Advanced search
Publication Cover
Epigenetics Volume 18, 2023 - Issue 1
Submit an article Journal homepage
1,293
Views
0
CrossRef citations to date
0
Altmetric
Review

Brain Tumors: Development, Drug Resistance, and Sensitization – An Epigenetic Approach

Sibaji Sarkara Division of Biotechnology, Quincy College, Quincy, MA, USA;b Division of Biology, STEM, MBC College, Wellesley, MA, USA;c Division of Biology, STEM, RC College Boston, Boston, MA, USACorrespondencessarkarmmb@gmail.com
ORCID Iconhttps://orcid.org/0000-0002-2204-3031View further author information
ORCID Icon,
Tara Deyounga Division of Biotechnology, Quincy College, Quincy, MA, USAView further author information
,
Hope Resslerb Division of Biology, STEM, MBC College, Wellesley, MA, USAView further author information
&
Whitney Chandlerb Division of Biology, STEM, MBC College, Wellesley, MA, USAView further author information
Article: 2237761 | Received 05 Feb 2023, Accepted 11 Jul 2023, Published online: 27 Jul 2023

ABSTRACT

In this article, we describe contrasting developmental aspects of paediatric and adult brain tumours. We hypothesize that the formation of cancer progenitor cells, for both paediatric and adult, could be due to epigenetic events. However, the progression of adult brain tumours selectively involves more mutations compared to paediatric tumours. We further discuss epigenetic switches, comprising both histone modifications and DNA methylation, and how they can differentially regulate transcription and expression of oncogenes and tumour suppressor genes. Next, we summarize the currently available therapies for both types of brain tumours, explaining the merits and failures leading to drug resistance. We analyse different mechanisms of drug resistance and the role of epigenetics in this process. We then provide a rationale for combination therapy, which includes epigenetic drugs. In the end, we postulate a concept which describes how a combination therapy could be initiated. The timing, doses, and order of individual drug regimens will depend on the individual case. This type of combination therapy will be part of a personalized medicine which will differ from patient to patient.

Introduction

Paediatric and adult brain tumours differ in developmental process that makes it challenging to treat them in the same manner [Citation1]. Tumours are derived from glial cells more frequently than other parts/cells of the brain and the central nervous system (CNS) [Citation1]. Standard treatment therapies for most brain tumours include surgery, radiation, and chemotherapy. One major restriction to chemotherapy agents is their limited access to the brain due to the blood–brain barrier (BBB). Although brain tumours may seem unique from other types of cancers, the mechanisms of tumour development are similar. To develop better treatment options and to grasp the causation of drug resistance in brain tumours, it is integral to consider the following questions: What are the basic characteristics of brain tumours and how do they differ from other tumour categories? What are the mechanisms that lead to the development of brain tumours? What are the available treatment options and how does drug resistance evolve? We address these questions in this article.

Vast literature is available on the description of different types of brain tumours, their classification, therapy, prognosis, and outcome. The purpose of this commentary is to discuss the above questions, without elaborately summarizing the literature which is already available. The emphasis of the review is to discuss these topics in terms of epigenetic mechanisms. In addition, we discuss how sensitization of drug-resistant cells could be achieved.

Brain tumours and types

There are approximately 150 types of brain tumours divided into two categories: primary and metastatic [Citation1,Citation2]. Primary brain tumours are mainly composed of glial cells forming glioblastomas. Additionally, they can consist of other structural cells including nerves, blood vessels, and glands. While most metastatic brain tumours originate in the brain, other types of tumours may develop outside the brain and subsequently travel to the brain through the bloodstream. The most common examples of this phenomenon arise from breast and lung cancers. The brain tumours are graded according to their types, metastatic ability, and prognosis [].

Table 1. The table describes different types of paediatric and adult brain tumours both benign and malignant, their location, treatability, age group, and mutations observed in those types of brain tumours.

The complexity of the different types of brain tumours and their prognosis depends on their origin, their development, and progression. It is extremely important that the origin, which involves the formation of cancer stem/progenitor cells, is investigated to understand the growth, prognosis, treatments, drug resistance, and relapse of the brain tumours.

