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Review paper

Receptor tyrosine kinase targeting in glioblastoma: performance, limitations and future approaches

Oana Alexandru
1
,
Cristina Horescu
2
,
Ani-Simona Sevastre
3
,
Catalina Elena Cioc
2
,
Carina Baloi
2
,
Alexandru Oprita
2
,
Anica Dricu
2

  1. Department of Neurology, University of Medicine and Pharmacy of Craiova and Clinical Hospital of Neuropsychiatry Craiova, Craiova, Romania
  2. Unit of Biochemistry, University of Medicine and Pharmacy of Craiova, Craiova, Romania
  3. Unit of Pharmaceutical Technology, University of Medicine and Pharmacy of Craiova, Craiova, Romania
Contemp Oncol (Pozn) 2020; 24 (1): 55-66
Online publish date: 2020/03/30
Article file
- Receptor.pdf  [0.30 MB]
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Introduction

Gliomas are a group of brain tumors originating from the glial cells (either astrocytic or oligodendroglial). Their classification is based on cell biology, histology and clinical evolution. Although the current classification of brain tumors includes genetic and epigenetic abnormalities and clinico-pathological features, clinicians are still using the historical classification to define the tumor entities. Until recently, gliomas were divided into low-grade gliomas (LGGs) (grade I–II) and high-grade gliomas (HGGs) (grade III and IV), according to the 2007 report of the WHO classification [1]. The WHO presented in 2016 a major restructuring of the embryonal central nervous system tumors, by incorporating new entities defined both by molecular and histological features, including IDH-wildtype glioblastoma, IDH-mutant glioblastoma; H3 K27M-mutant diffuse midline glioma; RELA fusion-positive ependymoma; WNT- and SHH-activated medulloblastoma; and C19MC-altered multilayered rosettes embryonal tumor [2]. There are several studies showing that the molecular background of the discussed entity is very complex [3, 4]. Basically, because of the discrepancies in the clinical evolution of tumors with different molecular background, this classification is a problematic issue. HGGs are the most aggressive brain tumors among gliomas. The median survival of patients diagnosed with HGGs is only 14.6 months [5]. HGGs include anaplastic astrocytoma (AA), anaplastic oligodendroglioma (AO) and glioblastoma (GB). The origin of these tumors is in the supporting neuroglial cells of the central nervous system. The most aggressive of these primary brain tumors are GB. It is obvious that GB individuals require special attention and care, mainly because all HGGs can be debilitating, causing physical and cognitive impairment, epileptic seizures, depression and personality changes. In the last years, specialists have focused their energy on providing new therapies for these patients, in order to improve their lifestyle and survival. In spite of the efforts made until now, the standard of care of newly diagnosed GB remains surgery (maximal safe resection) followed by radiotherapy and adjuvant chemotherapy [68]. The adjuvant temozolomide associated with radiotherapy has improved the median survival, which was only 12.1 months. However, several problems linked to resistance towards chemotherapy or radiotherapy need to be solved. Microenvironment, cellular morphology and genetic characteristics are a few of the aspects to which cancer cells can adapt in order to survive, leading to drug resistance [9]. In the light of these data, it is obvious that the decisions regarding the treatment must be taken on an individual basis. In recent years, specialists focused on targeted molecular therapies. Known to be involved in cancer development and therapy, receptor tyrosine kinases (RTKs) are of particular importance [1013].

New chemotherapeutic strategies in GB treatment are frequently proposed, but drug development and registration are consuming increased financial resources and time. Therefore, drug re-purposing represents a new pipeline for the pharmaceutical industry to find new uses in oncology for already existing non-cancer drugs. In this review we focused on some therapeutic agents that are at different stages of research or in clinical phases endowed with the potential to become re-purposing candidates for GB treatment.

Receptor tyrosine kinases

The molecular structure of RTKs includes a ligand-binding region in the extracellular domain, a single trans-membrane helix, and a cytoplasmic region. The cytoplasmic region includes the protein tyrosine kinase (TK) domain and the additional carboxy terminal and juxtamembrane regulatory regions. In the human proteome there are 58 currently known RTKs divided into 20 families [14]. RTKs are involved in regulating proliferation, differentiation, cell survival, metabolism, cell migration, and cell cycle control [15]. In 1990, Ulrich and Schlessinger demonstrated that the activation of RTKs by growth factor binding results in the dimerization and/or oligomerization of the receptor [16]. Actually, the dimerization can be ligand- or receptor-mediated, or both receptor- and ligand-mediated [17]. The dimerization of the extracellular regions of RTKs leads to activation of the intracellular tyrosine kinase domain. These changes lead to the release of the cis-autoinhibition while the trans-autophosphorylation is enabled and the tyrosine kinase domain becomes active [18]. Also, the autophosphorylation of RTKs results in the recruitment of downstream signaling proteins which contain Src homology-2 or phosphotyrosine-binding domains. By binding these domains to specific phosphotyrosine residues, the cellular signaling pathway is activated [19]

Another response to the activation of RTKs is the down-regulation of the receptor. The result of this process is the degradation of the ligand and of the receptor [20]. Also, it is known that there is a connection between the function of protein kinases and ubiquitylation, which is very important in some critical events involved in cell signaling such as regulation of protein degradation, processing and cellular trafficking [21]. The mutations or aberrant activation of the intracellular signaling pathways of RTKs are linked to a series of diseases including cancer, arteriosclerosis, diabetes, and angiogenesis. Therefore, in recent years serious efforts were made to develop molecular targeting drugs able to fight the RTK aberrations. The most studied molecular targets are epidermal growth factor receptor (EGFR), insulin growth factor receptor (IGFR), vascular endothelial growth factor receptor (VEGFR), platelet–derived growth factor receptor (PDGFR) and fibroblast growth factor receptor (FGFR) [22, 23].

Receptor tyrosine kinase inhibitors for glioblastoma treatment

In accordance with the National Cancer Institute (NCI) and the US Food and Drug Administration (FDA), targeted therapies are a set of drugs capable of blocking molecular targets involved in growth, spread and tumor progression [24]. Being designed to interact only with the molecular target, such therapies spare the normal cells. Also, being able to inhibit tumor cell proliferation, they are cytotoxic. Therefore, they can be considered instruments of precision medicine. Small molecule therapies against RTKs are among these targeted therapies. Currently, some of them are used in preclinical studies, while others have already been approved for clinical trials or for clinical use in tumor treatment including HGGs, as mentioned in Figure 1.

Fig. 1

Inhibitors used in glioblastoma therapy

/f/fulltexts/WO/40483/WO-24-94726-g001_min.jpg

The most relevant RTK inhibitory drugs used in cancer therapy are briefly presented in Table 1.

Table 1

Small molecule receptor tyrosine kinase inhibitors used in cancer therapy

TargetMoleculesObservations
EGFR1st generation inhibitors:
Gefitinib
Erlotinib
Lapatanib
They showed promising results in preclinical studies, but with mixed results in clinical trials [2225]
2nd generation inhibitors:
Afatinib
Dacomitinib
Both drugs were approved by the FDA
Afatinib had limited activity in combination with temozolomide [33]
3rd generation inhibitors:
AZD 9291
AEE 788
AZD 9291 proved to have better activity and selectivity than the previous inhibitors
The third-generation EGFR inhibitor AZD9291 overcomes primary resistance by continuously blocking ERK signaling in glioblastoma [36]
AEE 788 also inhibits VEGFR [38]
Others:
Vandetanib
Neratinib
AG556
Vandetanib also inhibits VEGFR [39]
AG556 had promising results when used in combination with radiotherapy [43]
PDGFRImatinib mesylate
Tandutinib
AG 1433
AG 1296
Imatinib showed no significant changes in the HGGs and especially GBM tumor growth [46]
Better results were obtained in combination with hydroxyurea [47]
Tandutinib had little effect [49]
AG 1433 and AG 1296 used alone are rather effective [50, 51]
IGF-RPQ 401
Picropodophyllin
BMS 536924
BMS 754807
NVP-AEW 541
OSI 906
AG 1024
PQ 401, BMS 536924 and picropodophyllin suppressed the growth and migration of GBM cells
GSK 1838705A and NVP-AEW541 induced apoptosis [6367]
OSI 906 and BMS 754807 had good results in vitro
AG1024 had rather modest inhibition activity alone or in combination with radiotherapy [68]
VEGFRVatalanib
Pazopanib
Sunitinib
Cediranib
Thalidomide
Cabozantinib
SU 1498
Vatalanib enhances the antiangiogenic activity [54]
Disappointing results were obtained for pazopanib in combination with lapatinib [57]
No promising activity for GBM patients treated with sunitinib [58]
Cediranib is an inhibitor of VEGFR, PDGFR, and c-kit [59]
Thalidomide had a good effect as palliative drug in advanced secondary glioblastoma [60]
Cabozantinib had good results both in vitro and in clinical trials [61, 62]
SU1498 had a limited anti-tumor activity [51]

