**3. Issues of drug repositioning for glioma**

Despite these studies, some problems remain in drug repositioning for the treatment of glioma because of the uniqueness of this brain tumor.

The biggest problem is the penetration of the blood-brain barrier (BBB), which restricts the passage of molecules, including candidate agents. The BBB is a multilayered barrier between the blood and brain tissues to regulate the environment of the brain. The BBB has a good permeability for nutrients that are required for nerve cells [116]. Additionally, the BBB adjusts the ionic composition and the concentration of neurotransmitters, such as neuroexcitatory amino acids, to maintain the optimal environment for synapses. If ions and neurotransmitters spread into the CNS in an uncontrolled manner, the synapse is insufficiently stimulated and brain tissue is damaged [116]. The BBB also prevents the penetration of macromolecules more than 400–500 Da to exclude neurotoxic molecules [117]. Some plasma proteins induce the apoptosis of nerve cells [116]. This multilayered barrier blocks these proteins and would block the penetration of candidate agents. To overcome this problem, techniques are being explored. Some studies have investigated a new drug delivery system that uses an ultrasound-sensitizing nanoparticle complex, as preliminary studies have revealed that an ultrasound with microbubbles could open the BBB locally [118]. Other studies have evaluated the usefulness of conventionenhanced delivery therapy, which is a local infusion therapeutic technique to directly introduce a drug to brain neoplasms [119, 120].

A malignant glioma has features that are different from those in other malignant tumors. First, a malignant glioma has heterogeneity. Some malignant cancers, such as acute leukemia, are homogeneous; thus, the appropriate candidate agent would induce remission because "the weak point" of all tumor cells is the same.

*Drug Repositioning for the Treatment of Glioma: Current State and Future Perspective DOI: http://dx.doi.org/10.5772/intechopen.92803*

However, a malignant glioma is a complicated aggregation, once called "glioblastoma multiforme" [121]. If one candidate agent exerts therapeutic effects for some glioma cells, other resistant glioma cells would multiply. To overcome this problem, several previous studies have performed multiple-drug combination therapy. This therapy would focus on multiple therapeutic targets at once with minimal side effects [85]; however, currently, there are no combination treatments that can replace the current treatments. Second, despite its clinical aggressiveness, 60–70% of the tumor cells in malignant glioma are in the nonproliferating phase [122]. This indicates that not only heterogeneous cells but also the cell cycle must be considered because resting cells indicate resistance to chemoradiotherapy [122]. Based on this, some studies have focused on candidate agents that can change the phase of the cell cycle [18, 45].

## **4. Perspective**

attenuates the stemness and viability of GSCs via the downregulated activity of GSK3β [88, 110, 111]. The combination of low-dose kenpaullone with TMZ enhances cytotoxicity against glioma via the induction of c-Myc-mediated apoptosis [110]. These results suggest that kenpaullone is a potential compound for

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

Recently, 2-FPA, a new fatty acid inhibitor compound, has been identified as a potential anti-glioma agent through a drug screening system for drugs that target cancer stem cells using existing drug libraries [62]. As an active chemical compound, the safety of 2-FPA for normal brain cells has not yet been revealed. There are no reports that have mentioned the effect of 2-FPA in other cancers. An in vitro investigation using GSCs and GBM cells [112] has shown that 2-FPA suppresses the viability and sphere-forming ability of GSCs; inhibits the proliferation of GBM cells via the dephosphorylation of ERK, which is essential for the proliferation and invasion of glioma [113]; and blocks the invasion of GBM cells via the suppression of the activity of MMP-2, which plays an important role in cell invasion [114]. In addition to its mono activity against glioma, the combination of 2-FPA with TMZ synergistically enhances the efficacy of TMZ against glioma in vitro via the increase in MGMT promoter methylation and downregulation of MGMT, the main and predominant reasons for TMZ resistance [115], which suggest that combination therapy may be one strategy to improve TMZ efficacy and overcome resistance. Overall, 2-FPA is a potential therapeutic agent against GBM. To extend these

Despite these studies, some problems remain in drug repositioning for the treat-

The biggest problem is the penetration of the blood-brain barrier (BBB), which restricts the passage of molecules, including candidate agents. The BBB is a multilayered barrier between the blood and brain tissues to regulate the environment of the brain. The BBB has a good permeability for nutrients that are required for nerve cells [116]. Additionally, the BBB adjusts the ionic composition and the concentration of neurotransmitters, such as neuroexcitatory amino acids, to maintain the optimal environment for synapses. If ions and neurotransmitters spread into the CNS in an uncontrolled manner, the synapse is insufficiently stimulated and brain tissue is damaged [116]. The BBB also prevents the penetration of macromolecules more than 400–500 Da to exclude neurotoxic molecules [117]. Some plasma proteins induce the apoptosis of nerve cells [116]. This multilayered barrier blocks these proteins and would block the penetration of candidate agents. To overcome this problem, techniques are being explored. Some studies have investigated a new drug delivery system that uses an ultrasound-sensitizing nanoparticle complex, as preliminary studies have revealed that an ultrasound with microbubbles could open the BBB locally [118]. Other studies have evaluated the usefulness of conventionenhanced delivery therapy, which is a local infusion therapeutic technique to

A malignant glioma has features that are different from those in other malignant tumors. First, a malignant glioma has heterogeneity. Some malignant cancers, such as acute leukemia, are homogeneous; thus, the appropriate candidate agent would induce remission because "the weak point" of all tumor cells is the same.

the treatment of glioma.

