Frontiers in CNS Drug Discovery: Volume 3 E-Book
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- Herausgeber: Bentham Science Publishers
- Kategorie: Fachliteratur
- Serie: Frontiers in CNS Drug Discovery
- Sprache: Englisch
Frontiers in CNS Drug Discovery is a book series devoted to publishing reviews which highlight the latest advances in drug design and discovery for disorders of the central nervous system (CNS). Eminent scientists write contributions on all areas of CNS drug design and drug discovery, including medicinal chemistry, in-silico drug design, combinatorial chemistry, high-throughput screening, drug targets, recent important patents, and structure-activity relationships. The book series is essential reading for all pharmaceutical scientists involved in CNS drug design and discovery who wish to keep abreast of rapid and important developments in the field.
The third volume of this series brings reviews on brain tumor treatment, neurodegeneration, hyperalgesia, cholinesterase inhibition and much more.
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Seitenzahl: 511
Veröffentlichungsjahr: 2017
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PREFACE
Central nervous system (CNS) disorders are on the rise globally. Neurological, psychiatric and age-associated neurodegenerative diseases are among the major medical, biomedical, and social problems affecting the health system of many societies. Effective drugs are lacking despite major progress made in the understanding of the CNS diseases at the molecular level. Brain research is the most active area of research in biomedical sciences, and world literature on CNS disorders is expanding rapidly, covering various aspects of CNS disease groups. Thus, there is a strong need of a series of books that provide insights into the latest developments in this important field.
The first two volumes of the series “Frontiers in CNS Drug Discovery” have been very well received as a welcome addition to the global literature on this dynamic topic. The present 3rd volume of this internationally recognized books series comprises five invited reviews on various aspects of CNS drug discovery, contributed by leading experts in this field.
The first review contributed by Shibata et al. provides a comprehensive account of the major developments in the identification of drug targets for brain tumors, and strategies to treat resistant brain tumors. Unfortunately, prognosis in cancerous brain tumor patients is dismal despite availability of many new classes of drugs and other interventions, such as radiotherapy and surgery. One of the major challenges in the treatment of brian tumors is the emergence of resistance against chemotherapy. The authors have described the molecular characteristics of brain tumors explaining the mechanisms of drug resistance. Modern techniques of genetics, epigenetics, proteomics, transcriptomics, and metabolomics have been used to identify new drug targets in various forms of brain tumors, including glioblastoma. This has led to a better understanding of diseases which can be utilized to develop new strategies for the treatment of the most lethal form of human cancers. Results of recent pre-clinical and clinical studies are also reviewed; some of which have already led to significant improvements in the survival of brain tumor patients.
Hassen et al. present a comprehensive review on the role of calpain in various neurodegenerative and neuromuscular diseases in Chapter 2. Calpain is an intracellular Ca2+-dependent cysteine protease. It is among the best-characterized cysteine proteases activated in brain disorders. Extensive research has revealed that the deregulation of calpains activity is a key event in a variety of neurodegenerative disorders. The authors have discussed the role of calpain in neurodegenerative and neuromuscular diseases processes, which led to its identification as a valid target for drug discovery. Targeted calpain inhibition have been successfully studied in animal models. Three new classes of calpain inhibitors have also been presented, with the results of pre-clinical studies on some of them. These studies firmly establish the importance of inhibition of calpain as therapeutic option, and thus open new ways of drug discovery against diseases such as muscular dystrophy and neurodegeneration.
In Chapter 3, Kumar et al. focussed on Alzheimer’s and Parkinson’s diseases, as well as on schizophrenia including molecular basis and novel mechanisms involved in the onset and progression of these complex diseases. These studies have led to the identification of several new targets for drug discovery and development against these diseases. The importance of Tau dysfunction and associated genetic variants is also discussed. Current therapeutic interventions against these devastating neurological disorders are presented.
The review by Verri Jr et al. focusses on the role of neuroimmune system in pathological pain and inflammation, and the importance of its regulation as a possible treatment approach. Chronic pain and inflammation involve complex interactions between sensory neurons and glial cells. The activation of glial cells plays an important role in both the initiation and maintenance of pain. Based on the current understanding of the role glial cells in chronic pain, and associated mechanisms, the authors discuss various therapeutic interventions to manage chronic pain, and inflammation. The results of clinical trials of some modulators of glial cell activation in pain management are also presented.
The importance of cholinesterase inhibition in the treatment of Alzheimer’s disease (AD) and other diseases is reemphasized by Potter and Kerecsen in their very well written final chapter. Acetylcholinesterase is among the classical targets for drug discovery and development against AD, and many of the first-generation and second generation blockbuster drugs act through the inhibition of cholinesterases (acetylcholinesterase, and butyrylcholinesterase). The authors have reviewed many classes of cholinesterase inhibitors, their merits and demerits, including toxicity associated with them. The therapeutic role of cholinesterase inhibitors in the treatment of other diseases such as glaucoma, Myasthenia gravis, etc has also been reviewed.
We would like to express our profound gratitude to all the authors of the above cited reviews for their excellent contributions in this vibrant, and exciting area of biomedical and pharmaceutical research. The efforts of Bentham Science Publishers for the timely production of the 3rd volume are deeply appreciated, particularly those of Ms. Faryal Sami (Assistant Manager Publications) and Mr. Mahmood Alam (Director Publications).
List of Contributors
Molecular Targeting of Brain Tumors
Kenta Masui1,Mio Harachi1,Paul S. Mischel2,Tomoko Yamamoto1,Noriyuki Shibata1,*Abstract
An array of molecular underpinnings that dictate brain tumor growth and progression have been unraveled over the past decades. However, brain tumors’ resistance to therapeutics remains a basic challenge, and patients with brain tumors still face a dismal prognosis despite an application of extensive surgery, radiotherapy and chemotherapy. Resistance mechanisms of brain tumors to chemotherapy drugs and other kinds of therapeutic molecules range from the failure of drugs to reach their intended sites due to physiological and pathological obstacles through to the molecular circuitry of the cells which can be easily manipulated by cancer cells themselves. Recent advances and knowledge in sequencing technologies of the human genome have made it possible to perform high throughput screening of compounds libraries against biological targets, shedding light on potential new approaches to treat brain tumors. In this chapter, we describe the molecular characteristics of brain tumors which will explain how cancers cleverly resist chemotherapeutics and molecularly targeted therapies, especially focusing on the most common and lethal brain tumor in human, glioblastoma. We then introduce many promising approaches with the preclinical and clinical developments in brain tumor treatments to overcome, circumvent, disrupt or manipulate the physiological and pathological barriers of brain tumors. We lastly depict the emerging new strategies to facilitate the drug discovery through genome, epigenome, transcriptome and proteome approaches, raising new challenges and identifying new leads in brain tumor therapeutics.