[i] EGFR – epidermal growth factor receptor, PDGFR – platelet-derived growth factor receptor, IGF-R – insulin-like growth factor receptor, VEGFR – vascular endothelial growth factor receptor, FDA – Food and Drug Administration, ERK – extracellular signal-regulated kinases, HGGs – high-grade gliomas, GBs – glioblastomas, c-kit – transmembrane tyrosine kinase receptor

Because EGFR is overexpressed in about 60% of GBs, small molecule EGFR inhibitors were developed [25]. Among the first small molecule inhibitors against EGFR preclinically tested are gefitinib (Iressa; ZD1839), erlotinib (Tarceva; OSI-774), and lapatinib (Tykerb/Tyverb; GW572016). These inhibitors showed promising results in preclinical studies [26, 27]. However, the results were rather mixed in clinical trials. Gefitinib alone or in association with radiotherapy proved to have only a minimal response in patients diagnosed with GBs, although the drug was well tolerated [28, 29]. However, in 2005, Franceschi et al. proved in a phase II study of the Grupo Italiano Cooperativo di Neuro-Oncologia (GICNO) that the drug could be more efficient as a second line treatment for patients with HGGs [30]. In recent years, clinical studies proved to have similar results [31].

Similar results were obtained with erlotinib [32, 33]. Even in more recent years the drug showed only minimal benefits [34]. Lapatanib, another first generation EGFR inhibitor, also had only limited results in clinical trials either alone or in combination with temozolomide [35, 36]. Because of these rather poor results, a second generation of EGFR inhibitors was designed to inhibit the EGFR. Among them, afatinib and dacomitinib were approved by the FDA. In 2015, a phase I/phase II study regarding afatinib alone or in combination with temozolomide proved that the drug was safe but with limited activity [37]. Also, single-agent dacomitinib proved to have limited activity in a phase II clinical trial in recurrent glioblastoma patients with EGFR amplification [38], following preclinical studies with good results [39]. The third generation of EGFR inhibitors is nowadays being tested pre-clinically, but also in clinical trials. AZD9291 demonstrated to be efficient both in vitro and in vivo GB models. This drug has better activity and selectivity than the previous inhibitors. The drug has a better capacity to inhibit proliferation and prolongs the survival of GB cells [40]. Since 2018, the drug is being tested in a phase I/phase II clinical trial [41]. Another EGFR/Erb inhibitor is AEE788. The drug also inhibits VEGFR. It was tested in a phase I clinical trial developed for patients diagnosed with recurrent GB. The results were disappointing due to the toxicity and minimal activity of the inhibitor [42]. Neratinib is another inhibitor of EGFRs investigated in clinical trials for GB patients [43].

In the last years, we also investigated a number of small molecule EGFR inhibitors as potential targeted therapy on HGG cell lines. In 2018 we investigated the effect of tyrphostin AG556 (an EGFR inhibitor) on 11 and 15 HGG cells. Currently used as monotherapy, the inhibitor had only modest results. However, when combined with radiotherapy, the inhibitor induced radiosensitivity in 11 HGG cells [44]. This proved once again that HGG cells are able to develop resistance to therapies. The capacity of these cells to synthesize constitutive active receptors makes the targeted therapies ineffective.

PDGFR is another family of receptor tyrosine kinases that is overexpressed in HGGs, especially in GBs [45]. PDGFRA is amplified in about 15% of GBs [46]. This explains the efforts made to discover and test new small molecule inhibitors to target this receptor. Currently, many inhibitors are undergoing in vitro and in vivo preclinical tests and some of them are already approved for clinical trials. Imatinib mesylate (Gleevec/ST1571) is a small molecule inhibitor which has inhibitory effects on PDGFR. Although the inhibitor proved to have good effects for other malignancies, in the case of HGGs and especially GBs, imatinib mesylate showed no significant changes in the tumor growth. The drug failed the clinical trials and the patient survival remained unchanged [47]. Because of these facts, the inhibitor was next tested in combination with hydroxyurea, another classical chemotherapeutic drug. The clinical trial concluded that the combination had no benefit when compared to the single treatment with hydroxyurea [48]. In the last years, in vitro studies on GB cells proved that imatinib mesylate increases the migration and invasion of GB cells, a fact that explains the anterior failures of the drug [49]. Tandutinib, a PDGFRB inhibitor, was also tested in clinical trials in patients with recurrent GB. The drug had little effect [50]. Even since 2008 we have been interested to test the effect of AG1433, which is also an in vitro PDGFR inhibitor in several HGG cell lines (8, 18, and 38). The results were promising [51].

In 2015 we also tested the effect of the same inhibitor, AG1433, on GB9B cells in vitro. The cytotoxic effect of the drug was rather modest [52]. In the same period, another tyrphostin, AG-1296, had good effects on GB cells both in vitro and in vivo [53].

In 2019, we reported the effect of AG1433 alone and in combination with radiotherapy on 11 and 15 HGG cell lines. We found that although the use of the inhibitor alone was rather effective, the association with radiation therapy was not more effective when compared with the single treatment [54].

VEGFR is another target for glioblastoma patients. Vatalanib (PTK787) is an inhibitor of VEGFR2, PDGFR and c-kit which had little effect on GB patients alone or in combination with other chemotherapeutics or radiotherapy. However, the drug seemed to enhance the antiangiogenic activity [55]. Sorafenib is another small molecule inhibitor of VEGFR with a small effect on GB when used in combination with temsirolimus. It is in a phase II clinical study [56]. Tivozanib is a small molecule inhibitor of angiogenesis with good anti-angiogenic effects on GB. However, the drug was not able to change the volume of the tumors [57]. Pazopanib was also tested in clinical trials in combinations with lapatinib. The results were rather disappointing [58] In 2013, Batchelor et al. reported that cediranib, a small molecule inhibitor of VEGFR, PDGFR, and c-kit, showed a small effect on the neurological status of the patients but did not improve the progression of the disease or the survival of the GB patients [59]. Another anti-angiogenic agent which proved good effects on GB patients is thalidomide. The drug had a good effect when used as a palliative drug for patients with advanced secondary GB [60]. SU1498 is a VEGFR inhibitor that proved to have a cytotoxic effect on GB9B cells. However, its anti-tumor activity was rather limited [52].

YKL-40, a mesenchymal marker known as human cartilage glycoprotein-39 or chitinase-like protein 1, seems to have a key role in the motility and migrating features of glioma stem like cells and in their differentiation into endothelial cells, involved in angiogenesis [61]. It was proven that YKL-40 upregulates VEGF expression, and tumor vasculogenesis induced by YKL-40 is partially dependent on VEGF [62]; therefore therapies targeting YKL-40 may have potential benefit in GB treatment.

IGF-1R is another receptor tyrosine kinase that proved to be an interesting target for GB treatment. In the last years, a number of small molecule inhibitors against IGF-1R have been tested on GB cells in vitro and in vivo. Among them, PQ401, BMS-536924 or PPP (picropodophyllin/AXL1717) proved to be able to suppress the growth and migration of GB cells, while GSK1838705A or NVP-AEW541 induced apoptosis either alone or in association with other chemotherapeutic drugs [6367]. Also, inhibitors such as OSI-906 and BMS-754807 proved good results in vitro on GB cells [68]. Our group studied since 2007 the capability of tyrphostin AG1024 to inhibit IGFR on a series of HGG cells lines. First we studied the 18 and 38 HGG cell lines [69]. In the next year, we added some other HGG cell lines: MO59J, MO59K, and 8. The activity of the inhibitor was rather modest. Similar results were obtained when combining the inhibitor with ionizing radiation [51].

Somatic mutations of FGFR are rare in GB, but there are studies suggesting that modifying FGFR signaling influences glioblastoma progression and patient survival [70]. Small molecules which inhibit the FGFR tyrosine kinases are currently being studied, emphasizing the therapeutic potential of this signaling pathway [71]. Some small-molecule inhibitors such as lenvatinib, ponatinib, dovitinib and brivanib, also target other RTKs, while others are FGFR selective, such as PD173074, BGJ398, AZ4547, and JNJ-493 [72].

In a recent study, a large-scale shRNA screen was used to identify FGFR signaling as a target in pediatric glioma, proving that dovitinib, ponatinib, AZ4547, and PD173074 better reduce the growth of glioma cells in vitro than temozolomide [73].

In December 2019, a trial involving BGJ398 in patients with recurrent glioblastoma was completed, but so far, no results have been published [74].

A phase I/II trial involving TAS-120 is currently recruiting patients with advanced solid tumors, with and without FGF/FGFR-related abnormalities [75].

