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Oncology
Glioblastoma (GBM) is characterized by fast-growing cells, genetic and phenotypic heterogeneity, and radio-chemo-therapy resistance, contributing to its dismal prognosis. Various medical comorbidities are associated with the natural history of GBM. The most disabling and greatly affecting patients’ quality of life are neurodegeneration, cognitive impairment, and GBM-related epilepsy (GRE). Hallmarks of GBM include molecular intrinsic mediators and pathways, but emerging evidence supports the key role of non-malignant cells within the tumor microenvironment in GBM aggressive behavior. In this context, hyper-excitability of neurons, mediated by glutamatergic and GABAergic imbalance, contributing to GBM growth strengthens the cancer-nervous system crosstalk. Pathogenic mechanisms, clinical features, and pharmacological management of GRE with antiepileptic drugs (AEDs) and their interactions are poorly explored, yet it is a potentially promising field of research in cancer neuroscience.
- brain tumor
- glioblastoma
- antiepileptic drug
- anti-cancer therapy
1. Glioblastoma-Related Epilepsy (GRE)
Glioma patients’ quality of life largely depends on the neurological decline due to the tumor itself or treatment-related toxicity and epilepsy (for definition, see [26]), which negatively affects neurocognitive functions and outcome [27].
In GBM patients, the diagnosis of epilepsy is usually made after one seizure episode. An inverse relationship between the degree of malignancy and the frequency of seizures has been reported: patients with low-grade glioma are affected by seizures in 65–95% of cases, while they occur in 30–50% of GBM patients [28]. GBM often originates in less epileptogenic areas, and patients may not live long enough to develop epilepsy, thus explaining the relative lower incidence of epilepsy in these tumors [29,30]. Multiple factors concur to GRE onset, such as increased intracranial pressure and edema, alterations of the peritumoral cortex, inflammation, and vascular insufficiency, likely triggering excitotoxicity and hyperexcitability of peritumoral neurons [31]. Underlying molecular mechanisms involve disruption of inhibitory/excitatory transmission balance mainly due to alterations of GABAergic and glutamatergic regulation [31], whose functions connecting epileptogenicity and GBM progression are detailed in the following paragraphs. The involvement of glioma-derived thrombospondin, a regulator of synaptogenesis, in excitatory synapse formation within the peritumoral cortex of a glioma-cell-implanted rat model has been described [32]. Furthermore, the association between connexin 43, a multifunction protein that forms gap junction channels, and GRE has been suggested and discussed [33,34].
Based on the relevance of alterations in GBM surrounding tissue in GRE, the pathophysiology of epilepsy may have roots in the tumor microenvironment; indeed, in the peritumoral area from a rat model of glioma, the density of GABAergic neurons was significantly decreased, and transcriptomic analysis revealed that 5 of 19 genes differentially expressed were associated with epilepsy and neurodevelopmental disorders [35].
The presence of GRE is considered one of the major risk factors for long-term disability since antiepileptic drugs often have heavy side effects and interactions with chemotherapy and supportive therapy; therefore, further investigation on neurons within the GBM microenvironment will identify targetable mechanisms in a translational perspective.
2. Antiepileptic Drugs in GRE: Clinical Management
Seizure control in GBM patients can be hardly accomplished by surgery alone; however, the extent of resection may determine better seizure outcome [36], while a beneficial effect of radio-chemo-therapy has not yet been defined: it seems effective for low-grade glioma [37] but not in GBM elderly patients [38]. Therefore, the best treatment strategy of GRE with AEDs can guarantee epilepsy control with a great impact on the patient’s quality of life. Management of GRE with a specific AED is challenging and controversial. Considering the risk of AED adverse events, physical disability, and neurocognitive impairments related to the tumor site, a multidisciplinary approach is needed.
To date, no universal guidelines are available for GRE therapy, and the antiepileptic efficacy of drugs in non-tumor epilepsy is not directly translatable to GBM patients due to drug–drug interactions and neurological conditions. In GRE, no superior efficacy of one AED over another has been demonstrated [39,40], and researchers are waiting for results from ongoing trials (NCT03048084, NCT03636958, NCT04497142). Current recommendations on AEDs use in newly diagnosed GBM suggest not treating patients who have never experienced a seizure episode, while it should be prescribed for patients who had at least one comitial episode to prevent the high risk of recurrent seizures [40,41]. Nevertheless, this issue is still discussed [42], and currently, refractory seizures may be treated with the combination of AEDs with a different mechanism of action [39].