All types of brain cells, including glial cells and neuronal cells, originate from a single pluripotent stem cell during embryogenesis. The lineage of these brain cells is decided around day 16 of embryo development and from that point on, rapidly differentiate and divide until birth. Expression of both growth- and differentiation-related genes change rapidly at this point. This fast alteration in the expression of different genes is regulated by both internal and external signalling processes, including the contribution of stromal cells. Any deregulation of this process may create a cancer progenitor cell. The developmental stage of the brain at which the progenitor cells are formed determines the type of brain tumours. Growth and differentiation require several factors including fibroblast growth factor (FGF) [Citation1,Citation2,Citation18] as well as epigenetic alterations in terms of histone modification and DNA methylation [Citation18–24]. The involvement of FGF indicates that a cascade of signalling events occur during tumour development. It has been demonstrated that signalling mechanisms regulate epigenetic events and vice versa [Citation25]. However, there is a distinct difference between the development of adult and paediatric brain tumours. Adult brain tumours harbour different gene mutations. Paediatric brain tumours caused by H3K27me3 mutation suggest that epigenetic alterations are more prevalent in the development of paediatric brain tumours. They also harbour reversible epigenetic alterations in terms of differential levels of acetylation and methylation in both histones and upstream regions of genes [Citation26–28].

Brain tumours are either benign or malignant, and both types are found in adults and children. It is striking to realize that the complexity of location, aetiology, prognosis, and treatment of adult and paediatric brain tumours can be very different but can also overlap. The classification of brain tumours initially was based on their histological and physiological characteristics [Citation26,Citation29]. These classifications have gradually evolved to include genetic and molecular characteristics. The major classification of malignant vs benign brain tumours has always been based on metastatic ability indicating how aggressive the tumour develops. More recently, genetic information has upgraded this classification.

provides a list of benign and malignant brain tumours. Benign brain tumours have a better prognosis, but they can affect hormone productions and often damage nearby tissues or generate pressure beneath the skull. Glioblastomas are the most common type of brain tumours. Medial survival of glioblastoma is less than 2 y, and it is the most common malignant primary brain tumour [Citation29].

Brain tumour development

Usually, brain tumours have similar oncogene and tumour suppressor gene mutations as in other types of cancers. The current paradigm states that sequential mutations promote the development of tumours [Citation30]. The Hallmarks of Cancer Theory discusses the pathways and mechanisms involved in these processes [Citation31]. We have recently proposed that early events in carcinogenesis are a consequence of the formation of cancer progenitor cells. We also emphasized that cancer progenitor cell formation is an epigenetic event [Citation20,Citation32–34].

This idea is relevant considering the major differences between paediatric and adult brain tumours in their origin and development. Paediatric patients ordinarily have a better treatment outcome, although they may later develop chronic issues arising from the side effects of chemotherapy. Adult brain tumours are habitually more metastatic, and the prognosis is unfavourable. Recent studies have shown that paediatric tumour development requires epigenetic alterations [Citation18]. In younger patients, cells are rapidly growing, which presents an opportunity for cells at various stages to develop into cancer progenitor cells. These stage-selective cancer progenitor cells will then grow quickly along with high rates of developing paediatric brain tumours. In contrast, adult cells are well differentiated and require mutations [Citation35–38]. While epigenetic alterations possibly cause cancer progenitor cell formation and progression, mutations drive the tumour development and progression faster [Citation20,Citation30,Citation32,Citation34]. For example, IDH mutation is often found in Glioblastoma [Citation39]. In contrast, mutations in histone 3 or of enzymes that cause methylation of histone 3 tail amino acid residues in H3K27me3 are observed in paediatric tumours [Citation26]. Metastasis requires epithelial–mesenchymal transition (EMT) followed by mesenchymal–epithelial transition (MET) when the detached tumour cells settle in a different organ or tissue type. EMT–MET is a reversible process and as such supports the proposition that these transitions could potentially include epigenetic events [Citation40].