Rapamycin (sirolimus) has been identified to inhibit the mTOR and, specially, the mTORC1 complex [76]. Rapamycin derivatives (temsirolimus, everolimus and ridaforolimus), also named rapalogues, have been synthesized. At present, they are gaining considerable interest. By using clinicaltrials.gov lists regarding sirolimus/everolimus/temsirolimus treatment in GB patients, we found that 7 clinical trials were recruiting in 2019 [77].

The multitargeted approaches may represent a method for effective selection of resistant tumor subclones. Vandetanib is a multitargeted tyrosine kinase inhibitor (VEGFR, EGFR) that was studied in clinical trials. The drug was well enough tolerated but the antitumor effects were limited [78]. In 2015 another phase I clinical study determined that the co- administration of vandetanib in association with sirolimus is safe for patients with recurrent GB [79]. Also, in another clinical trial vandetanib proved to be safe in association with standard chemotherapy in newly diagnosed GB patients [80]. Two other multitarget small molecule inhibitors which target VEGFR and other receptors are XL-184 (cabozantinib) and PD173074. Cabozantinib had good results both in vitro and in clinical trials, and PD173074 had good results in vitro [81, 82]. Sunitinib is a multiple kinase inhibitor of VEGFR, PDGFR, FLT1, FLT1/KDR, FLT3, and RET kinases with no promising activity for GB patients [83].

In conclusion, targeted therapy against receptor tyrosine kinases represents a hope for GB patients. However, the efforts made by specialists should also be focused on fighting against resistance to therapy, to discover drugs able to pass the blood brain barrier, to use multi-targeted therapies, but also to discover and use biomarkers that can predict the outcome of therapies.

Antibody therapies targeting the RTKs’ extracellular domain

Apart from the kinase domain, the extracellular domain of RTKs may represent a viable target by using antibody therapies as antagonists. Because of their large size, they do not freely cross the blood–brain barrier (BBB); therefore engineered antibodies (such as directed antibodies with transferrin receptor optimized binding) must be used to enable them to access the GB tumors. Also, to bypass the BBB, alternative antibodies can be delivered inside the brain using Ommaya reservoirs [22].

Cetuximab is a monoclonal EGFR targeting antibody used for GB treatment. It prevents RTK activation by targeting the extracellular domain of EGFR [84]. Its activity was minimal in phase II clinical trials on recurrent GB patients [85]. Also, onartuzumab was used to inhibit the tumor growth of orthotopic U87 GBM xenograft [86]. Dalotuzumab (MK-0646 or H7C10/F50035) is a humanized monoclonal IGF-1R antibody shown to induce apoptosis and to reduce cell proliferation [87].

RTK drug resistance in glioblastoma patients

The resistance to RTK drugs has many causes. Usually, monotherapies yield minor results, mostly because of the functionally redundant pathways. Due to the fact that intracellular signal redundancy is the main cause of therapeutic failure by using a single inhibitor, concurrent blocking of multiple receptors or of an RTK inhibitor together with radio-, chemo or immunotherapy is an applicable strategy. Recent preclinical and clinical studies suggest the need for concomitant inhibition of multiple RTKs or for inhibition of their common downstream signaling. Hence, there has been a growing interest in testing the inhibitors of PI3K, AKT and the TORC1/2 complexes. A multitarget treatment may be a good solution when certain subclones of the tumor become resistant to single treatment by creating mutations; therefore an option to overcome resistance is to act selectively on these mutations.

There are two types of approaches mentioned in the literature: the vertical inhibition approach in which the molecular targets are part of the same cellular signaling axis, and the horizontal inhibition approach where the multitarget ligand is involved in distinguished nodes of different pathways [88]. These approaches are achieved by using co-administration of drugs (Akt/mTOR, MDM2/mTOR, PI3K/CDK inhibitors) or by using multi-target ligands (PDK1/Aurora A, PDK1/CHK1, Akt/p70S6K, EGFR/PKC inhibitors) [89]. For example, a study performed by Graves-Deal et al. showed that the multi-RTK inhibition strategy managed to overcome both de novo and acquired resistance to EGFR therapies. The efficiency of multiple EGFR-targeted antibodies (panitumumab, cetuximab, and MM-151) could be enhanced by adding small molecule RTK inhibitors (crizotinib, cabozantinib, and BMS-777607). Also, by adding crizotinib, resistance to cetuximab in nude mice xenografts was overcome [90]. This strategy could also be applied for GB treatment. Wei et al. performed a study on patient-derived glioblastoma xenografts grown in mice. The results showed that copy number variations and mutations did not correlate with drug resistance, but increased heterogeneity and activation of the ERK and SRC kinases in drug-resistant tumors. The tumor growth was prevented by combining the different pathway inhibitors (mTOR, ERK, SRC) in mTOR inhibitor-resistant GB mice. The rewiring events were detected a few days after the beginning of the treatment, at the single-cell level [91].

Another option to overcome the RTK inhibitors resistance is to use blockers for the apoptosis inhibitors. In a study performed by Ziegler et al., in vitro inhibition of PDGFR in human GB cells started the apoptosis intrinsic pathway, but caspase activation could be blocked by inhibiting the apoptosis proteins. Therefore, concomitant inhibition of apoptosis proteins may overcome the resistance to RTK inhibitors, improving treatment outcomes [92].

In conclusion, the concurrent inhibition of different cellular pathways is a new promising strategy that is attempting to overcome the onset of chemoresistance. These strategies may involve the combination of multiple selective inhibitors blocking different targets in the same pathway, the concurrent blockade of key proteins of the signaling pathways, or the multidirectional inhibition of specific oncoproteins. All these approaches represent a valid strategy in GBM therapy, especially when the patient genetic pattern is the target.

Repurposed drugs with potential use in glioblastoma therapy

There are many innovative chemotherapeutic strategies developed in GB treatment, but nowadays regulations concerning drug development and registration require a long time and increased financial resources. The pharmaceutical industry is trying various other pathways in order to put drugs faster on the market. Besides that, it is known that physicians may prescribe “off-label” drugs, though this represents a controversial practice in some fields (pediatrics, oncology) [93]. One strategy applied is drug repositioning, also known as drug re-purposing. It is a pharmaceutical strategy applied in oncology and other areas based on finding new indications for already approved drugs, in order to treat off-label diseases [94].

The reason for using drug re-purposing is due to the ability of small molecule agents to target distinct cellular proteins. Thus, the same molecule can be used to target multiple pathways involved in malignant diseases that are usually considered to be unrelated (polypharmacology) [95].

Because it skips many phases [96], as can be seen in Figure 2, this strategy has many advantages.

Fig. 2

De novo and re-purposing drug development phases. Unlike the drugs that follow the conventional pathway to the pharmaceutical market, re-purposing candidates shorten the time needed to market by omitting some initial steps, which go directly into the clinical study phases (FDA – Food and Drug Administration. I, II, III – stages in the clinical development [clinical phases])

/f/fulltexts/WO/40483/WO-24-94726-g002_min.jpg

The molecules already in use have well-known pharmacological data, a fact that shortens the period for approval, but also the final price. Furthermore, most of these drugs are generics, so their cost of production is lower than for the patented drugs [97].

However, key obstacles must be mentioned such as registration, reimbursement and implementation of the re-purposed drugs. For example, in Europe only the holder of the marketing authorization can apply for the extension of a marketing authorization [98]. Also, non-commercial organizations usually lack resources required to finish and maintain the marketing authorization. There is still a doubt regarding the necessity of large randomized controlled trials to confirm the efficiency of a re-purposed agent and the use of the authorization dossiers’ safety data, in order to overleap phase I studies [99].

For example, out of 44 off-label recommendations listed in the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines), only 14 were approved by the FDA and/or are subjects of randomized controlled trials [100].

Concerning central nervous system (CNS) therapy, only the FDA approved agents with ability to cross the blood brain barrier (BBB) may become re-purposing candidates [95]. By using the PubMed database published between 2010 and 2019 and the site clinicaltrials.gov, we gathered a list of agents that have re-purposing potential for GB treatment. In this short review, we indicated the various approaches used to repurpose drugs in GB therapy and we also highlighted their limitations.

Some of the mechanisms involved in GB therapy were completely elucidated, but many still remain unclear. In Figure 3, we illustrated the plethora of drugs with repurposing potential in GB therapy, but the number of studies in this field is significantly higher [94, 101126].

Fig. 3

Drugs with re-purposing potential in glioblastoma therapy

/f/fulltexts/WO/40483/WO-24-94726-g003_min.jpg

In this review, we focused on the following drugs that were tested as re-purposing candidates: CNS drugs (chlorpromazine, pimozide, fananserin, trifluoperazine, thioridazine, imipramine, valproate, propentofylline), antimalarial drugs (chloroquine, mefloquine), antidiabetics (metformin), disulfiram, lonidamine, rapamycin, temsirolimus, everolimus and ridaforolimus.