Introduction – Cancer Drug Discovery in the Era of Molecular Genetics
Unified comprehension of the intricate molecular mechanisms that regulate tumor development has been introduced over the past years. However, it still remains a fundamental challenge to translate an array of the molecular genetic information on cancer into promising therapeutic strategies, especially for patients with brain cancers. The most successful example of effective anti-cancer drug development was represented by that of chemotherapeutic drugs. These agents could halt cell proliferation and induce cell death in rapidly proliferating cells, but the fundamental problem is that they did not effectively discern tumor cells from normal constituents [1]. Thus, caution should be taken in use of chemotherapeutics, where efficacy can be maximized while non-tumor side-effect can be minimized.
Advances in the knowledge of cancer genomics and epigenomics achieved by next-generation sequencing and large-scale DNA methylation profiling techniques have ushered in a new era of molecular diagnostics, especially represented in the field of brain tumors as “integrated diagnoses” [2, 3]. One of the genomically well-characterized brain tumors is gliomas, a potentially deadly type of brain tumors in human. They have been traditionally classified as astrocytic, oligodendroglial, oligoastrocytic (mixed) or ependymal tumors based on histological characteristics in the World Health Organization (WHO) classification of central nervous system (CNS) tumors [4]. Further, depending on morphologic features of anaplasia including mitotic activities, microvascular proliferation and necrosis, the WHO classification additionally assigns each tumor a histologic grade ranging from WHO grade I to grade IV, reflecting low to high grade of malignancy. The WHO classification and grading system has served as the guidance of post-operative treatment for many decades. However, the current comprehension of molecular genetics in brain tumors have been drastically changing the diagnostic scheme as well as therapeutic strategies against them.
The promising implication of advances in genetics and epigenetics in cancer is their potential to develop “molecularly targeting therapeutics” that specifically target the cancer-relevant genetic and epigenetic lesions, potentially without the major side effects in normal constituents in comparison with chemotherapeutics [5]. Nevertheless, it has become evident that drug resistance to this category of therapy could also occur irrelevant to the target and mechanism of drugs. In spite of the resistance which could hinder the effective cancer treatment, we remain clinically dependent on both chemotherapeutic and molecularly targeting drugs due to their unique advantages for treating cancer. As resistance remains the critical obstacle to success of both types of the drug, the challenge is to determine how to rationally and effectively use and combine these drugs based on the knowledge on molecular genetics.
Understanding the mechanisms by which cancer cells evade drug treatments and at the same time translating this knowledge into more effective treatment strategies will require a thoughtful as well as basic, clinical and translational approach. An empiric approach will not suffice as cancer cells possess too many targetable mutations and activated signaling pathways. Scientifically justified combination of targeted agents will pose significant challenges including cost-effectiveness, intellectual property considerations and cumulative toxicities [6]. Therefore, maximally harnessing the molecular genetic information of tumors and identifying mechanisms of inherent and acquired resistance to cytotoxic and targeted agents could provide potential hints that could guide the next generation of treatments against brain tumors.
This chapter will describe the molecular characteristics of brain tumors which will explain how cancers cleverly resist chemotherapeutics and molecularly targeted therapies, especially focusing on the most common and lethal brain tumor in human, glioblastoma (GBM) because of the breadth of its genomic and epigenomic information [7]. We then introduce many promising approaches with the preclinical and clinical developments in brain tumor treatments to overcome, circumvent, disrupt or manipulate the physiological and pathological barriers of brain tumors. We lastly depict the emerging new strategies to facilitate the drug discovery through genome, epigenome, transcriptome, proteome and metabolome approaches, raising new challenges and identifying new leads in brain cancer therapeutics.
New Molecular Framework for the Classification and Therapeutics of Gliomas
Major cellular constituents in the CNS system are neurons and glial cells including astrocytes, oligodendroglia and microglia. Until recently, most of the brain tumor classifications including gliomas had been based on the purely histological system of the classification scheme developed by Bailey and Cushing in 1926 [A Classification of the Tumors of the Glioma Group on a Histogenetic Basis with a Correlated Study of Prognosis], forming the foundation on which modern pathological diagnosis still rests. Their system relied on the histological resemblance of glioma cells to the normal glial constituents and putative developmental stages of glia. For instance, astrocytoma cells histologically resemble astrocytes in their star-shaped appearance and oligodendroglioma cells are similar to oligodendrocytes with round nuclei and perinuclear halo. Further, malignant transformation of these tumors can be understood as dedifferentiation of these tumor cells to immature states which have similar characteristics of glial progenitors and neural stem cells, normally residing in the specific niches of CNS [8]. The classification of gliomas based on histology thus seemed reasonable, but have in fact caused several problems in the clinic. Firstly, some tumor entities show histological phenotypes overarching several cellular lineages, well exemplified by the existence of mixed gliomas or oligoastrocytomas [4]. Second, glioma classification using histologic criteria suffers from a considerable degree of interobserver variability [9], especially prominent in regard to the detection of oligodendroglioma components. Third, histological classification does not necessarily well correspond to the patients’ survival and therapeutic efficacy.
