smaller tumours than untreated control mice: 1.05 cubic mm versus 4.71 cubic mm in experiment 1 (immediate treatment), and 4.07 cubic mm versus 7.52 cubic mm in experiment 2 (delayed treatment). Notably, a very small concentration of minocycline was used in this study: 10 ng minocycline per millilitre drinking water.

A second study [42], again using a syngeneic GL261 mouse glioma model, administered a higher minocycline dose: 30 mg per kilogram mouse body weight in the drinking water. This study measured survival rather than tumour volume, and showed a slight, but statistically significant advantage to the minocycline treatment group. It may be that therapies such as minocycline are better evaluated by tumour invasiveness in experimental animals (who don’t undergo surgical debulking), rather than by animal survival.

Potential adverse reactions of minocycline are categorized into gastrointestinal, hepatic, skin, renal, hypersensitivity reactions, blood (including lowered platelet and neutrophil counts), and central nervous symptoms (including dizziness and vertigo). People taking minocycline are advised to avoid direct sunlight or UV light due to potential photosensitivity reactions. Retinoids such as isotretinoin (Accutane) are contraindicated while on minocycline.

Minocycline is usually taken at a dose of 200 mg per day (100 mg every 12 hours) until the infection is cleared up. Maximum dose is 400 mg per day. Doses of 100 mg per day (50 mg twice per day) may be prescribed for tetracycline-resistant acne, which typically resolves within 3 months. The safety of longer term minocycline usage is probably not well known. Despite the potential side-effects, minocycline is an already-approved drug which could slow glioma invasiveness by targeting glioma-associated microglia.

Mebendazole (Vermox)

Mebendazole is an FDA approved drug for the treatment of roundworm, hookworm, pinworm and whipworm infestations. Its mechanism of action is to bind to tubulin subunits in the gut of the parasite, preventing parasite growth. Several years ago, a team of brain tumour researchers at Johns Hopkins University fed fenbendazole to their mouse colony to deal with a pinworm outbreak. The researchers noticed that experimental brain tumour grafts failed to take after the fenbendazole treatment. This led to the testing of mebendazole as a brain tumour therapy in further studies with mice [32]. In the syngeneic GL261 model, mebendazole treatment increased median survival from 30 days in the control group, to 49 days in the treatment group, a highly statistically significant effect (p<0.0001). In the xenograft model, median survival was increased from 48 days in the control group to 65 days in the treatment group, also highly statistically significant (p=0.0016). The dosing used clinically in humans for anti-parasitic uses is 200 mg per day. However, far higher doses of mebendazole may be safely used as the drug has little toxicity, likely partially due to its sub-optimal absorption. 500 mg mebendazole three times per day has been used in trials without toxicity. Dose escalation even far beyond this is quite possible if the drug is tolerated well, and most patients experience no, or only mild side-effects. The main drawback of this drug is the extremely low oral bioavailability, and it has yet to be shown that levels of unbound drug sufficient to disrupt glioma cell proliferation can be achieved in human blood plasma (plasma protein binding for this drug is 90-95%).

Mebendazole is currently being tested in a phase I clinical trial for newly diagnosed high grade gliomas combined with temozolomide. Estimated primary completion date is February 2015. Teva Pharmaceuticals, the manufacturer of the drug in the United States, discontinued their product in October 2011. Mebendazole is manufactured and sold in Canada as Vermox, and is also available over-the-counter in some European countries.

Prazosin

Prazosin is an old drug, first approved by the FDA in 1976 (brand name Minipress) to treat hypertension, through antagonism of α1 and α2B adrenergic receptors (adrenoceptors). It is off-patent and cheap, costing as little as $10 (US) for 30 1mg capsules.

In the spring of 2016, a French group published research showing that prazosin could inhibit the growth of recently-resected human GBM xenografts injected into the brains of immunodeficient NOD scid gamma (NSG) mice [63].

In vitro, five different α-adrenergic receptor antagonists were tested for effects on glioma-initiating cell viability. Of these, only prazosin showed significant inhibitory effects on cell viability, also inhibiting sphere-forming ability of the cells. Prazosin also negatively impacted survival of differentiated GBM cells, while having little effect on healthy neural stem cells.

Freshly-resected human GBM cells were sorted for the markers CD133 and EGFR, and injected into the brains of immunodeficient NSG mice. Upon the detection of tumor mass, the mice were then treated by intraperitoneal injection with prazosin twice weekly for 45 days. Prazosin treatment significantly reduced tumor size and increased mouse survival in these models, compared to untreated tumor-bearing mice. Prazosin treated mice also showed a reduction in the proportion of CD133+ cells in the tumors (CD133 is a marker of GBM stem-like cells, with high tumor initiating potential). A 10-fold lower dose of prazosin, comparable to a typical anti-hypertension dose, also significantly reduced tumor size and increased mouse survival. Additionally, prazosin treatment similarly reduced tumor volume and increased mouse survival in a syngeneic GL-261 mouse glioma model using immunocompetent mice.

The specific mechanism responsible for these observations was next investigated. The researchers found that prazosin causes glioma cell death by apoptosis, both in vitro and in vivo, but did not induce apoptosis in non-tumor cells in the mice. The lack of effect of other adrenergic receptor blockers (besides prazosin) on GBM cells suggested its effects were independent of α-adrenergic receptor blocking activity. Instead, they found that the effects of prazosin on GBM cell death were dependent on PKC𝛿 (protein kinase C, delta isoform), as silencing of PKC𝛿 protected the GBM cells from the effects of prazosin. Prazosin also significantly inhibited the activation of AKT (also known as protein kinase B), which is a central hub in GBM pathology, at the center of the PI3K/AKT/mTOR proliferative signaling pathway. However, the silencing of PKC𝛿 in the cells reversed these effects on AKT. In mice, PKC𝛿-silenced tumors were unresponsive to prazosin.

In summary, these observations indicate that prazosin, a cheap off-patent hypertension drug, may have clinical use in GBM, especially those with alterations in the PI3K/Akt pathway.

CUSP9 (Coordinated undermining of survival paths with 9 repurposed drugs)

For a review of 9 repurposed drugs (plus temozolomide) as a potential therapy for recurrent glioblastoma, please see the paper authored by Richard Kast and others, published in April 2013 in the online journal Oncotarget [33]. An updated version of CUSP9 was published in Oncotarget in August 2014.

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