This scenario raises an interesting dilemma. As paediatric brain tumour cells are not well differentiated in the first place, they may lack extensive EMT-MET transition mechanisms and thus are not often metastatic. Further study is necessary to answer this question, but it raises the compelling possibility that due to the lack of metastasis, many types of paediatric brain tumours could be comparatively easier to treat.

If we can determine which factors either stop or slow the differentiation markers during childhood development, we could potentially understand the early evolution of tumours in children and how some of them develop metastatic tumours. For adults, this scenario is different. The terminally differentiated cells could de-differentiate, grow swiftly, and conceivably become metastatic. The differences could be explained if we look carefully at the location of paediatric vs. adult brain tumours. Paediatric brain tumours preferentially occur in the lower level of the brain that principally dictates movement and coordination. The lower part includes the brain stem and cerebellum. In contrast, adult tumours are often formed in the upper area of the brain which regulates memory, language, and thought. It remains to be determined whether different types of stromal cells contribute to the metastatic nature of adult brain tumours [Citation40, ].

Figure 1. Figure 1 describes the regions of brain and their functions. (a) Upper Brain, (b) Mid-Brain, and (c) Lower Brain.

Figure 1. Figure 1 describes the regions of brain and their functions. (a) Upper Brain, (b) Mid-Brain, and (c) Lower Brain.

Another important characteristic of paediatric brain tumours is that they usually do not involve alterations in inherited genes. A further distinction is that paediatric brain tumours commonly present as lower grades when compared to adult tumours that are typically higher-grade tumours [Citation41–43]. If we believe that epigenetic alterations play a significant role in the cancer progenitor cell formation in adults, which accumulate with age, lifestyle, and environment, then the development of paediatric brain tumours is contradicted. Recent results, though, support the notion that epigenetic alterations possibly develop paediatric tumours which lack many mutations [Citation18]. That raises a question whether the environment and lifestyle to which the parents are exposed contributes to the formation of cancer progenitor cells in the predisposed offspring. It is possible that the offspring inherits an altered epigenetic system from their parents. With this question in mind, it would be rewarding to investigate the epigenetic markers of the parents of both healthy children and children with brain tumours.

Epigenetics

The formation of lineage-specific stem cells from the pluripotent stem cells is an epigenetic event. This event consists of both histone and DNA modifications and contribution of different types of RNAs including microRNAs. Major histone modifications include acetylation/deacetylation and methylation/demethylation. The alterations on DNA are mainly methylation of the cytosine residue. Both methylation/demethylation and acetylation/deacetylation of histones could be activating or deactivating in terms of gene expression. Additionally, histone modification and DNA methylation can complement or antagonize gene expression depending on the players and location on the gene. For example, H3K9me3 recruits DNMT1 at the CpG residues in the upstream promoter regions of genes, which methylates these residues inhibiting POL II binding and thus inhibiting transcription [] [Citation44,Citation45]. However, upstream de-methylation of selected genes which binds H3K4me3 activates gene expression [Citation34].

Figure 2. (continued).

Figure 2. (continued).

Another important aspect of DNA methylation is in the enhancer region. H3K27me3 recruits polycomb group of regulatory proteins which facilitate the binding of CTCF protein to the CCCT motif in the enhancer region. This binding creates an insulated zone which does not allow bending of the enhancer region preventing POL II from binding to the promoter region []. This binding of CTCF to CCCT motif requires that CpG residues are not methylated in the enhancer region. In short, methylation at the promoter region inhibits transcription, but methylation at the enhancer region overrides the inhibition of transcription. An interesting consequence of this process has been observed in carcinogenesis. CpG residue methylation around promoter region usually silences tumour suppressor genes, whereas methylation around enhancer regions may facilitate expression of oncogenes. Therefore, methylation at two different sites uses two different mechanisms, but both scenarios promote tumour growth.