Several studies investigated the properties of some FDA-approved psychotropic molecules to inhibit the proliferation and migration of GB cells [109, 127].

For example, chlorpromazine is a specific and potent inhibitor of the kinesin KSP/Eg5 leading to mitotic arrest and defective, monopolar spindles [128]. It is also involved in autophagic cell death due to inhibition of the AKT/mTOR signal transduction axis in human glioma cells [129]. Antipsychotic drugs such as chlorpromazine and pimozide were tested on glioblastoma cells and they showed tumor suppressing ability [130].

Fananserin, a dopamine receptor D4 (DRD4) inhibitor, selectively induced autophagy in GB stem cells [131].

Trifluoperazine, a dopamine receptor D2 antagonist, inhibits both growth and proliferation of GB cells in a dose-dependent manner [132].

A recent study showed that thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide, inhibiting tumor growth in vivo and increasing survival in tumor-bearing animals [133].

It has been recently observed that antidepressants, especially imipramine and amitriptyline, can downregulate the “stemness genes” Sox1, Sox2, Ki67, Nestin, and CD44 after tricyclic antidepressant treatment. They also hypothesized that these compounds can affect tumor plasticity and immunity by influencing immune cells, reactive oxygen species and pro/anti-inflammatory cytokines [134].

Valproic acid is an anti-epileptic agent which acts by blocking sodium channels, GABA transaminase, and calcium channels [135]. Valproate is prescribed in epilepsy, migraines and acute manic episodes [136]. It was shown to have anticancer effect in glioblastoma, by reducing PON2 expression, which increases ROS production and triggers Bim output that inhibits malignant progression through the cascade PON2-Bim [137]. Furthermore, valproic acid induced autophagy through the ERK1/2 pathway which led to glioma cell death. By using the combination of valproic acid and temozolomide or rapamycin, autophagy was enhanced both in vivo and in vitro [138]. Valproic acid is also studied in different drug combinations, to increase the treatment efficiency of GB [139]. Between 2018 and 2021, valproic acid is in a phase 4 clinical trial for glioma patients with their first seizure [140].

Also, the neuroprotective drug propentofylline tested for Alzheimer’s disease and vascular dementia [141] was proven to target TROY, a receptor involved in the tumor necrosis factor receptor (TNFR) microglial signaling pathway [142].

Furthermore, the antimalarial agent chloroquine improved chemo-radiation treatment in GB [143], making it suitable as a re-purposing candidate [144]. Briefly, chloroquine (alone or in combination with temozolomide) leads to accumulation of autophagic vacuoles with non-functional properties, thus inhibiting autophagy [117, 145]. Several clinical trials are currently being conducted [146].

In 2019, a phase 1 study reported unexpectedly low rates of neuropsychiatric side effects of another antimalarial agent, mefloquine, repurposed for the treatment of GB [147].

Interestingly, a possible target in GB treatment is chloride intracellular channel1 (CLIC1), known to be inhibited by the anti-diabetic biguanides [148]. Metformin is a representative of biguanides and it is the most used oral antidiabetic drug. In 2016, a set of kinases were identified as potential targets, including SGK1 and EGFR [149]. Clinical trials are currently in different stages regarding metformin in association with other drugs, in GB therapy [150].

Disulfiram is an ALDH1 inhibitor, a staminal marker for GB [151]. The activity of disulfiram increases if administered together with divalent cations (Cu gluconate). Recently, disulfiram has been reported to inhibit NF-κB [152] and methylguanine-DNA methyltransferase [153]. Eight clinical trials are currently in different stages regarding disulfiram in association with other drugs, from which 2 are completed, in GB therapy [154].

Lonidamine is a reversible inhibitor of spermatogenesis. During its clinical use in combination with other anti-cancer drugs, it exhibited promising results in brain tumors [155]. Recently, new studies show that lonidamine inhibits the lactic acid efflux mediated by the MCT proteins. In addition, lonidamine also elicits a cytotoxic autophagic response in GB cells [156].

All these agents could be re-purposed for GB treatment, but not before a better understanding of their mechanism and formulation. Also, some researchers consider that combining the drugs with re-purposing capacity may be advantageous. In 2013, the Coordinated Undermining of Survival Paths protocol (CUSP9) was developed to assess the safety of temozolomide in GB in combination with other drugs [157]. This protocol used combinations of 9 re-purposed drugs (aprepitant, minocycline, disulfiram, celecoxib, sertraline, captopril, itraconazole, ritonavir, auranofin) and low doses of temozolomide. In this monocentric trial, all patients are treated at Ulm University Hospital Germany. This clinical trial is currently in phase 2. The estimated study completion date is March 2020 [158].

Despite the efforts, many drugs have failed to be approved for re-purposing in the treatment of GB [159, 160], as can be observed in Table 2.

Table 2

Repurposing candidates that did not receive approval for glioblastoma treatment. Although they have been considered as candidates in the re-purposing process, many old active molecules have failed to complete all steps to enter the pharmaceutical market for glioblastoma treatment, being rejected at different stages of development

ClassDrugs
AntiparasiticsHydroxychloroquine, quinacrine,
pyrvinium pamoate
Anti-infectiousAtazanavir, ribavirin, ciprofloxacin, salinomycin, doxycycline, chloramphenicol, tigecycline
Central nervous systemChlorpromazine, fluphenazine, perphenazine, olanzapine, penfluridol, quetiapine, paroxetine, fluoxetine, fluvoxamine, amitriptyline, clomipramine, doxepin, propofol
Cardiovascular systemDigitoxin, lovastatin, simvastatin, pitavastatin, fluvastatin, evastatin, cerivastatin, verapamil, carvedilol
BloodTiclopidine
Respiratory systemIbudilast, amlexanox
Alimentary tract and metabolismRepaglinide, rosiglitazone, ciglitazone, phenformin, sulfasalazine, cimetidine
DermatologicalsIsotretinoin, ivermectin
Genito-urinary system and sex hormonesEstradiol

Conclusions

The above described drugs are not target-specific drugs, but they can represent a therapeutic option designed rather to “target” cancer cell dependencies. Because of the heterogeneity of GB, the re-purposing approach has great potential, since their combined administration, together with current therapeutic options, could target cancer cell survival mechanisms, thus providing a strategy to avoid drug resistance in GB treatment. The information presented herein highlights the necessity of extensive research to elucidate some of the unclear biological mechanisms that underly the therapeutic effects. This step is mandatory, in order to go through all stages of developing clinical trials, until drug marketing.

Acknowledgements

This work was supported by grant PN-III-P1-1.1-MC-2019-1185

Notes

[2] Conflicts of interest The authors declare no conflict of interest.

References

1 

Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P , authors. The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 2007. 114:p. 97–109

2 

Louis DN, Perry A, Reifenberger G, et al. , authors. The 2016 World Health Organization classification of tumors of the central nervous system. Acta Neuropathol. 2016. 131:p. 803–820

3 

Huse JT, Diamond EL, Wang L, Rosenblum MK , authors. Mixed glioma with molecular features of composite oligodendroglioma and astrocytoma: a true “oligoastrocytoma”? Acta Neuropathol. 2015. 129:p. 151–153

4 

Wilcox P, Li CC, Lee M, et al. , authors. Oligoastrocytomas: throwing the baby out with the bathwater? Acta Neuropathol. 2015. 129:p. 147–149

5 

Stupp R, Heigi ME, Mason WP, et al. , authors. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomized phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009. 10:p. 459–466

6 

Keles GE, Lamborn KR, Chang SM, Prados MD, Berger MS , authors. Volume of residual disease as a predictor of outcome in adult patients with recurrent supratentorial glioblastomas multiforme who are undergoing chemotherapy. J Neurosurg. 2004. 100:p. 41–46

7 

Stupp R, Mason WP, van den Bent MJ, et al. , authors. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005. 352:p. 987–96

8 

Stupp R, Hegi ME, Gilbert MR, Chakravarti A , authors. Chemoradiotherapy in malignant glioma: standard of care and future directions. J Clin Oncol. 2007. 25:p. 4127–4136

9 

Salvatore V, Teti G, Focaroli S, Mazzotti MC, Mazzotti A, Falconi M , authors. The tumor microenvironment promotes cancer progression and cell migration. Oncotarget. 2017. 8:p. 9608–9616

10 

Mizuno T, Kyoizumi S, Suzuki T, Iwamoto KS, Seyama T , authors. Continued expression of a tissue specific activated oncogene in the early steps of radiation-induced human thyroid carcinogenesis. Oncogene. 1997. 15:p. 1455–1460