Recent advances in deciphering the genomic landscape of gliomas have begun to reshape the practice of brain tumor diagnosis and classification. Our understanding on glioma pathogenesis and biology have been facilitated by the identification of important genetic, epigenetic and transcriptional aberrations in the various types of gliomas which also revealed that certain molecular alterations are associated with response to therapy and prognosis, while others may serve as diagnostic markers for more accurate classification [10, 11]. Thus, a major goal in current glioma diagnostics, and potentially subsequent therapeutic application, was proposed by incorporating molecular information into routine, primarily histology-oriented tumor classification. For the purpose of achieving that promising goal, 27 neuropathologists from 10 countries gathered in Haarlem, the Netherlands, in May 2014, under the auspices of the International Society of Neuropathology (ISN), and discussed how molecular criteria can be best incorporated into brain tumor diagnostics with improving current patient management. The meeting came up with the “ISN-Haarlem guidelines” proposing that brain tumor diagnostics should be layered, with histology (layer 2), WHO grading (layer 3) and molecular information (layer 4), listed under an integrated diagnosis (layer 1), so that brain tumor entities can be defined as narrowly as possible to improve interobserver compatibility, clinicopathologic predictions and therapeutic strategies [2]. Indeed, feasibility of this integrated diagnostic approach was well demonstrated, achieving a more accurate classification of biologically distinct glioma entities as well as a better prognostic stratification [12]. The ISN-Haarlem concept has been adapted by the updated version of WHO classification 2016, with the major glioma entities now being defined by not only histologic features but also molecular marker profiles [13].
One of the major discoveries that led to the current molecular classification of gliomas was the identification of isocitrate dehydrogenase 1 (IDH1) gene mutations as a new hotspot alteration in a subset of GBMs from younger patients and secondary GBMs progressed from pre-existing lower grade gliomas [14]. Since then, the overall concept of gliomas has dramatically changed. IDH1 or, less common IDH2 mutations are observed in more than 70% of lower grade (WHO grade II and grade III) astrocytic and oligodendroglial gliomas, as well as in secondary GBMs [15]. Numerous studies have revealed that IDH mutation separates gliomas with distinct biology and clinical behavior [10]. Additionally, it has been shown that gliomas occurring in children usually lack IDH mutations and can be subdivided into #1) low-grade tumors with circumscribed growth that are frequently associated with BRAF abnormalities activating downstream mitogen-activated protein kinase (MAPK) signaling [16, 17], and #2) high-grade gliomas with diffuse growth and frequent mutations in the histone H3 (H3F3A) gene [13, 18]. This dynamic transition from histology to molecular genetics enables us not only to sophisticate the classification of gliomas but also to illustrate the potential to transform our approaches towards performing chemotherapies as well as guiding targeted therapies to those patients most likely to benefit from them (Fig. 1).
Fig. (1))Molecular classifications of gliomas and relevant therapeutic targets. In adult gliomas, alterations in IDH, a very early genetic event in glioma development, are followed by the p53-ATRX mutational pathway (astrocytic tumors) or the 1p/19 co-deletion and TERT pathway (oligodendroglial tumors). IDH-wildtype glioblastomas are characterized by mutations in EGFR and TERT. Pediatric gliomas are usually IDH-independent, and can be classified into benign, localized tumors associated with BRAF abnormalities and diffuse midline gliomas with abnormal histone H3 variant. This molecular information will be available not only for accurate classifications of each entity but for therapeutic strategies specifically targeting each tumor with a distinct genetic background. wt, wild type; mt, mutant; GBM, glioblastoma.Chemotherapeutics Against Gliomas
Current Standard Chemotherapy of Gliomas
Gliomas are potentially incurable brain tumors, and GBM is the most frequent and devastating primary brain cancer with a median survival in the range of 12-15 months even after the intensive treatment [19, 20]. Treatment options for gliomas include surgery, radiation and chemotherapy, involving neurosurgeons, neuro-oncologists, radiation therapists and pathologists. Surgery is the most commonly performed therapeutic option for gliomas. The extent of the removal of tumor tissue is an important prognostic factor for glioma patients, guided by intraoperative MRI and administration of fluorescent agents such as 5-aminolevulinic acid (5-ALA) [21, 22]. Importantly, surgery can also allow for the precise diagnosis of the tumor by the pathologists. Radiation therapy and chemotherapy usually follow surgery as adjuvant treatments once the diagnosis of the tumor is determined. Radiation therapy generally ranges from whole-brain radiation to stereotactic radiosurgery according to the tumor types, locations and patients’ status [23].
The general concept for cancer chemotherapeutics relies on the fact that chemotherapy uses highly potent chemicals that hit rapidly proliferating cells. Tumor cells are especially sensitive to these drug treatments because of their fast growing capability well recognized as one of the hallmarks of cancer [24]. Chemotherapeutic drugs interfere with cell division, often at the level of DNA, and are divided into several classes based on the mechanism [1]. Alkylating agents (e.g. carmustine and platinum compounds cisplatin) damage DNA at any phase of the cell cycle, inducing a DNA-damage response (DDR) that leads to apoptosis. Mitotic inhibitors such as the taxanes (paclitaxel, docetaxel) and vinca alkaloids (vinblastine, vincristine) halt cell division by affecting microtubules which are used during cell divisions. Antitumor antibiotics, represented by the anthracyclines such as doxorubicin, interfere with DNA synthesis by intercalating between DNA strands. Topoisomerase inhibitors, such as irinotecan and topotecan, prevent DNA replication by inhibiting the activity of topoisomerases which are involved in the normal replication processes of DNA. Antimetabolites work by substituting for normal constituents of DNA, RNA or other cellular metabolites during the cell cycle where these molecules are synthesized. Administration of these drugs causes macromolecular damage and eventually cell death, and such antimetabolites include the pyrimidine antagonist 5-fluorouracil (5-FU) and capecitabine as well as the folate antagonist methotrexate.