In , we describe possible combinations of DNA methylation and histone modifications. We refer to these combinations as epigenetic switches [Citation20,Citation32–34]. shows a scenario where both the promoter region and the enhancer region are not methylated. If the enhancer region is not methylated, H3K27me3 will create insulation to certain genes which will be prevented from being transcribed. These usually consist of tissue-specific genes. When these certain genes are not transcribed, other genes, not silenced by CTCF binding to CCCT, will be transcribed []. In , we explain the situations when the enhancer regions of the same genes described in are methylated. Usually, these epigenetic switches are a result of environmental changes, including changes in surrounding stromal cells which produce different signalling. Methylation in the enhancer region disrupts CTCF binding and reverses the inhibition, allowing for transcription of the genes. For example, expression of some of the tumour promoting genes is controlled by this mechanism, and once the enhancer region is methylated, they can be highly expressed. displays a demethylated enhancer region, resulting in CTCF recruitment for inhibition, while the promoter region is methylated. This is a scenario where the genes regulated by enhancer insulation as well as promoter methylation are not transcribed. Even for the genes where CTCF is not recruited, the promoter methylation still prevents transcription from occurring. This inhibition is usually observed for the silencing of tumour suppressor genes in cancer. shows methylation of both the enhancer and promoter regions. The methylation at the promotor region will most likely still inhibit transcription, despite the lack of inhibition in the enhancer region.

Figure 2. This diagram shows the change in methylation at the enhancer and the promoter regions. With no methylation at the enhancer region, the folding will not occur. (a, c). This will limit the amount transcribed (a), with methylation at the enhancer CCCTC motif, CTCF protein is prevented from binding and the enhancer region will fold over to the promoter to encourage transcription (b, d). Methylation by DNMT1 at the promoter region prevents transcription by not allowing POL II to bind to the region (c, d). When the promoter is not methylated, POL II is able to bind to the sequence and transcribe the genes (a, b).

Figure 2. This diagram shows the change in methylation at the enhancer and the promoter regions. With no methylation at the enhancer region, the folding will not occur. (a, c). This will limit the amount transcribed (a), with methylation at the enhancer CCCTC motif, CTCF protein is prevented from binding and the enhancer region will fold over to the promoter to encourage transcription (b, d). Methylation by DNMT1 at the promoter region prevents transcription by not allowing POL II to bind to the region (c, d). When the promoter is not methylated, POL II is able to bind to the sequence and transcribe the genes (a, b).

Essentially, alteration of these combinations causes overall epigenetic change and selective expression or inhibition of oncogenes and tumour suppressor genes for the formation of cancer progenitor cells [Citation20,Citation32–34]. These epigenetic changes are reversible and are the result of environmental effects and changes in lifestyles. As children are not exposed to environment for a longer period of time like adults, these alterations could be inherited from their parents. When the enhancer region is unmethylated, H3K27me3 will bind to the enhancer region, creating an insulation zone, inhibiting gene expression. Recent discoveries have shown that the enhancer element plays a crucial role in lineage-specific gene expression and lineage-specific stem cell formation [Citation20,Citation32,Citation34,Citation46,Citation47]. Methylation of that specific region releases the H327Kme3 binding and activates gene expression. These examples explain how histone modifications and DNA modifications work together.

Furthermore, depending on the type of modification the histone has and where the methylation is on the DNA, their interaction could either promote or inhibit gene expression. Once the lineage-specific stem cells are formed, a certain combination of DNA methylation and histone modification leads to a particular lineage-specific stem cell formation [Citation20,Citation46,Citation47]. The status of this combination is stable in those stem cells but may alter, as described in the formation of cancer progenitor cells.

This combination can be altered depending on whether the lineage-specific stem cells produce only one or multiple types of cells. For example, brain-specific stem cells produce all types of different cells found in the brain, including glial cells, neurons, and CNS cells. The differentiation requires further epigenetic change. Once these different lineage-specific cells are formed, they have a conserved histone and DNA pattern which does not modify any further, as the cells continue to grow and duplicate. This type of unique combination of histone modifications and DNA methylation, known as an epigenetic switch, was proposed by the authors previously [Citation33,Citation34,Citation40,Citation48].