11 

Wang M, Xie YT, Girnita L, et al. , authors. Regulatory role of mevalonate and N-linked glycosylation in proliferation and expression of the EWS/FLI-1 fusion protein in Ewing’s sarcoma cells. Exp Cell Res. 1999. 246:p. 38–46

12 

Shawver LK, Slamon D, Ullrich A , authors. Smart drugs: tyrosine kinase inhibitors in cancer therapy. Cancer Cell. 2002. 1:p. 117–123

13 

Cosaceanu D, Carapancea M, Alexandru Oana, et al. , authors. Comparison of three approaches for inhibiting insulin-like growth factor I receptor and their effects on NSCLC cell lines in vitro. Growth Factors. 2007. 25:p. 1–8

14 

Lemmon MA, Schlessinger J , authors. Cell signaling by receptor tyrosine kinases. Cell. 2010. 141:p. 1117–1134

15 

Blume-Jensen P, Hunter T , authors. Oncogenic kinase signaling. Nature. 2001. 411:p. 355–365

16 

Ulrich A, Schlessinger J , authors. Signal transduction by receptors with tyrosine kinase activity. Cell. 1990. 61:p. 203–212

17 

Leppanen VM, Prota AE, Jeltsch M, et al. , authors. Structural determinants of growth factor binding and specificity by VEGF receptor 2. Proc Natl Acad Sci USA. 2010. 107:p. 2425–2430

18 

Hubbard SR, Miller WT , authors. Receptor tyrosine kinases: mechanisms of activation and signaling. Curr Opin Cell Biol. 2007. 19:p. 117–123

19 

Pawson T , author. Specificity in signal transduction: From phosphotyrosine-SH2 domain interactions to complex cellular systems. Cell. 2004. 116:p. 191–203

20 

Zwang Y, Yarden Y , authors. Systems biology of growth factor – induced receptor endocytosis. Traffic. 2009. 10:p. 349–363

21 

Critchley WR, Pellet-Many C, Ringham-Terry B, Harrison MA, Zachary IC, Ponnambalam S , authors. Receptor tyrosine kinase ubiquitination and de-ubiquitination in signal transduction and receptor trafficking. Cells. 2018. 7:p. 22

22 

Pearson JRD, Regad T , authors. Targeting cellular pathways in glioblastoma multiforme. Signal Transduct Target Ther. 2017. 2:p. 17040

23 

Popescu AM, Purcaru SO, Alexandru O, Dricu A , authors. New perspectives in glioblastoma antiangiogenic therapy. Contemp Oncol (Pozn). 2016. 20:p. 109–118

24 

US Food and Drug Administration, Office of Combination Products , author. Annual Report to Congress: Federal Food, Drug, and Cosmetic Act as amended by the Medical Device User Fee Act of 2002. 2003 October 26. Rockville, MD: National Press Office;

25 

Kesari S, Ramakrishna N, Sauvageot C, et al. , authors. Targeted molecular therapy of malignant gliomas. Curr Neurol Neurosci Rep. 2005. 5:p. 186–197

26 

Ohgaki H , author. Genetic pathways to glioblastomas. Neuropatholology. 2005. 25:p. 1–7

27 

Halatsch ME, Gehrke EE, Vougioukas VI, et al. , authors. Inverse correlation of epidermal growth factor receptor messenger RNA induction and suppression of anchorage-independent growth by OSI = 774, an epidermal growth factor receptor tyrosine kinase inhibitor, in glioblastoma multiforme cell lines. J Neurosurg. 2004. 100:p. 523–533

28 

Rich JN, Reardon DA, Peery T, et al. , authors. Phase II trial of gefitinib in recurrent glioblastoma. J Clin Oncol. 2004. 22:p. 133–142

29 

Lieberman FS, Cloughesy T, Fine H, et al. , authors. NABTC phase I/II trial of ZD-1839 for recurrent malignant gliomas and unresectable meningiomas. J Clin Oncol. 2004. 22:p. 1510

30 

Franceschi E, Lonardi S, Tosoni A, et al. , authors. ZD1839 (Iressa) treatment for adult patients with progressive high-grade gliomas (HGG): an open label, single-arm, phase II study of the Gruppo Italiano Cooperativo di Neuro-Oncologia (GICNO). J Clin Oncol. 2005. 23:p. 1564a

31 

Brown N, McBain C, Nash S, et al. , authors. Multi-center randomized phase II study comparing cediranib plus gefitinib with cediranib plus placebo in subjects with recurrent/progressive glioblastoma. PloS One. 2016. 11:p. e0156369

32 

Vogelbaum MA, Peereboom D, Stevens G, et al. , authors. Phase II trial of the EGFR tyrosine kinase inhibitor erlotinib for single agent therapy of recurrent glioblastoma multiforme: Interim results. J Clin Oncol. 2004. 22:p. 1558a

33 

Raizer JJ, Abrey LE, Wen P, et al. , authors. A phase II trial of erlotinib (OSI-774) in patients (pts) with recurrent malignant gliomas (MG) not on EIAEDs. J Clin Oncol. 2004. 22:p. 1502a

34 

Peereboom DM, Ahluwalia MS, Ye X, et al. , authors. New Approaches to Brain Tumor Therapy Consortium: NABTT 0502: a phase II and pharmacokinetic study of erlotinib and sorafenib for patients with progressive or recurrent glioblastoma multiforme. Neuro-Oncol. 2013. 15:p. 490–496

35 

Thiessen B, Stewart C, Tsao M, et al. , authors. A phase I/II trial of GW572016 (lapatinib) in recurrent glioblastoma multiforme: clinical outcomes, pharmacokinetics an molecular correlation. Cancer Chemother Pharmacol. 2010. 65:p. 353361

36 

Karavasilis V, Kotoula V, Pentheroudakis G, et al. , authors. A phase I study of temozolomide and lapatinib combination in patients with recurrent high-grade gliomas. J Neurol. 2013. 260:p. 1469–1480

37 

Reardon DA, Nabors LB, Mason WP, et al. , authors. BI 1200 36 Trial Group and the Canadian Brain Tumour Consortium: Phase I/randomized phase II study of afatinib, an irreversible ERBB family blocker, with or without protracted temozolomide in adults with recurrent glioblastoma. Neuro-Oncol. 2015. 17:p. 430–439

38 

Sepúlveda-Sánchez JM, Vaz MÁ, Balañá C, et al. , authors. Phase II trial of dacomitinib, a pan-human EGFR tyrosine kinase inhibitor, in recurrent glioblastoma patients with EGFR amplification. Neuro Oncol. 2017. 19:p. 1522–1531

39 

Zahonero C, Aguilera P, Ramírez-Castillejo C, et al. , authors. Preclinical Test of Dacomitinib, an Irreversible EGFR Inhibitor, Confirms Its Effectiveness for Glioblastoma. Mol Cancer Ther. 2015. 14:p. 1548–1558

40 

Liu X, Chen X, Shi L, et al. , authors. The third-generation EGFR inhibitor AZD9291 overcomes primary resistance by continuously blocking ERK signaling in glioblastoma. J Exp Clin Cancer Res. 2019. 38:p. 219

41 

An Z, Aksoy O, Zheng T, Fan QW, Weiss WA , authors. Epidermal growth factor receptor and EGFRvIII in glioblastoma: signaling pathways and targeted therapies. Oncogene. 2018. 37:p. 1561–1575

42 

Reardon DA, Conrad CA, Cloughesy T, et al. , authors. Phase I study of AEE788, a novel multitarget inhibitor of ErB- and VEGFR family tyrosine kinases in recurrent glioblastoma patients. Cancer Chemother Pharmacol. 2012. 69:p. 1507–1518

43 

Brian MA, Trippa L, Gaffey S, et al. , authors. Individualized Screening Trial of Innovative Glioblastoma Therapy (INSIGhT): A Bayesian Adaptive Platform Trial to Develop Precision Medicines for Patients With Glioblastoma. JCO Precision Oncology. 2019. 3:p. 1–13

44 

Alexandru O, Purcaru SO, Tataranu LG, Lucan L, Castro J, Folcuţi C, Artene SA, Tuţă C, Dricu A , authors. The Influence of EGFR Inactivation on the Radiation Response in High Grade Glioma. Int J Mol Sci. 2018. 19:p. 229

45 

Paulsson J, Ehnman M, Ostman A , authors. PDGF receptors in tumor biology: prognostic and predictive potential. Future Oncology. 2014. 10:p. 1695–1708

46 

Brennan CW, Verhaak RG, McKenna A, et al. , authors. The somatic genomic landscape of glioblastoma. Cell. 2013. 155:p. 462–477

47 

De Witt H , author. Small molecule kinase inhibitors in glioblastoma: a systematic review of clinical studies. PCNeuro Oncol. 2010. 12:p. 304–16