Fig. (2))Mechanisms of TMZ action, repair and resistance. TMZ is spontaneously converted to 3-methyl-(triazen-1-yl)imidazole-4-carboximide (MTIC) which is subsequently broken down to methyldiazonium cation and 5-aminoimidazole-4-carboxamide (AIC). Methyldiazonium ions deliver methyl groups to the purine bases of DNA such as O6-guanine, N7-guanine and N3-adenine, forming O6-methylguanines, N7-methylguanines and N3-methyladenines, respectively [28]. The O6-methylguanine DNA adduct can be removed and restored by MGMT. Alternatively, the mismatched base pair of the persistent O6-methylguanine with thymine is recognized by the mismatch repair (MMR) pathway, resulting in futile repair cycling and cell death. N7-methylguanines and N3-methyladenines of DNA are repaired by the base excision repair (BER) pathway, and they usually do not contribute much to the cytotoxicity of TMZ.Alkylating agents had been the mainstay of treatment for brain tumors, and despite the development of efficient drug delivery systems such as convection-enhanced delivery (CED) including pressure-driven infusion of chemotherapeutic drug via an intracranial catheter [25], the role of chemotherapy in the treatment of gliomas has been controversial for decades until Stupp et al. demonstrated the first convincing data that the addition of an alkylating agent temozolomide (TMZ) to radiotherapy increased median survival in comparison with radiation alone, leading to a new “standard of care” for GBM [26]. TMZ is an orally available alkylating agent that is used for patients newly diagnosed with GBM. TMZ belongs to a new class of alkylating agents imidazotetrazines, and it is well applicable to brain tumors because it is lipophilic and crosses the blood-brain barrier (BBB) which is a major hindrance to the use of agents for CNS tumors [27]. TMZ is spontaneously hydrolyzed to the active metabolite 3-methyl-(triazen-1-yl)imidazole-4-carboxamide (MTIC), which further breaks down to the reactive methyldiazonium ion. The methyldiazonium ion donates the methyl-group to guanine residues in the DNA, resulting in the formation of O6- and N7-methylguanine, and the O6-methylguanine is primarily responsible for the cytotoxic effects of TMZ [28, 29] (Fig. 2). TMZ does not chemically cross-link the DNA strands, and thus it is less harmful to the bone marrow than are the nitrosoureas (i.e., carmustine, lomustine), platinum compounds and procarbazine, which do cross-link the DNA. Indeed, various studies have reported that TMZ was well tolerated with a survival benefit in comparison with other alkylating agents. Adjuvant and concomitant use of TMZ with radiation significantly improved the median progression-free survival over radiation alone (6.9 vs 5 months), the overall survival (14.6 vs 12.1 months), and the likelihood of 2-year survival (26% vs 10%) [26].
As for the conventionally used nitrosourea compounds, intraoperatively-performed chemotherapeutic strategies have been developed using bis-chloroethylnitrosourea (BCNU, carmustine)-polymer wafers (Gliadel), which were approved by the U.S. Food and Drug Administration (FDA) in 2003. The wafer is composed of the gel containing BCNU. After removing the tumor tissue, the wafers are intraoperatively placed in the resected space. Placed wafers release BCNU into the area over the next few days, and the wafers eventually dissolve over 2 to 3 weeks [30]. Gliadel wafers for initial treatment have shown a modest increase in median survival over placebo (13.8 vs 11.6 months) in the phase III trial, but may also be associated with the leakage of cerebrospinal fluid and increased intracranial pressure secondary to brain edema, especially with the combination of TMZ radio-chemotherapy [31, 32].
Predictive Molecular Markers for Glioma Chemotherapeutics
Recent advances in the molecular diagnostics in gliomas have a profound impact even on predicting the efficacy of glioma chemotherapeutics on each patient basis. The O6-methylguanine-DNA methyltransferase (MGMT) acts as a DNA repair enzyme that can neutralize the efficacy of chemotherapy with TMZ by removing TMZ-induced methylation at the O6-position of guanine residues of the DNA strands (Fig. 2) [33]. The MGMT gene at 10q26 is transcriptionally silenced by aberrant DNA methylation of its 5'-associated CpG island, an epigenetic aberration which is referred to as “MGMT promoter methylation”, in around 40% of IDH-wildtype GBMs as well as the vast majority of IDH-mutant gliomas which constitutes specific glioma subgroups, glioma-CpG island methylator phenotype (G-CIMP) [34]. Importantly, GBMs with MGMT promoter methylation respond better to treatment with DNA alkylating agents including TMZ [35, 36] and carmustine [34], and survive longer compared to GBMs with unmethylated MGMT promoter. Thus, MGMT promoter methylation is an important prognostic marker in GBM patients treated with the current standard therapy (i.e., radiotherapy combined with concomitant and adjuvant TMZ chemotherapy). However, combined radiochemotherapy may be too aggressive in the elderly patients with GBM (> 65 years of age). As stated above, MGMT promoter methylation is detectable in the vast majority of IDH-mutant gliomas, and the predictive power of MGMT promoter methylation may be associated with the high coincidence of other prognostic molecular markers in the tumors, including 1p/19q-codeletions [37-39] and IDH mutations [40-42]. The MGMT status is usually tested by methylation-specific PCR or methylation-specific pyrosequencing based on bisulfite conversion of unmethylated cytosines into uracils. Application of other techniques like methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), combined bisulfite restriction analysis (COBRA) or methylation-specific high resolution melting (HRM) analyses are currently less common in the clinic [43, 44].
In the revised WHO classification 2016, together with IDH mutation, codeletion of the whole chromosome arms 1p and 19q serves as an essential diagnostic marker that defines IDH-mutant and 1p/19q-codeleted oligodendroglioma (WHO grade II) and anaplastic oligodendroglioma (WHO grade III). Importantly, the phase III trials revealed evidence for a role of 1p/19q-codeletion in predicting patients’ survival with oligodendroglial tumors following chemotherapy with procarbazine, 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU, lomustine) and vincristine, namely PCV chemotherapy [45, 46]. Patients with 1p/19q-codeleted anaplastic oligodendrogliomas had significantly longer median overall survival when treated upfront with radiotherapy plus PCV chemotherapy in comparison with upfront radiotherapy alone. The findings underscore the importance of molecular testing for 1p/19q-codeletion not only for more accurate classification of diffuse gliomas but also for the stratification of patients to the best treatment [47]. Commonly used methods for 1p/19q-codeletion testing include microsatellite analysis for loss of heterozygosity (LOH), fluorescence in situ hybridization (FISH) and multiplex ligation-dependent probe amplification (MLPA) [43]. A microarray-based assessment of genome-wide DNA methylation and copy number profiling has been recently developed and used for simultaneous detection of IDH mutation/G-CIMP status, 1p/19q-codeletion and MGMT promoter methylation [48].