The development of the brain starts around day 16 in embryogenesis and neuron production begins around day 42 post-conception. Initially, the rudimentary structures of the brain and the central nervous system start taking shape, including the major fibre pathways. Many other major events in brain development continue until adolescence [Citation49]. Following fertilization, human gain enhancers (HGE) play an important role in the development of human accelerated regions (HAR). It has already been observed that alteration in the HAR may result in other types of brain disorders or diseases. For example, autism spectrum disorder (ASD) has been linked to disturbances in the HAR [Citation50]. The HGE are regulated by CTCF binding proteins, creating an insulation zone to inhibit gene expression. The major player in this region is H3K27me3. As described before, H3K27me3 binds to an unmethylated enhancer region facilitating binding of CTCF proteins creating an insulated zone []. If the enhancer regions that dictate the differentiation of brain cells are hypomethylated, and the promoter regions of the differentiating genes are methylated, then differentiation will slow down, the same way growth can pick up at an unregulated speed. This process can lead to the formation of cancer progenitor cells later in childhood. shows that one of the epigenetically altered cells, as described above, may transform into cancer progenitor cells, which will develop into a tumour.

Figure 3. (a) Pediatric Brain Tumour Development. (I) Pluripotent Brain Cells. (II) Differentiation of cells to many specific types of brain cells, (III) One differentiated cells becomes a cancer progenitor cell, and (IV) Rapid growth of this cancer progenitor cell becomes a full-fledged tumour. (b) Adult Brain Tumour Development. (I) Normal differentiated adult cells. (II) One of the differentiated cells become cancer progenitor cells, (III) Rapid growth forming a group of cancer cells, and (IV) Brain tumour including heterogenous call population formed. EMT-epithelial mesenchymal transition, MET-mesenchymal epithelial transition.

Figure 3. (a) Pediatric Brain Tumour Development. (I) Pluripotent Brain Cells. (II) Differentiation of cells to many specific types of brain cells, (III) One differentiated cells becomes a cancer progenitor cell, and (IV) Rapid growth of this cancer progenitor cell becomes a full-fledged tumour. (b) Adult Brain Tumour Development. (I) Normal differentiated adult cells. (II) One of the differentiated cells become cancer progenitor cells, (III) Rapid growth forming a group of cancer cells, and (IV) Brain tumour including heterogenous call population formed. EMT-epithelial mesenchymal transition, MET-mesenchymal epithelial transition.

Adult neurons and glial cells, and the tumours associated with them, differ in their origins. These cells are much more terminally differentiated and, as such, must de-differentiate to support their fast growth, ultimately resulting in metastasis [Citation40]. This is a similar process which occurs in other types of metastatic tumours. These types of cancer progenitor cells arise from predisposed cells with either inherited and/or acquired epigenetic alterations including mutation in epigenetic players [].

Brain tumour therapy

The treatment of brain tumours often includes surgery, radiation, and chemotherapy. Surgery is the most common treatment for brain tumours followed by radiation. Chemotherapy is used as an adjuvant where applicable. In any case, the survival rate of metastatic brain tumours is not encouraging and warrants further investigation. The chemotherapy used to treat paediatric tumours can successfully shrink the tumour, but there could also be grave consequences. The side effects of chemotherapy usually have long-term or permanent effects on these young patients, and recurrence of tumours at a later age remains a possibility. Adult brain tumours in some cases are removed by surgery or treated with radiation followed by chemotherapy. Unfortunately, over time, the tumours frequently relapse [Citation51].

While the blood–brain barrier (BBB) protects the brain from various unwanted molecules, it fails to prevent the entrance of these metastatic cancer cells [Citation52–54]. Typically, the drugs administered cannot cross the BBB and are therefore instead directly applied to the brain or are administered through spinal fluid [Citation55]. Current research is exploring potential methods of conjugating drugs to molecules that will cross the BBB. Strategies are of two types: invasive and non-invasive. Invasive methods aim to disrupt the BBB. The non-invasive procedures use drug delivery through known receptors, which allow passage of other permeable molecules including nano particles [Citation56–60].