48 

Dresemann G, Weller M, Rosenthal MA, et al. , authors. Imatinib in combination with hydroxyurea versus hydroxyurea alone as oral therapy in patients with progressive pretreated glioblastoma resistant to standard dose temozolomide. J Neurooncol. 2010. 96:p. 393–402

49 

Frolov A, Evans IM, Li N, et al. , authors. Imatinib and Nilotinib increase glioblastoma cell invasion via Abl-independent stimulation of p130Cas and FAK signalling. Sci Rep. 2016. 6:p. 27378

50 

Batchelor TT, Gerstner ER, Ye X, et al. , authors. Feasibility, phase I, and phase II studies of tandutinib, an oral platelet-derived growth factor receptor-beta tyrosine kinase inhibitor, in patients with recurrent glioblastoma. Neuro Oncol. 2016. 19:p. 567–575

51 

Carapancea M, Alexandru O, Fetea AS, et al. , authors. Growth factor receptors signaling in glioblastoma cells: therapeutic implications. J Neurooncol. 2009. 92:p. 137–147

52 

Popescu AM, Alexandru O, Brindusa C, et al. , authors. Targeting the VEGF and PDGF signaling pathway in glioblastoma treatment. Int J Clin Exp Pathol. 2015. 8:p. 7825–7837

53 

Li H, Zheng J, Guan R, Zhu Z, Yuan X , authors. Tyrphostin AG 1296 induces glioblastoma cell apoptosis in vitro and in vivo. Oncol Lett. 2015. 10:p. 3429–3433

54 

Alexandru O, Sevastre AS, Castro J, Artene SA, Tache DE, Purcaru OS, Sfredel V, Tataranu LG, Dricu A , authors. Platelet-Derived Growth Factor Receptor and Ionizing Radiation in High Grade Glioma Cell Lines. Int J Mol Sci. 2019. 20:p. 4663

55 

Gerstener ER, Eichler AF, Plotkin SR, et al. , authors. Phase I trial with biomarker studies of vatalanib (PTK787) in patients with newly diagnosed glioblastoma treated with enzyme inducing anti-epileptic drugs and standard radiation and temozolomide. J Neurooncol. 2011. 103:p. 325–332

56 

Lee EQ, Kuhn J, Lamborn KR, et al. , authors. Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North America Brain Tumor Consortium study. Neuro Oncol. 2012. 14:p. 1511–1518

57 

Kalpathy-Cramer J, Chandra V, Da X, et al. , authors. Phase II study of tivozanib an oral VEGFR inhibitor, in patients with recurrent glioblastoma. J Neurooncol. 2016. 131:p. 603–610

58 

Reardon DA, Groves MD, Wen Py, et al. , authors. A phase I/II trial of pazopanib in combination with lapatinib in adult patients with relapsed malignant glioma. Clin Cancer Research. 2013. 19:p. 900–908

59 

Batchelor TT, Mulholland P, Neyns B, et al. , authors. Phase III randomized trial comparing the efficacy of cediranib as monotherapy, and in combination with lomustine, versus lomustine alone in patients with recurrent glioblastoma. J Clin Oncol. 2013. 31:p. 3212–3218

60 

Hassler MR, Sax C, Flechl B, et al. , authors. Thalidomide as palliative treatment in patients with advanced secondary glioblastoma. Oncology. 2015. 88:p. 173–179

61 

Batista KM, Eulate-Beramendi S, Pińa K, et al. , authors. Mesenchymal/proangiogenic factor YKL-40 related to glioblastomas and its relationship with the subventricular zone. Folia Neuropathologica. 2017. 1:p. 14–22

62 

Francescone RA, Scully S, Faibish M, et al. , authors. Role of YKL-40 in the angiogenesis, radioresistance, and progression of glioblastoma. J Biol Chem. 2011. 286:p. 15332–15343

63 

Zhou X, Zhao X, Li X, et al. , authors. PQ401, an IGF-1R inhibitor, induces apoptosis and inhibits growth, proliferation and migration of glioma cells. J Chemother. 2016. 28:p. 44–49

64 

Zhou Q , author. BMS-536924, an ATP-competitive IGF-1R/IR inhibitor, decreases viability and migration of temozolomide-resistant glioma cells in vitro and suppresses tumor growth in vivo. Onco Targets Ther. 2015. 8:p. 689–697

65 

Yin S, Girnita A, Stromberg T, et al. , authors. Targeting the insulin-like growth factor-1 receptor by picropodophyllin as a treatment option for glioblastoma. Neuro Oncol. 2010. 12:p. 19–27

66 

Zhou X, Shen F, Ma P, et al. , authors. GSK1838705A, an IGF-1R inhibitor, inhibits glioma cell proliferation and suppresses tumor growth in vivo. Mol Med Rep. 2015. 12:p. 5641–5646

67 

Premkumar DR, Jane EP, Pollack IF , authors. Co-administration of NVP-AEW541 and dasatinib induces mitochondrial-mediated apoptosis through Bax activation in malignant human glioma cell lines. Int J Oncol. 2010. 37:p. 633–643

68 

Gong Y, Ma Y, Sinyuk M, et al. , authors. Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation. Neuro-Oncology. 2016. 18:p. 48–57

69 

Carapancea M, Cosaceanu D, Budiu R, et al. , authors. Dual targeting of IGF-1R and PDGFR inhibits proliferation in high-grade gliomas cells and induces radiosensitivity in JNK-1 expressing cells. J Neurooncol. 2007. 85:p. 245–254

70 

Lasorella A, Sanson M, Iavarone A , authors. FGFR-TACC gene fusions in human glioma. Neuro Oncol. 2017. 19:p. 475–483

71 

Jimenez-Pascual A, Siebzehnrubl FA , authors. Fibroblast Growth Factor Receptor Functions in Glioblastoma. Cells. 2019. 8:p. 715

72 

Dieci MV, Arnedos M, Andre F, Soria JC , authors. Fibroblast growth factor receptor inhibitors as a cancer treatment: from a biologic rationale to medical perspectives. Cancer Discov. 2013. 3:p. 264–279

73 

Schramm K, Iskar M, Statz B, et al. , authors. DECIPHER pooled shRNA library screen identifies PP2A and FGFR signaling as potential therapeutic targets for diffuse intrinsic pontine gliomas. Neuro Oncol. 2019. 21:p. 867–877

76 

Seto B , author. Rapamycin and mTOR: a serendipitous discovery and implications for breast cancer. Clin Transl Med. 2012. 1:p. 29

77 

Yadavalli S, Yenugonda V, Kesari S , authors. Repurposed Drugs in Treating Glioblastoma Multiforme: Clinical Trials Update. Cancer J. 2019. 25:p. 139–146

78 

Kreisl TN, McNeill KA, Sul J, Iwamoto FM, Shih J, Fine HA , authors. A phase I/II trial of vandetanib for patients with recurrent malignant glioma. Neuro Oncol. 2012. 14:p. 1519–1526

79 

Chheda MG, Wen PY, Hochberg FH, et al. , authors. Vandetanib plus sirolimus in adults with recurrent glioblastoma: results of a phase I and dose expansion cohort study. J Neurooncol. 2015. 121:p. 627–634

80 

Quant EC, Batchelor T, Lassman AB, et al. , authors. Preliminary results from a multicenter, phase II, randomized, noncomparative clinical trial of radiation and temozolomide with or without vandetanib in newly diagnosed glioblastoma (GB). J Clin Oncol. 2011. 29:p. 2069

81 

Wen PY, Prados M, Schiff D, et al. , authors. Phase II study of XL184(BMS 907351), an inhibitor of MET, VEGFR2, and RET, in patients (pts) with progressive glioblastoma (GB). J Clin Oncol. 2010. 28 15 Suppl:p. 2006

82 

Loilome W, Joshi AD, ap Rhys CM, et al. , authors. Glioblastoma cell growth is suppressed by disruption of Fibroblast Growth Factor pathway signaling. J Neurooncol. 2009. 94:p. 359–366

83 

Grisanti S, Ferrari VD, Buglione M, et al. , authors. Second line treatment of recurrent glioblastoma with sunitinib: results of a phase II study and systematic review of literature. J Neurosurg Sci. 2019. 63:p. 458–467

84 

Belda-Iniesta C, Carpeno Jde C, Saenz EC, Gutierrez M, Perona R, Baron MG , authors. Long term responses with cetuximab therapy in glioblastoma multiforme. Cancer Biol Ther. 2006. 5:p. 912–914

85 

Neyns B, Sadones J, Joosens E, et al. , authors. Stratified phase II trial of cetuximab in patients with recurrent high-grade glioma. Ann Oncol. 2009. 20:p. 1596–1603

86 

Martens T, Schmidt NO, Eckerich C, et al. , authors. A novel one-armed anti-c-Met antibody inhibits glioblastoma growth in vivo. Clin Cancer Res. 2006. 12:p. 6144–6152