Fig. (3))Resistance mechanism to cytotoxic chemotherapies. Resistance to cytotoxic therapy generally results from a failure of the drug to reach its intended target. This is mediated by pharmacokinetic/pharmacodynamic problems (#1), induction of drug-inactivating enzymes (#2), enhanced activity of drug transporters (#3), sequestration of drugs (#4), induction of rescue genes to promote the repair of damaged DNA (#5), or disruption of mitochondrial-dependent apoptotic pathways (#6). Gray boxes represent the major resistant mechanisms to cytotoxic treatments.Resistance to Cytotoxic Chemotherapy
Resistance of cancer cells to chemotherapy drugs falls into two categories, extrinsic and intrinsic resistance mechanisms (Fig. 3). Extrinsic resistance involves the failure of drugs to reach their intended site of action due to pharmacokinetic/pharmacodynamic problems, such as a short half-life or rapid clearance [49]. Alterations in tumor drug metabolism involving such enzymes as cytochrome P450 (CYP) also affect the response to chemotherapy, and genetic polymorphisms of drug-metabolizing enzymes influence the plasma levels of active drug as well as drug sensitivity [50]. In order to circumvent these problems, chemotherapeutics can be conjugated to tumor-related antibodies or loaded into carriers such as liposomes or nanoparticles. These approaches have improved drug uptake and decreased drug-induced toxicity to normal tissue by enhancing specific drug delivery to the tumor. The tumor microenvironment is another emerging component of extrinsic drug resistance. The abnormal vasculature of tumors often prevents the access of chemotherapeutic drugs, and agents to affect the tumor vasculatures can improve drug distribution and delivery. The hypoxic environment of tumors is also known to cause chemoresistance by inhibiting cell proliferation since most chemotherapeutic drugs rest on rapid cell cycles for their efficacy. In addition, the transcriptional shifts induced by hypoxia contribute to resistance [51]. Thus, targeting of hypoxia inducible factor 1 (HIF-1), the major mediator of a hypoxic response, is one of the approaches to restore tumor oxygenation in an effort to increase drug sensitivity and response [52].
Intrinsic resistance mechanisms include the processes such as drug removal from its site of action by increased efflux or decreased uptake, enzymatic modification/inactivation of the drug, and alteration of drug targets within the cell. All the processes represent the ways tumor cells can utilize to acquire multi-drug resistance (MDR), enabling tumor cells to be cross-resistant to several cytotoxic drugs simultaneously. P-glycoprotein family of proteins in the context of MDR [53, 54] are components of the ATP-binding cassette (ABC) transporter efflux pumps that effectively remove drugs from the tumor cell. Another strategy that tumor cells exploit to avoid the effects of chemotherapeutics is to sequester the drug away from its action site. Drug-resistant cells facilitate the localization of chemotherapeutic drugs in specific organelles within the cytoplasm, whereas drug-sensitive cells tend to display nuclear drug localization and a more general distribution throughout the cytosol [55]. It is thought that the weak basic charge of many chemotherapy drugs promotes their trapping within acidic vesicles, followed by secretion from the tumor cells by harnessing normal vesicular trafficking.
As cancer cells depend on DNA synthesis to meet their proliferative demands, most of the chemotherapeutic drugs act in the way of damaging DNA molecules. DNA damage forces repair of the damaged DNA or induction of apoptosis as a means for preventing the cells with damaged DNA from abnormally expanding. The DNA repair machinery is an enzymatic complex which assures the integrity of DNA strands when damaged. DNA damage induces specific repair enzymes such as direct reversal (DR), transcription coupled repair (TCR), mismatch repair (MMR), homologous recombination (HR), Mre11–Rad50–Nbs1 (MRN) complex, base excision repair (BER), nucleotide excision repair (NER), global genome repair (GGR) and non-homologous end joining (NHEJ) [56], which tumor cells usurp to rescue the DNA damage caused by chemotherapy. MGMT promoter methylation-dependent resistant mechanism to TMZ is one of such examples utilized by glioma cells [35]. Another avenue to chemo-resistance is through the reprogramming of apoptotic pathways. Suppression of pro-apoptotic proteins and related pathways is often associated with the emergence of resistance to chemotherapy. The Bcl-2 family of proteins [57], the p53-regulated pro-apoptotic members [58] as well as inhibitor of apoptosis (IAP) family members are necessary for apoptotic cell death in response to DNA damaging agents, or chemotherapies. Therefore, significant effort has been made to overcome chemotherapy-induced resistance to apoptosis by using agents that specifically target the intracellular apoptotic machinery shown above [59]. We will later discuss how we could overcome this clever resistance mechanism of cancer cells against chemotherapies by combining several promising agents with chemotherapeutic drugs.
Molecularly Targeted Therapy Against Gliomas
The Current Status of Molecular Therapies Targeting the EGFR-mTOR Signaling Pathway
The field of the cancer treatment field has evolved considerably over the past decades with the introduction of molecular targeted therapies with higher specificities than chemotherapy, promising the potential for tumor cell eradication with decreased side effects. Cancer cells typically possess multiple mutations, but may develop dependence on a single chief mutation for survival rendering them preferentially susceptible to targeted inhibition [60, 61]. Experimental models and clinical studies support the hypothesis of “oncogene addiction”, providing compelling rationale for targeted cancer therapy [62, 63]. Molecularly targeting agents comprise small molecules (usually < 900 daltons) or monoclonal antibodies that block tumor cell proliferation and can induce apoptosis. The small molecules penetrate cellular membranes to reach their intended targets within cells, whereas the monoclonal antibodies are generally directed against cellular surface or extracellular antigens.
Recent progress in large-scale, multi-disciplinary molecular analyses of cancers based on novel array-based DNA methylation profiling and next-generation sequencing approaches have made possible the molecular stratification of GBMs by assessing the combination of molecular genetic signatures, as opposed to evaluating the individual markers [3, 11]. The Cancer Genome Atlas (TCGA) Research Network has been established to make the comprehensive catalog of genomic abnormalities driving tumorigenesis, and has revealed biologically relevant alterations in three core pathways in GBMs: namely, RTK/RAS/PI3K signaling, p53 and Rb pathways [64, 65]. Among these, the genomic characterization of most frequent subtypes of IDH-wildtype GBMs reveals frequent genetic alterations of key components of the epidermal growth factor receptor (EGFR)-PI3K-Akt signaling pathway which is integrated into mechanistic target of rapamycin (mTOR) signaling [64, 66] (Fig. 4).