The non-enzyme inducing AEDs, levetiracetam (LEV), lamotrigine (LMG), topiramate (TPM), lacosamide (LCM), pregabalin (PRG), and valproic acid (VPA) are preferred as monotherapy, as they have fewer adverse effects and interactions with other concomitant therapies in cancer patients. VPA acts as an inhibitor of glucuronidation; TPM is a weak inducer of CYP3A4 and might also inhibit CYP2C19. Perampanel (PER) and brivaracetam (BRV) are potentially broad-spectrum antiepileptic drugs that may be useful in add-on and do not appear to act as potent inducers of cytochrome P450 isoenzymes [43]. However, VPA, TPM, and PER can induce enzyme inhibition, increasing the toxicity of antitumor substrates. [44,45].
The use of enzyme-inducing AEDs (phenytoin, PHT, phenobarbital, and carbamazepine) is generally discouraged as they are potent inducers of several CytP450 isoenzymes, leading to clinically relevant alteration of antitumor agent pharmacokinetics (e.g., lomustine, vincristine), possibly increasing their side effects and reducing efficacy [40]. When a drug interaction is suspected, AEDs serum concentrations should be monitored [46]. However, taking into account that the metabolism of TMZ is not affected by old AEDs, the main reason for their limited use is the higher safety, tolerability, and effectiveness of newer AEDs [47].
A systematic review demonstrates that monotherapy with LEV, PHT, and PRG had higher efficacy in GRE, with LEV showing a lower failure rate [47], although variability among studies and patient populations prevents a definite statement. LEV shows a more favorable efficacy profile compared to VPA, with similar toxicity [47,48].
Drug resistance to first-line monotherapy in patients with GRE occurs in approximately 30% of patients and requires an add-on. However, no evidence of the superiority of a drug over another in resistant patients has been reported [40]. Among add-on treatments, PER efficacy and safety in GRE have been described [49,50], as well as for BRV [51], an analog of LEV, currently under evaluation (NCT05029960), although larger prospective studies are lacking.
Given the emerging interest in cannabinoids (i.e., cannabidiol, CBD) as promising antiepileptic agents in patients with refractory seizures [52], CBD-enriched products might help control seizures also in glioma patients. CBD showed good safety and tolerability [53], while clinical efficacy in GRE needs to be tested.
Therapeutic criteria for GRE are still based on studies on general epilepsy; thus, a satisfactory GRE therapy is still challenging. In this scenario, further insights into specific pathophysiological mechanisms underpinning GRE and drug resistance might improve AED choice and patient outcome.
5. Repurposing Antiepileptic Drugs for the Treatment of Glioblastoma: Pharmacologic Targets
The scenario so far described underlines critical point in GBM prognosis and management: (i) GBM has a fatal clinical course despite aggressive and multimodal treatments; (ii) epilepsy frequently develops in GBM patients; (iii) the two diseases show shared pathogenic processes.
Drug repurposing, identifying new therapeutic uses for already-available drugs, is a promising tool that speeds up drug discovery time. In GBM, several known compounds have been explored for new use as antitumor activity [112,113,114]. Therefore, repositioning AEDs can be a promising option able to improve patient survival and control both seizures and GBM growth and recurrence.
LEV and VPA are the most studied drugs, possibly having a dual function as antiepileptic and antineoplastic, and are largely used in patients with GRE. Studies have also been carried out on other AEDs generally used as a second choice or add-on in case of therapeutic failure on the basis of the mechanism of action potentially impacting tumor growth (e.g., PER and CBD).
3.1. Antitumor Efficacy of AEDs Used in GRE: Preclinical and Clinical Perspectives
3.1.1. Levetiracetam
LEV exerts its antiepileptic effects through binding to the synaptic vesicle glycoprotein 2A (SV2A), which regulates neurotransmitter vesicular dynamics in neurons, reducing Ca2+ release and acting as a negative allosteric modulator of GABA- and glycin-gated currents, thus supporting GABA release [115,116].
Antitumor efficacy of LEV, analyzed in GBM cell lines, has been attributed to the inhibitory action on MGMT, overcoming this GBM resistance mechanism and enhancing TMZ effects [117] by decreasing MGMT expression and activating apoptotic pathway [118]. Interestingly, LEV shows antitumor effects at concentrations in the serum therapeutic range for seizure prophylaxis [119]. In addition, LEV, combined with IFN-α, enhanced the anti-tumor activity of TMZ in MGMT-positive GBM cells [120].
In the clinical setting, the survival benefit of LEV has been evaluated in GBM patient treated with current SOC.
Retrospective analyses show that LEV improves patients’ PFS and OS [121,122,123]. However, a pooled analysis of four different clinical trials (NCT00943826, NCT00689221, NCT00884741, NCT00813943) on a large series of cases treated with LEV at the start of chemo-radio-therapy failed to find an association with patients’ survival [124]. This controversial association between LEV and clinical outcome was further investigated in an observational study on IDHwt GBMs, reporting a possible OS benefit when LEV is used during the whole standard SOC duration [125].