87 

Singh P, Alex JM, Bast F , authors. Insulin receptor (IR) and insulin-like growth factor receptor 1 (IGF-1R) signaling systems: novel treatment strategies for cancer. Med Oncol. 2014. 31:p. 805

88 

Yap TA, Omlin A, de Bono JS , authors. Development of therapeutic combinations targeting major cancer signaling pathways. J Clin Oncol. 2013. 31:p. 1592–1605

89 

Sestito S, Runfola M, Tonelli M, Chiellini G, Rapposelli S , authors. New multitarget approaches in the war against glioblastoma: a mini-perspective. Front Pharmacol. 2018. 9:p. 874

90 

Graves-Deal R, Bogatcheva G, Rehman S, Lu Y, Higginbotham JN, Singh B , authors. Broad-spectrum receptor tyrosine kinase inhibitors overcome de novo and acquired modes of resistance to EGFR-targeted therapies in colorectal cancer. Oncotarget. 2019. 10:p. 1320–1333

91 

Wei W, Shin YS, Xue M, et al. , authors. Single-cell phosphoproteomics resolves adaptive signaling dynamics and informs targeted combination therapy in glioblastoma. Cancer Cell. 2016. 29:p. 563–573

92 

Ziegler DS, Wright RD, Kesari S, et al. , authors. Resistance of human glioblastoma multiforme cells to growth factor inhibitors is overcome by blockade of inhibitor of apoptosis proteins. J Clin Investig. 2008. 118:p. 3109–3122

93 

Gazarian M, Kelly M, McPhee JR, Graudins LV, Ward RL, Campbell TJ , authors. Off-label use of medicines: consensus recommendations for evaluating appropriateness. Med J Aust. 2006. 185:p. 544–548

94 

Pantziarka P, Bouche G, Meheus L, Sukhatme V, Sukhatme VP , authors. Repurposing Drugs in Oncology (ReDO)-mebendazole as an anti-cancer agent. Ecancermedicalscience. 2014. 8:p. 443

95 

Tan SK, Jermakowicz A, Mookhtiar AK, Nemeroff CB, Schürer SC, Ayad NG , authors. Drug Repositioning in Glioblastoma: A Pathway Perspective. Front Pharmacol. 2018. 9:p. 218

96 

Andresen V, Gjertsen B , authors. Drug Repurposing for the Treatment of Acute Myeloid Leukemia. Frontiers in Medicine. 2017. 4:p. 211

97 

Verbaanderd C, Meheus L, Huys I, Pantziarka P , authors. Repurposing drugs in oncology: next steps. Trends Canc. 2017. 3:p. 543–546

98 

Shorthose S , author. Guide to EU Pharmaceutical Regulatory Law. 2017. Bird & Bird LLP;

99 

Pantziarka P , author. Scientific advice – is drug repurposing missing a trick? Nat Rev Clin Oncol. 2017. 14:p. 455–456

100 

Kurzrock R, Gurski LA, Carlson RW, et al. , authors. Level of evidence used in recommendations by the National Comprehensive Cancer Network (NCCN) guidelines beyond Food and Drug Administration approvals. Annals of Oncology. 2019. mdz232

101 

Vasilev A, Sofi R, Tong L, Teschemacher AG, Kasparov S , authors. In search of a breakthrough therapy for glioblastoma multiforme. Neuroglia. 2018. 1:p. 292–310

102 

Lefranc F, Yeaton P, Brotchi J, Kiss R , authors. Cimetidine, an unexpected anti-tumor agent, and its potential for the treatment of glioblastoma (review). Int J Oncol. 2006. 28:p. 1021–1030

103 

Michelakis ED, Sutendra G, Dromparis P, et al. , authors. Metabolic modulation of glioblastoma with dichloroacetate. Sci Transl Med. 2010. 2:p. 31–34

104 

Alonso-Basanta M, Fang P, Maity A, Hahn SM, Lustig RA, Dorsey JF , authors. A phase I study of nelfinavir concurrent with temozolomide and radiotherapy in patients with glioblastoma multiforme. J Neurooncol. 2014. 116:p. 365–372

105 

Pantziarka P, Sukhatme V, Bouche G, Meheus L, Sukhatme VP , authors. Repurposing Drugs in Oncology (ReDO)-diclofenac as an anti-cancer agent. Ecancermedicalscience. 2016. 10:p. 610

106 

Cheng HW, Liang YH, Kuo YL, et al. , authors. Identification of thioridazine, an antipsychotic drug, as an antiglioblastoma and anticancer stem cell agent using public gene expression data. Cell Death Dis. 2015. 6:p. e1753

107 

Sukhatme V, Bouche G, Meheus L, Sukhatme VP, Pantziarka P , authors. Repurposing Drugs in Oncology (ReDO)-nitroglycerin as an anti-cancer agent. Ecancermedicalscience. 2015. 9:p. 568

108 

Kast RE , author. Glioblastoma chemotherapy adjunct via potent serotonin receptor-7 inhibition using currently marketed high-affinity antipsychotic medicines. Br J Pharmacol. 2010. 161:p. 481–487

109 

Lee JK, Nam DH, Lee J , authors. Repurposing antipsychotics as glioblastoma therapeutics: Potentials and challenges. Oncol Lett. 2016. 11:p. 1281–1286

110 

Lee H, Kang S, Kim W , authors. Drug repositioning for cancer therapy based on large-scale drug-induced transcriptional signatures. PLoS ONE. 2016. 11:p. e0150460

111 

Krauze AV, Myrehaug SD, Chang MG, et al. , authors. A Phase 2 study of concurrent radiation therapy, temozolomide, and the histone deacetylase inhibitor valproic acid for patientswith glioblastoma. Int J Radiat Oncol Biol Phys. 2015. 92:p. 986–992

112 

Hothi P, Martins TJ, Chen L, Deleyrolle L, Yoon JG, Reynolds B, Foltz G , authors. High-throughput chemical screens identify disulfiram as an inhibitor of human glioblastoma stem cells. Oncotarget. 2012. 3:p. 1124–1136

113 

Kim YH, Kim T, Joo JD, Han JH, Kim YJ, Kim IA, Yun CH, Kim CY , authors. Survival benefit of levetiracetam in patients treated with concomitant chemoradiotherapy and adjuvant chemotherapy with temozolomide for glioblastoma multiforme. Cancer. 2015. 121:p. 2926–2932

114 

Friesen C, Hormann I, Roscher M, Fichtner I, Alt A, Hilger R, Debatin KM, Miltner E , authors. Opioid receptor activation triggering downregulation of cAMP improves effectiveness of anti-cancer drugs in treatment of glioblastoma. Cell Cycle. 2014. 13:p. 1560–1570

115 

Arrieta O, Guevara P, Escobar E, García-Navarrete R, Pineda B, Sotelo J , authors. Blockage of angiotensin II type I receptor decreases the synthesis of growth factors and induces apoptosis in C6 cultured cells and C6 rat glioma. Br J Cancer. 2005. 92:p. 1247–1252

116 

Robe PA, Bentires-Alj M, Bonif M, et al. , authors. In vitro and in vivo activity of the nuclear factor-kappaB inhibitor sulfasalazine in human glioblastomas. Clin Cancer Res. 2004. 10:p. 5595–5603

117 

Huang C, Hu S, Chen B , authors. Growth inhibition of epidermal growth factor-stimulated human glioblastoma cells by nicardipine in vitro. J Neurosurg Sci. 2001. 45:p. 151–155

118 

Assad Kahn S, Costa SL, Gholamin S, et al. , authors. The anti-hypertensive drug prazosin inhibits glioblastoma growth via the PKC-dependent inhibition of the AKT pathway. EMBO Mol Med. 2016. 8:p. 511–526

119 

Liu WT, Huang CY, Lu IC, Gean PW , authors. Inhibition of glioma growth by minocycline is mediated through endoplasmic reticulumstress-induced apoptosis and autophagic cell death. Neuro-Oncoloy. 2013. 15:p. 1127–1141

120 

Durmaz R, Deliorman S, Uyar R, Isiksoy S, Erol K, Tel E , authors. The effects of anticancer drugs in combination with nimodipine and verapamil on cultured cells of glioblastoma multiforme. Clin Neurol Neurosurg. 1999. 101:p. 238–244

121 

Zhang Y, Cruickshanks N, Yuan F, et al. , authors. Targetable T-type Calcium Channels Drive Glioblastoma. Cancer Res. 2017. 77:p. 3479–3490

122 

Weiger TM, Colombatto S, Kainz V, Heidegger W, Grillo MA, Hermann A , authors. Potassium channel blockers quinidine and caesium halt cell proliferation in C6 glioma cells via a polyamine-dependent mechanism. Biochem Soc Trans. 2007. 35:p. 391–395