Fig. (4))mTOR complexes are the key integrators of growth factor receptor signaling. mTORC1 and C2 play a key role in integrating signal transduction and metabolic pathways in GBM. Schematic representation shows intricate pathways that regulate or are regulated by mTOR signaling in GBM, which affect the efficacy of molecularly targeting therapies but could be an achele’s heel of GBM from a therapeutic point of view.The fact that most of the GBMs depend on the abnormally activated EGFR-mTOR pathway suggest that they may be quite vulnerable to the inhibition of EGFR-mTOR pathways according to the hypothesis of oncogene addiction. An array of clinical experiences suggests that tumor cell responses to EGFR-mTOR-targeting treatments are greatly affected by context-dependent oncogene addiction and an alternative acquired resistance. Our group demonstrated that expression of the constitutively active mutant EGFR variant III (EGFRvIII) made tumors sensitive to EGFR inhibitor, but only if the PTEN tumor suppressor protein was intact. In fact, loss of PTEN uncoupled the inhibition of EGFR from the inhibition of downstream PI3K signaling, demonstrating that PTEN loss was a critical factor in promoting resistance to EGFR inhibitors, partly because maintained PI3K signal flux was maintained in PTEN deficient tumors [67]. These studies indicate that intact regulation of PI3K signaling appears to be critical for predicting effective response to EGFR-targeting therapies.
Understanding the complex role of mTOR in regulating signal transduction is essential in developing more effective mTOR-targeted therapies although studies in human patients with recurrent malignant gliomas failed to demonstrate consistent responses to allosteric mTORC1 inhibitor rapamycin and its analogues because of several resistance mechanisms [19, 68]. Combinatorial molecular therapies may be useful to overcome the resistance, and a dual PI3K/mTOR inhibitor was indeed efficacious at halting the growth of GBM cells, independent of PTEN status [69]. Dual PI3K/mTOR inhibitors may also suppress extracellular signal-regulated kinase (ERK) signaling led by mTORC1 inhibition as a remarkable plasticity of tumor cells and their capacity for rewiring [70]. mTORC2 signaling in GBM is less well understood than that in mTORC1. We recently demonstrated that mTORC2 is frequently activated in GBM, resulting in the growth and survival of the tumor cells by activating NF-κB [71]. We also showed that mTORC2 is involved in feedback activation of Akt in rapamycin-treated patients, demonstrating a need to inhibit both mTORC1 and mTORC2 to achieve a better clinical response, and such clinical trials are currently on-going. However, this study also identified a previously unsuspected role for mTORC2 in mediating chemotherapy resistance, and EGFRvIII-expressing GBMs are exquisitely resistant to a platinum compound cisplatin [71]. We will further discuss the resistant mechanisms of tumor cells to molecularly targeting therapies in the following section.
Anti-angiogenic Therapy
One of the hallmarks of malignant gliomas is the capability to promote angiogenesis including microvascular proliferation in GBM [72]. The anti-angiogenic agent bevacizumab (Avastin; Genentech), a humanized monoclonal antibody against vascular endothelial growth factor (VEGF) ligands was approved by the U.S. FDA for recurrent GBM in 2009 [73]. When combined with irinotecan, bevacizumab prolonged 6-month survival in recurrent glioma patients to 46% compared with 21% in patients treated with TMZ [74]. Patients with supratentorial GBM received intravenous bevacizumab or placebo, plus radiotherapy and an oral TMZ, demonstrating that the median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months). The benefit relevant to progression-free survival was observed across subgroups, but overall survival was not significantly different between each group [75]. Intriguingly, gene expression analyses with the data from TCGA subclassified GBM into 4 transcriptomic groups (classical, proneural, neural and mesenchymal) [76, 77], and a proneural transcriptional signature has been connected to better response to upfront anti-angiogenic treatment with bevacizumab [78]. Anti-angiogenic agents also decrease peritumoral brain edema, potentially reducing the necessity to use corticosteroid. What is more, bevacizumab can improve the efficacy of combined cytotoxic agents through several mechanisms; 1) efficient delivery of cytotoxic drugs to the tumor by normalizing the tumor vasculature, 2) inihibition of rapid re-population of the tumor cells after cytotoxic therapies, and 3) enhancement of the anti-vascular effects of chemotherapeutic agents [79, 80]. However, to the contrary, it also has the potential to foil the effect of the combinatorial therapy by normalizing blood vessels and reconstituting the BBB in brain tumors, thereby preventing the diffusion of anti-cancer drugs.
Resistance to Molecularly Targeted Cancer Therapy
Like chemotherapeutics, resistance to molecular targeted drugs can be subclassified as intrinsic (primary) or acquired (secondary) and often counts on cellular reprogramming that sustain the signaling flux through alteration of downstream effectors, and/or disable the cell death machinery via compensatory cell survival pathways (Fig. 5).
Fig. (5))Resistance mechanism to molecular targeted therapies. The major mechanisms for molecular targeted therapy resistance include pharmacokinetic/pharmacodynamic problems (#1), co-activation of other RTKs (#2), persistence of activated downstream signaling (#3), bypass mechanisms including activation of alternative driver-oncogenes or other downstream signaling pathways (#4, 5), dampening of mitochondrial-dependent apoptotic pathways (#6), genetic alteration/mutation of the target itself including the dynamic regulation of extrachromosomal DNA (episomes) (#7), or mTOR-mediated dual regulation of cancer metabolism (#8). Gray boxes denote resistance mechanisms to target therapies.One of the most common resistant mechanisms to molecular targeted therapies involves the maintenance of oncogenic signaling via downstream pathways in spite of efficient target inhibition by a drug. A typical example for this type of resistance occurs in use of the drug to target the growth factor receptor or receptor tyrosine kinases (RTKs). When treating tumors with RTK inhibitors such as EGFR inhibitors, cancer cells display various resistance mechanisms including co-activation of other RTKs, signaling by physiologically regulated RTKs while mutant RTKs are inhibited, and secondary activating resistance mutations. EGFR tyrosine kinase inhibitors (TKIs) and the allosteric mTOR inhibitor rapamycin (and its derivatives) have failed to display durable efficacy in gliomas despite the rationale for targeting these molecules as aforementioned [67, 68, 81-83]. These failures could be explained by the relative ease with which cancer cells develop alternative resistance mechanisms to sustain downstream signaling flux. When treated with EGFR inhibitors, other RTKs including c-MET and/or platelet-derived growth factor receptor (PDGFR) become co-activated, engaging the shared PI3K to maintain downstream pathway activation [84, 85]. Thus, effective targeted therapy may require the combinatorial regimens targeting multiple RTKs simultaneously. Further, Akt inhibition induces the expression and phosphorylation of multiple RTKs, due to mTORC1 inhibition and a subsequent FoxO-dependent transcriptional activation of receptor expression [86]. Additionally, preclinical studies in GBMs have shown that upon EGFR inhibition, compensatory signaling is sustained by fibroblast growth factor (FGF) receptor and Src kinases and involves the inactivating phosphorylation of PTEN at Y240 [87].