One interesting phenomenon could potentially facilitate drug delivery. Blood–tumour barrier (BTB) is different from the blood–brain barrier (BBB) and is more permeable. BTB also does not efflux the drugs as fast as the BBB does and the influx is facilitated. However, this phenomenon is heterogeneous with variable outcomes. The new blood vessels formed around tumours do not have tight junctions. The BTB possesses pores which may allow small molecules to enter. They have reduced the expression of tight junction proteins ZO-1 and occludin. In contrast, expression and secretion of vascular endothelial growth factor (VEGF) is increased which potentiates new blood vessel formation around the tumour. The non-invasive procedure exploits this difference between BBB and BTB [Citation61–66]. Generally, there are two types of chemotherapies that are extensively used against tumours: target-specific drugs and non-specific drugs [Citation67,Citation68]. Target-specific drugs are designed to inhibit specific molecules. Genes of these proteins are usually mutated which up-regulate or down-regulate specific signalling pathways. Some of these targeted proteins are cell surface proteins, for example, HER-2 receptors in breast cancer cells and epidermal growth factor receptor (EGFR). The specific inhibitor of HER-2, a monoclonal antibody, in common practice is Herceptin. Gefitinib, Erlotinib, and Afatinib are EGFR inhibitors. Other proteins that are usually mutated are intracellular signalling kinases such as src, RAS, Raf, MAP kinases, and fusion protein BCR-Abl. Usually, mutations in these genes result in upregulated signalling pathways that drive uncontrolled cell cycles. Inhibitors of these signalling molecules include Vemurafenib and Dabrafenib (BRAF), Trametinib (MEK), and imatinib mesylate and Nilotinib (BCR-Abl).

In about 50% of glioblastoma (GBM), EGFR is mutated. Mutations could be of different types. Mutations in the active site, deletions, and rearrangements of the open reading frame are some of the ways mutations occur in EGFR gene. One of the most important outcome of the mutations is constitutively active EGFR which transduce downstream signalling without ligand EGF binding [Citation69–71]. Some of the downstream signalling players of EGFR are RAS/MEK/ERK and PI3/PTEN/AKT/mTOR, STAT, and Notch signalling. The deregulation of these signalling pathways causes GMB progression. In addition, PI3K/AKT/mTOR pathway promotes cancer stem cell maintenance [Citation72,Citation73]. These are expected outcomes as it is well known that this pathway exerts anti-apoptotic effects. EGFR inhibitors are used to treat GB. In addition, monoclonal antibodies as mentioned for HER-2 and vaccine are also used. Another approach is to reduce the levels of expression of EGFR similar to HER-2 as discussed earlier. EGFR inhibitors including Gefitinib, Erlotinib, and Afatinib are not that effective because of inefficient permeability through BBB. Third-generation EGFR inhibitors like Osimertinib look more promising having a better permeability [Citation74–76].

Other mutations associated with cancer occur in tumour suppressor genes. Usually, these gene products are checkpoint inhibitors of the cell cycle. These molecules also edit mistakes in DNA replication and induce apoptosis when mistakes cannot be resolved. p53, p21, p16, p15, RB, RER, MGMT, BRCA1, BRCA2, and ARHI are some of the tumour suppressor genes that are non-functional in many types of cancers. While p53, p21, p16, and p15 are silenced in an array of cancers, BRCA1, BRCA2, and ARHI are specific to breast and ovarian cancer. Interestingly, p21, p16, p15, RER, BRAC1, BRCA2, MGMT, and ARHI are partially or completely silenced by upstream promoter region methylation [Citation32–34,Citation45,Citation48,Citation77,Citation78]. Methylation of this region allows recruitment of methyl-domain-binding proteins (MDBP) and HDACs. This recruitment inhibits POL II binding and impedes transcription (). RER gene is a differential marker and is silenced in many types of tumours. An existing idea is that re-expression of this gene will slow down tumour growth. Epigenetic drugs re-express RER by demethylation, with the addition of ATAR (retinoic acid), they reduced tumour growth. In vitro studies show that MGMT could be re-expressed in brain tumour cells by the addition of epigenetic drugs. ARHI is an imprinted proapoptotic gene which is only expressed from the paternal allele. In about 30% of breast and ovarian cancers, there is a loss of heterozygosity, and the paternal allele is silenced by upstream methylation. Recent studies have shown that treatment with HDACi demethylated ARHI, re-expressed the gene, and produced cancer cell death including autophagy in combination with other cytotoxic drugs [Citation79,Citation80].