Overall, the observational retrospective studies contain information and selection bias, while prospective randomized controlled trials and studies including specific molecular profiles will help address the actual efficacy of LEV in GBM. Currently, an open-label single-arm phase 2 study, with external and historical control, enrolling 73 patients (NCT02815410), reported minimal survival benefits over the radio-chemo-therapy [126]. A study protocol for a double-blind randomized clinical trial focusing on the clinical benefits of LEV + TMZ in the treatment of GBM has been planned [127].
3.1.2. Valproic Acid
VPA is a potent anticonvulsant acting through multiple mechanisms, such as interaction with GABA transaminase, succinate semialdehyde dehydrogenase, postsynaptic GABA and glutamate receptors, and ion channels [128]. Antitumor effects of VPA have been extensively explored in both the pre-clinical and clinical settings [129] being a histone deacetylase (HDAC) inhibitor (epigenetic drug) [130], changing not only in histone acetylation but also in DNA methylation in glioma cell lines [131].
Besides HDAC, other targets have been associated with VPA antitumor activity in GBM cells, such as the upregulation of brain-derived neurotrophic factor (BDNF) [132] and signaling pathways, such as ERK/Akt [133], Akt/mTOR [134], and Wnt [135]. In glioma cells, VPA promotes apoptosis [133,134] and autophagy [134,136] and impairs cell proliferation and invasiveness [135,137]. However, the effective dose (millimolar) of VPA is far above that used for the treatment of epilepsy [138]. At a concentration of up to 100 µM, VPA failed to inhibit glioma cell growth and metastasis in vitro [139]. Beyond antitumor effects as a single agent, VPA sensitizes GBM cells to several anticancer drugs, such as nitrosoureas [140], TMZ [141,142,143], gefitinib [144], etoposide [145], and radiation therapy [143,146].
Therefore, based on in vitro and in vivo preclinical results, VPA may manage both epilepsy and glioma as a potential adjuvant drug to enhance patients’ response to SOC.
Several studies show that VPA increases the median survival of patients affected by GBM [147,148,149]. Retrospective studies suggest that adding VPA to TMZ-based chemoradiotherapy in newly diagnosed GBMs slightly prolongs survival at the expense of increased thrombocytopenia and leukopenia [148,149,150]. In addition, VPA used during radiotherapy decreases side effects and prolongs OS and PFS [151].
A recent update of an open-label phase 2 study (NCI-06-C-0112) on 37 patients confirms previous data reporting that the addition of VPA improves their PFS and OS [152]. A meta-analysis confirmed the prolonged survival with VPA combined treatment [153]; conversely, analysis of pooled randomized trials enrolling 1869 patients did not associate with extended PFS or OS [124].
As a whole, preclinical evidence supports VPA antitumor and TMZ-sensitizing efficacy, while in the clinical setting, further investigation is needed to justify VPA as a potential adjuvant in current GBM therapy.
3.1.3. Perampanel
PER is a selective non-competitive AMPA receptor antagonist. The shared mechanism of AMPA-activation connecting seizure activity and GBM growth support the rationale for AMPA-receptor blocker evaluation of antitumor activity, first investigated with talampanel, a PER analog, which is still not on the market due to its poor pharmacokinetics and short half-life [154], without reaching concordant significant results [155,156,157].
The antiproliferative mechanism of PER is not yet clear and preliminary data are obtained in a wide range of concentrations and different established glioma cell lines. In a study comparing antitumor effects in GBM cell lines of various AEDs, including LEV and VPA, only PER showed inhibitory effects on cell proliferation, migration, and invasion, without induction of apoptosis and reduction of extracellular glutamate levels [139,158]. Whereas, in other works, PER antineoplastic activity is mediated by apoptosis, possibly due to increased GluR2/3 expression synergizing with TMZ [159,160].
In in vivo experiments in C6 rat glioma xenografts, PER did not affect either tumor growth or animal survival, while it blocked epileptiform discharges in organotypic glioma slices and reduced glucose uptake in C6 glioma cells in vitro [161]. Similarly, in another orthotopic rat model of glioma (F98), which promotes an epileptiform phenotype, the therapeutic efficacy of PER, as an adjuvant to standard radiochemotherapy, failed to impact tumor progression and animal survival, while tumor-associated epilepsy was abolished, maintaining the glutamatergic network activity on healthy peritumoral tissue of treated animals [162].
Interestingly, in the scenario of neuro-glioma synapses which produce postsynaptic currents mediated by AMPA receptors, the 14-day treatment of GBM xenografted mice with PER exerts significant antiproliferative activity on GBM cells [95] and in mice bearing pediatric glioma [94].