Another type of acquired (secondary) drug resistance is facilitated by tumor cells through re-wiring of downstream signaling pathways thereby providing faulty brakes on growth checkpoints, secondary mutations in downstream signaling effectors, and/or feedback loop activation. As loss of chromosome 10 or PTEN is a common event in GBM, expression of EGFRvIII without functional PTEN can be a critical factor to display resistance to an EGFR inhibitor erlotinib due to uncoupled inhibition of EGFR from PTEN-mediated inhibition of downstream PI3K signaling [67]. Consistent with this, patients carrying tumors with high levels of EGFR coupled with low levels of activated Akt were prone to respond better to the TKI treatments [82]. These studies indicate that intact PI3K signaling seems to be critical for effective response to EGFR inhibitors and that efficacy of targeted agents requires consideration of genetic synthetic lethality or complementation for optimal effect. Rapamycin treatment which inhibits mTORC1 activity results in Akt activation by disturbing the negative feedback loop that normally mitigates PI3K signaling and is associated with significantly shorter time to tumor progression [68]. Additionally, it has been increasingly recognized that rapamycin only demonstrates the partial inhibition of the phosphorylation of 4E-BP1, which may explain the resistance to rapamycin treatment in cancer [88].
The failure to cause cell death due to disabling of the cellular death machinery is a mechanism which is involved not only in chemotherapy resistance but also in that of molecularly targeted therapies. For instance, high levels of the pro-apoptotic Bcl-2 family protein Bim expression are necessary for the induction of apoptosis upon TKI exposure [89]. However, the novel Bim isoform found in some cancers lacks the pro-apoptotic Bcl-2 homology domain 3 (BH3), and it is incapable of inducing apoptosis and contributes to poor clinical response to TKI treatment. For these patients, sensitivity to targeted therapy might be heightened by combining TKI and BH3 mimetics [89].
Together, all the examples provide compelling evidences that the approach to achieve the best clinical response to molecular targeted therapy will result from the utilization of molecular genetic information to stratify patients and clinical trials to assess the most effective strategy to inhibit both the driver mutations and the mechanisms that evade drug efficacy. Importantly, several studies with massively parallel sequencing technologies have demonstrated intra-tumoral genetic heterogeneity in solid cancers [90, 91] and revealed that specific mutations, including PIK3CA or PTEN mutations, may only preside in a subset of tumor cells in a given cancer [92, 93]. Additionally, GBM cells were reported to demonstrate completely unexpected mechanism of resistance mediated through modulation of extrachromosomal DNA of EGFRvIII [94]. These observations imply the necessity to develop accurate diagnostic biomarkers to collect representative tumor specimens and personalize therapies throughout the disease course. We will lastly depict the novel strategy to forestall the resistant mechanism which cancer cells exploit, and introduce the emerging effort of drug discovery which may much more effectively and specifically target malignant gliomas.
Next Generation Drug Treatments for Gliomas – Beyond the Genetics
Therapeutic Combination of Cytotoxic and Molecular Targeted Agents
Drug resistance is the dominant factor which prevents the successful application of cytotoxic chemotherapy as well as molecular targeted therapy. The complex biology of cancer cells and tumors prevents the success of both types of the agent. Each therapeutic approach hinges upon an essential dependency: chemotherapies on DNA synthesis/cell division, and molecular targeted treatments on the targeted pathway/addicted oncogene. Like their dependencies, resistance mechanism is reflective of each type of drug. Resistance to cytotoxic therapy generally results from the failure of the drug to reach the target site in an active form within a tumor cell. By contrast, the major mechanisms for resistance to molecular targeted therapy are genetic alteration of the target itself, and subsequent persistent activation of downstream signaling pathways. Analogous to the concept of genetic complementation or synthetic lethality [95], the combination of these two classes of drugs appear to be a promising avenue to overcome the resistance of each drug by complementing each other. However, combinations should be approached rationally and carefully, and not in the opportunistic way in which combinations have been tested and failed to demonstrate clinical benefit. In illuminating this point, it would be helpful to refer to and consider examples of combinatorial approaches that have demonstrated clinical efficacy as a way to inform and achieve the development of future treatment paradigms. For more information, see review [Masui et al., 2013] [6].
Emerging Targeted Therapies and Biomarkers
Important spinoffs derived from the advances in the glioma molecular diagnostics are the development of several molecular markers which may serve as predictive biomarkers for response of malignant gliomas to different types of targeted therapy. These include activating BRAF V600E mutation as a predictive marker for response to mutant BRAF inhibitors vemurafinib in anaplastic pleomorphic xanthoastrocytoma [96] and GBM [97-99]. Detection of IDH mutation in diffuse gliomas may provide predictive information when novel therapeutic strategies are applied such as mutant IDH inhibitors [100] or vaccination against IDH1-R132H [101]. Detection of FGFR-TACC fusion genes could identify GBM patients who are susceptible to FGFR kinase inhibition [102]. Subependymal giant cell astrocytoma (SEGA) is a WHO grade I glioma, and usually occur in patients with tuberous sclerosis complex (TSC) with mutations in the hamartin gene (TSC1) or the tuberin gene (TSC2) which may serve as therapeutic target when using mTOR inhibitors like everolimus [103]. The selectively high frequency of the telomerase reverse transcriptase (TERT) promoter mutations was observed among 1p/19q-codeleted oligodendrogliomas and the IDH-wildtype GBM [104], and a recently developed, novel TERT-targeting therapy [105, 106] might be a promising therapy to specifically target IDH-wildtype GBM with poorer prognosis and fewer effective therapeutics.