*2.10.2 2-Fluoropalmitic acid (2-FPA)*

results, physiological studies are required.

**3. Issues of drug repositioning for glioma**

ment of glioma because of the uniqueness of this brain tumor.

directly introduce a drug to brain neoplasms [119, 120].

**148**

The strategy to discover the most effective drug is the key to accomplish a successful drug repositioning. One of the main methods is an in vitro or in vivo drug screening system in which target cells are treated by various existing drugs and the alteration to the malignant phenotype, such as by cytotoxicity, is analyzed. Drugs that exert cytotoxicity in GBM cells, especially GSCs, at low concentrations would be good candidates. Since the previous reports mention that GSCs were the cause of recurrence of GBM [100], GSCs can be good target. Lower drug concentration can minimize side effects. However, to achieve this strategy, appropriate experimental resources, including candidate agents, drug screening systems, and established cell lines are required. Epidemiological discovery is another option, such as the measurement of the incidence of a certain disease in the population to which specific drugs are administered. Serendipity is an important factor in this strategy. For instance, a prospective cohort study revealed a lower cancer incidence in people with schizophrenia [123]. This led us to the idea that antipsychotic drugs possess therapeutic effects against cancers including glioma [57, 62]. However, the most efficient method might be mutual molecular and structure analyses between target cells and drugs using artificial intelligence (AI). Different biochemical and mathematical techniques have been designed and optimized to accurately infer links between target cells and drugs. Drug-target interaction prediction is an important part of most rational drug repositioning pipelines. The major target molecules for malignant glioma are Akt, ERK, and STAT3, which sustain malignant phenotype [62, 103, 113].

The supply of research resources is also important. Pharmaceutical companies hold the materials for drug repositioning such as drug libraries and useful knowledge for bringing new drugs to market. Thus, a collaboration between researchers who establish efficient screening systems and pharmaceutical companies that own various drugs, including those that failed in clinical trials, can lead to a successful drug repositioning.

Although drug repositioning may be useful in the future, there are hurdles to the transition of this research into clinical practice owing to financial problems. Drug repositioning involves reinvestment in inexpensive drugs with expired patents; therefore, the benefits to pharmaceutical companies are small, which results in a reluctance to cooperate to broaden the indications of their drugs. This is especially true for rare diseases, such as glioma. Currently, the only way for researchers to raise public and private funds is by themselves, and they must conduct physicianled clinical trials without the support of pharmaceutical companies. An effective system in which the government supports drug repositioning is required to

overcome the issue of budget constraints. From an economic perspective, it would be beneficial to patients and countries to treat patients with inexpensive drugs with expired patents.

MMP-2 matrix metalloproteinase-2 mTOR mammalian target of rapamycin

*DOI: http://dx.doi.org/10.5772/intechopen.92803*

NF-κB nuclear factor-kappaB OS overall survival

PGE2 prostaglandin E2

SAS sulfasalazine SHH sonic hedgehog

TCF T-cell factor

TMZ temozolomide

VPA valproic acid

**Author details**

and Mitsutoshi Nakada<sup>1</sup>

University, Kanazawa, Japan

Sho Tamai<sup>1</sup>

**151**

PFS progression-free survival

PRL phosphatase of regenerating liver RdRP RNA-dependent RNA polymerase ROCK Rho-associated protein kinase

TERT telomerase reverse transcriptase TGF-β transforming growth factor-β

VEGF vascular endothelial growth factor

WHO World Health Organization

, Nozomi Hirai<sup>1</sup>

provided the original work is properly cited.

\*

, Shabierjiang Jiapaer<sup>1</sup>

1 Department of Neurosurgery, Graduate School of Medical Science, Kanazawa

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

2 Department of Pathology, Kurume University, Kurume, Japan

\*Address all correspondence to: mnakada@med.kanazawa-u.ac.jp

, Takuya Furuta<sup>2</sup>

STAT3 signal transducer and activator of transcription 3

*Drug Repositioning for the Treatment of Glioma: Current State and Future Perspective*

After the appearance of TMZ, drug development for GBM has stagnated. A huge advance in the treatment of patients with GBM can be expected if effective drugs are identified via drug repurposing.