123 

Yung WK, Kyritsis AP, Gleason MJ, Levin VA , authors. Treatment of recurrent malignant gliomas with high-dose 13-cis-retinoic acid. Clin Cancer Res. 1996. 2:p. 1931–1935

124 

Toler SM, Noe D, Sharma A , authors. Selective enhancement of cellular oxidative stress by chloroquine: Implications for the treatment of glioblastoma multiforme. Neurosurg. Focus. 2006. 21:p. E10

125 

Baumann F, Bjeljac M, Kollias SS, Baumert BG, Brandner S, Rousson V, Yonekawa Y, Bernays RL , authors. Combined thalidomide and temozolomide treatment in patients with glioblastoma multiforme. J Neurooncol. 2004. 67:p. 191–200

126 

Rosenfeld MR, Ye X, Supko JG, et al. , authors. A phase I/II trial of hydroxychloroquine in conjunction with radiation therapyand concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy. 2014. 10:p. 1359–1368

127 

Triscott J, Lee C, Hu K, et al. , authors. Disulfiram, a drug widely used to control alcoholism, suppresses the self-renewal of glioblastoma and over-rides resistance to temozolomide. Oncotarget. 2012. 3:p. 1112–1123

128 

Lee MS, Johansen L, Zhang Y, et al. , authors. The novel combination of chlorpromazine and pentamidine exerts synergistic antiproliferative effects through dual mitotic action. Cancer Res. 2007. 67:p. 11359–11367

129 

Shin SY, Lee KS, Choi YK, et al. , authors. The antipsychotic agent chlorpromazine induces autophagic cell death by inhibiting the Akt/ mTOR pathway in human U-87MG glioma cells. Carcinogenesis. 2013. 34:p. 2080–2089

130 

Harder BG, Blomquist MR, Wang J, Kim AJ, Woodworth GF, Winkles JA, Loftus JC, Tran NL , authors. Developments in blood-brain barrier penetrance and drug repurposing for improved treatment of glioblastoma. Front Oncol. 2018. 8:p. 462

131 

Dolma S, Selvadurai HJ, Lan X, et al. , authors. Inhibition of dopamine receptor D4 impedes Autophagic flux, proliferation, and survival of glioblastoma stem cells. Cancer Cell. 2016. 29:p. 859–873

132 

Pinheiro T, Otrocka M, Seashore-Ludlow B, Rraklli V, Holmberg J, Forsberg-Nilsson K, Simon A, Kirkham M , authors. A chemical screen identifies trifluoperazine as an inhibitor of glioblastoma growth. Biochemical and Biophysical Research Communications. 2017. 494:p. 477–483

133 

Johannessen TC, Hasan-Olive MM, Zhu H, et al. , authors. Thioridazine inhibits autophagy and sensitizes glioblastoma cells to temozolomide. Int J Cancer. 2019. 144:p. 1735–1745

134 

Bielecka-Wajdman AM, Lesiak M, Ludyga T, Sieron A, Obuchowicz E , authors. Reversing glioma malignancy: a new look at the role of antidepressant drugs as adjuvant therapy for glioblastoma multiforme. Cancer Chemother Pharmacol. 2017. 79:p. 1249–1256

135 

Meldrum BS , author. Update on the mechanism of action of antiepileptic drugs. Epilepsia. 1996. 37:p. S4–11

136 

Johannessen CU, Johannessen SI , authors. Valproate: past, present, and future. CNS Drug Rev. 2003. 9:p. 199–216

137 

Tseng J-H, Chen C-Y, Chen P-C, et al. , authors. Valproic acid inhibits glioblastoma multiforme cell growth via paraoxonase 2 expression. Oncotarget. 2017. 8:p. 14666–14679

138 

Fu J, Shao CJ, Chen FR, Ng HK, Chen ZP , authors. Autophagy induced by valproic acid is associated with oxidative stress in glioma cell lines. Neuro Oncol. 2010. 12:p. 328–340

139 

Sachkova A, Sperling S, Mielke D, Schatlo B, Rohde V, Ninkovic M , authors. Combined applications of repurposed drugs and their detrimental effects on glioblastoma cells. Anticancer Res. 2019. 39:p. 207–214

140 

Seizure Treatment in Glioma , author. ClinicalTrials.gov [Internet]. Available from: urihttps://clinicaltrials.gov/ct2/show/NCT03048084https://clinicaltrials.gov/ct2/show/NCT03048084 Retrieved December 28th 2019.

141 

Rother M, Erkinjuntti T, Roessner M, Kittner B, Marcusson J, Karlsson I , authors. Propentofylline in the treatment of Alzheimer’s disease and vascular dementia: a review of phase III trials. Dement Geriatr Cogn Disord. 1998. 9 Suppl 1:p. 36–43

142 

Jacobs VL, Liu YN, De Leo JA , authors. Propentofylline targets TROY, a novel microglial signaling pathway. PLoS One. 2012. 7:p. e37955

143 

Sotelo J, Briceno E, Lopez-Gonzalez MA , authors. Adding chloroquine to conventional treatment for glioblastoma multiforme: a randomized, double-blind, placebo-controlled trial. Ann Intern Med. 2006. 144:p. 337–343

144 

Weyerhauser P, Kantelhardt SR, Kim EL , authors. Re-purposing chloroquine for glioblastoma: potential merits and confounding variables. Front Oncol. 2018. 8:p. 335

145 

Yan Y, Xu Z, Dai S, Qian L, Sun L, Gong Z , authors. Targeting autophagy to sensitive glioma to temozolomide treatment. J Exp Clin Cancer Res. 2016. 35:p. 23

146 

Compter I, Eekers D, Hoeben A, et al. , authors. CHLOROBRAIN phase IB trial: The addition of chloroquine, an autophagy inhibitor, to concurrent radiation and temozolomide for newly diagnosed glioblastoma. Annals Oncol. 2019. 30 Suppl 5:p. v143–v158

147 

Nevin RL , author. Unexpectedly low rates of neuropsychiatric adverse effects associated with mefloquine repurposed for the treatment of glioblastoma. Cancer. 2019. 125:p. 1384–1385

148 

Barbieri F, Würth R, Pattarozzi A, et al. , authors. Inhibition of Chloride Intracellular Channel 1 (CLIC1) as Biguanide Class-Effect to Impair Human Glioblastoma Stem Cell Viability. Front Pharmacol. 2018. 9:p. 899

149 

Hart T, Dider S, Han W, Xu H, Zhao Z, Xie L , authors. Toward repurposing metformin as a precision anti-cancer therapy using structural systems pharmacology. Sci Rep. 2016. 6:p. 20441

150 

Bioavailability of Disulfiram and Metformin in Glioblastomas (INSIDE). urihttps://clinicaltrials.gov/ct2/show/NCT03151772https://clinicaltrials.gov/ct2/show/NCT03151772, Retrieved December 28th 2019.

151 

Rasper M, Schafer A, Piontek G, et al. , authors. Aldehyde dehydrogenase 1 positive glioblastoma cells show brain tumor stem cell capacity. Neuro-Oncology. 2010. 12:p. 1024–1033

152 

Liu P, Brown S, Goktug T, et al. , authors. Cytotoxic effect of disulfiram/copper on human glioblastoma cell lines and ALDH-positive cancer-stem-like cells. Br J Cancer. 2012. 107:p. 1488–1497

153 

Paranjpe A, Zhang R, Ali-Osman F, Bobustuc GC, Srivenugopal KS , authors. Disulfiram is a direct and potent inhibitor of human O6-methylguanine-DNA methyltransferase (MGMT) in brain tumor cells and mouse brain and markedly increases the alkylating DNA damage. Carcinogenesis. 2014. 35:p. 692–702

155 

Carapella CM, Paggi MG, Calvosa F, et al. , authors. Lonidamine in the combined treatment of malignant gliomas. A randomized study. J Neurosurg Sci. 1990. 34:p. 261–264

156 

Davidescu M, Macchioni L, Scaramozzino G, et al. , authors. The energy blockers bromopyruvate and lonidamine lead GL15 glioblastoma cells to death by different p53-dependent routes. Sci Rep. 2015. 5:p. 14343

158 

Kast RE, Boockvar JA, Brüning A, et al. , authors. A conceptually new treatment approach for relapsed glioblastoma: Coordinated undermining of survival paths with nine repurposed drugs (CUSP9) by the International Initiative for Accelerated Improvement of Glioblastoma Care. Oncotarget. 2013. 4:p. 502–530

160 

Abbruzzese C, Matteoni S, Signore M, Cardone L, Nath K, Glickson JD, Paggi MG , authors. Drug repurposing for the treatment of glioblastoma multiforme. J Exp Clin Cancer Res. 2017. 36:p. 169

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