Immunotherapy for Gliomas
A promising avenue of clinical research in brain cancer is the use of immune system-targeting therapies including immune checkpoint inhibitors despite the fact that CNS is generally considered as an immune-privileged organ. These treatments act by hitting molecules which serve as brakes on immune responses. By blocking the inhibitory molecules, the treatments are aimed to augment pre-existing anti-cancer immune responses. The efficacy of this type of treatment was well demonstrated in several cancers including melanomas [107], and was also examined in brain cancer using anti-PD-1 (programmed cell death 1) and anti-CTLA-4 (cytotoxic T lymphocyte-associated protein 4) antibodies [108, 109]. Oncolytic virus therapy is another immune system-based strategy to use a modified virus that can force tumor cells to self-destroy and generate a strong immune response against the cancer as well [110, 111]. Several clinical trials are under way. Moreover, in an adoptive cell therapy, including the use of chimeric antigen receptors (CARs) designed to redirect T cells to specific antigens; immune cells taken from a patient are genetically modified or treated with chemicals to enhance their activity, and re-introduced into the patient with the aim to strengthen the immune response to the specific cancer. In this scenario, EGFRvIII may become an important predictive biomarker in GBM when peptide-based vaccination strategies, which recently showed promising activity [112, 113], will eventually enter the clinic.
Electric-field Therapy in Conjunction with Chemotherapy
The recently developed Optune device utilizes low-intensity, intermediate-frequency, alternating electric fields (tumor-treating fields: TTF) in order to hit rapidly dividing cells in GBM whereas not harming normal constituents in the brain. The electrodes are placed on the scalp according to the patient's magnetic resonance imaging, generating the TTFs for the treatment. “Optune” or “NovoTTF-100A System”, was approved in 2011 for use in patients with recurrent or progressed GBM. In the first controlled trial, any improvement was not demonstrated in overall survival, but efficacy and activity with the chemotherapy-free device treatment appears to be comparable to chemotherapy regimens for recurrent GBM. Further, TTF was favored in comparison with chemotherapy with respect to toxicity and quality of life [114]. In 2015, the FDA expanded its approval to allow for use of the device in conjunction with TMZ chemotherapy in the first-line option, based on the results of a randomized phase III trial, demonstrating that median overall survival was 19.4 months with use of the device plus TMZ, versus 16.6 months with chemotherapy alone [http://www.medscape.com/viewarticle/852196].
Targeting Cancer Metabolism and Epigenetics
A key mechanism to connect the genetic alterations with the glioma biology including epigenetic changes and therapeutics resistance is through metabolic reprogramming by cancer cells [115] (Fig. 6). The oncogenic transcription factor c-Myc is one of the main regulators of cancer metabolic reprogramming [116]. Studies from our group identify a set of interlacing molecular mechanisms by which EGFRvIII, an activating mutant of EGFR, engages c-Myc to reprogram intracellular metabolism and drive tumor cell proliferation [117-119]. Importantly, multiple upstream signaling pathways converge on c-Myc in cancer cells, raising the possibility that bromodomain and extraterminal (BET) bromodomain inhibitors that interfere with c-Myc-dependent target gene expression [120], may have a role in PI3K and mTOR activated tumors including GBM. In addition to the shift in nutrient within the cell, we recently made the novel discovery that exogenous fuel sources, glucose and acetate which are widely available in the brain and readily taken up by cancer cells [121, 122], are required for mutant EGFR signaling, affecting the therapeutic efficacy including chemotherapeutics [123] and molecularly targeted treatments [124-126]. This further suggests the importance to targeting cancer metabolism as next generation glioma therapeutics.
Fig. (6))Interaction of genetics and metabolism, a novel therapeutic target. Metabolic reprogramming in gliomas is driven by mutations in the cardinal genes related to gliomagenesis. Through metabolic reprogramming promoted by genetic aberrations, glioma cells vigorously take up extracellular nutrients and metabolize them into intermediary metabolites which in turn tailor the genetic signaling by altering epigenetics as well as post-translationally modifying oncogenic proteins in the cytoplasm. Targeting Myc-mediated metabolism or epigenetics could be a novel therapeutic strategy against GBMs. Ac, acetyl-group; Me, methyl-group; K, lysine residues.Diffuse midline glioma H3-K27M mutant (WHO grade IV), is a new WHO entity that is characterized by midline tumor location, including thalamus, brain stem and spinal cord, K27M mutation in either H3F3A (encoding histone H3.3) or HIST1H3B (encoding histone H3.1), and includes the vast majority of diffuse intrinsic pontine gliomas (DIPG) [18, 127, 128]. H3-K27M mutation mechanistically leads to global reduction in H3K27 trimethylation in glioma cells [129], and pharmacologic inhibition of the K27 demethylase JMJD3 with the GSK-J4 inhibitor increased H3K27 trimethylation and demonstrated potent antitumor activity against H3-K27M mutant glioma cells [130]. In addition, the multi-histone deacetylase inhibitor panobinostat also showed antitumor activity against H3-K27M mutant glioma synergistic with GSK-J4 treatment [131], suggesting promising novel approaches for targeting epigenetics in cancer. Other important regulatory mechanisms of epigenetics in gliomas are through IDH mutations in lower grade gliomas represented by G-CIMP and aberrant histone methylation [132], and through constitutive PI3K and mTOR activation in EGFR-mutant IDH-wildtype GBMs [133]. Future studies are necessary to examine whether these epigenetic changes could also be a druggable target to treat gliomas.
For the effective targeting of cancer metabolism and epigenetics, a new paradigm shift will be required since normal cells and cancer cells generally share the fundamental mechanisms to regulate intracellular metabolism and epigenetics. Thus, the cancer metabolism and epigenetics should be targeted in a genotype-specific and context-dependent fashion. Further, the influence of metabolic heterogeneity and microenvironment in tumor, which potentially contribute to the utilization of metabolic fuels by tumor cells, should be taken into consideration [134