At the clinical level, only one retrospective study evaluated PER impact on seizures and tumor progression in 12 GBM patients with refractory epilepsy, detecting by MRI a reduction of tumor volume [163]. Currently, while in the management of GRE, PER in add-on could be a valid therapeutic option, and a study is ongoing to confirm its safety and efficacy (NCT04650204); trials evaluating PER efficacy on GBM progression and survival are lacking.
However, the connection between increased neuronal activity and glioma progression mediated by glutamatergic synapses warrants further investigation in which AMPA receptor inhibition by PER may be exploited both at the preclinical and clinical levels.
3.1.4. Cannabidiol
Cannabidiol (CBD) is one of the major molecules found in cannabis and hemp, and pharmaceutical-grade CBD has FDA and ENMA approval for seizures in Dravet syndrome and Lennox–Gastaut syndrome, as well as for tuberous complex [164].
Although the mechanism of action is not yet fully understood, CBD has numerous targets; in particular, its anticonvulsant activity is due to the interaction with three receptors—the transient receptor potential vanilloid-1 (TRPV1), the orphan G protein-coupled receptor-55 (GPR55) and the equilibrative nucleoside transporter 1 (ENT-1), implicated in the regulation of neuronal excitability [165].
The in vitro and in vivo anti-glioma activity of different CB1/CB2 agonists (cannabinoids) and endocannabinoids has been described (for a review, see [97]).
Phytocannabinoids, namely CBD, in preclinical studies, demonstrated antiproliferative and pro-apoptotic effects and inhibition of the migration of GBM [166], acting as a sensitizer to chemotherapeutic agents [167]. In human primary GBM stem-like, CBD exerts cytotoxic activity likely through modulation of a key transcription factor in GBM, the nuclear factor kappa B (NF-κB), by promoting DNA binding and preventing posttranslational modification of the NF-κB subunit RELA/p65 [168].
In a retrospective trial, CBD seems to demonstrate an increase in the survival of patients with GBM [169].
Results from a phase 1b randomized trial of cannabinoid oromucosal spray (nabiximols, containing delta-9-tetrahydrocannabinol-THC, CBD, and additional cannabinoid and non-cannabinoid components) with TMZ in patients with recurrent GBM showed satisfactory safety and tolerability, no drug–drug interaction, and survival at 1 year of 83% for nabiximols and 44% for placebo arm [170].
Currently, there is an ongoing phase 1b trial (NCT03529448) assessing the safety and antitumor activity of the THC + CBD combination with standard therapy in newly-diagnosed GBM.
Further studies will show whether compounds that exert promising effects on tumor cells, in addition to the psychoactive THC, such as CBD and inhibitors of endocannabinoid degradation, could be potential combination partners for established chemotherapeutic agents in GBM treatment.
3.2. Potential Repositioning of Other AEDs Used in GRE
Few in vitro investigations report on the potential antitumor effects of other approved AEDs used in GRE.
Among them, LCM has been shown to be ineffective [171] or to exert cytotoxicity and anti-migratory effects in the micromolar range [172] in GBM cells lines, likely via HDAC inhibition, as observed in a breast cancer model [173]. Curiously, the inactive enantiomer of this AED, S-lacosamide (S-LCM), is able to decrease GBM cell proliferation and the growth of orthotopic tumors in a murine GBM model [174].
BRV, with a 15- to 30-fold higher affinity for SV2A than LEV, shares the above-described antitumor effects with LCM [172].
LMG fails to reach significant cytotoxicity at therapeutic concentrations in vitro [138]; however, P3K/AKT signaling might represent its additional target, also blocking voltage-dependent calcium and sodium channels, to exploit antitumor effects as observed in breast cancer models [175].
PGB, a GABA analog, exhibits anti-neuroinflammatory effects, preventing substance P (SP)-mediated IL-6 and IL-8 production in the U373 GBM cell line through the inhibition of p38 MAPK and NF-κB signaling molecules [176].
Similarly, a slight cytotoxic activity in GBM cells has been described for TPM [138].
Stiripentol, an agonist of GABAAR, approved for the treatment of seizures associated with Dravet syndrome [177], showed selective cytotoxic and anti-migratory activity in GBM cells and additive or synergistic effects with TMZ [178]. Interestingly, stiripentol decreases GBM invasion and growth in xenografted mice [179], likely via lactate dehydrogenase (LDH) block, an enzyme involved in both neuron hyperpolarization [180] and highly glycolytic metabolism of GBM cells, which catalyzes lactate production and correlates with high proliferation and invasion [181].
This entry is adapted from the peer-reviewed paper 10.3390/biomedicines11020582
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