When specific targets in the tumours are not well defined, the drugs of choice are platinum-based drugs, Taxol, etc. [Citation81,Citation82]. For example, the drug which is often used for brain tumours is temozolomide (Temodar-TMZ) [Citation83]. This drug inhibits DNA replication by attaching a methyl group to the guanine residue. As a result, tumours shrink, making them more susceptible to radiation therapy. This alkylating agent induces cell-cycle arrest at G2/M and activates apoptosis. Taxol disrupts the microtubule assembly causing cell death. These types of drugs are non-specific in the sense that they can affect to some extent the normal cells, so they are often toxic [Citation84]. MGMT has been extensively studied as methylation of MGMT poses a better outcome in Glioblastoma (GBM) treatment. MGMT is a DNA repair protein that saves DNA from mutations by alkylating agents. MGMT also reverses the effects of alkylating agents. Silencing of MGMT makes alkylating agents like TMZ more potent in GMB patients. Commonly, MGMT in GBM patients is silenced by promoter methylation [Citation85,Citation86]. Therefore, silencing of MGMT in GBM provides a better outcome when treated with TMZ.

GBM is divided into two types, IDH wild type (90%) and IDH mutant (10%) [Citation87]. Mutant IDH inhibits the enzymatic activity of TET2 that performs hydroxylation of 5-methylcytosine to 5-hydroxymethyl cytosine [Citation88]. These results in hyper-methylation [Citation89,Citation90]. Hyper-methylation of CpG islands in the promoter region silences many genes and enhances tumourigenesis [Citation89,Citation90]. This phenomenon is in contrast to the methylation of MGMT, which seems beneficial for TMZ treatment. More research is needed to clarify, in what situation methylation of which gene is favourable and which one is not. For example, more TERT methylation is observed in both types IDH wild type and mutant GBM [Citation91]. In paediatric brain tumour, TERT hypermethylation is associated with a worse prognosis [Citation92–94,].

These tumours in question often gain drug resistance. This occurs with both target-specific and non-specific drug therapies. As described in depth in the Hallmarks of Cancer [Citation1] there are six pathways for the development of cancer including sustaining proliferative signalling, evading growth suppressors, enabling replicative immortality, inducing angiogenesis, resisting cell death, and activating invasion and metastasis. Research from the last few decades has identified almost all the players of these pathways, including approximately 100 oncogenes. Most of the targeted drugs, which inhibit one or more players of these pathways, are currently being used for different types of tumours. Unfortunately, most of these regimens result in drug resistance.

Drug resistance

Drug resistance is the principal cause of tumour relapse. Discovery of aberrations in signalling pathways, as well as genetic alterations and/or mutations involved in and associated with carcinogenesis, has provided increased optimism in the ongoing advancement of specific chemotherapies. Huge numbers of target-specific drugs have been developed in the last 30 y, and many others are in the pipeline. In addition, there are some standard non-target specific drugs such as platinum drugs and taxols, which are often used when no other specific drugs would be effective. However, in most cases, prolonged use of chemotherapy results in drug resistance. Unfortunately, both target specific and non-specific drugs result in this resistance.

The mechanisms of development of drug resistance in cancer cells are diverse and widely discussed in literature [Citation32,Citation45,Citation48,Citation77,Citation78,Citation95]. One of the most important mechanisms by which cancer cells become drug resistant is the efflux of the drug. Cancer cells over-express the efflux pump multi-drug-resistant P-glycoprotein (MDR1 gene product), which pumps out any drug transported inside the cytoplasm. MDR is known to efflux many types of chemotherapeutic agents including vinca alkaloids, anthracyclines, and small-molecule inhibitors [Citation96–98]. Interestingly, this evolutionary phenomenon is paralleled in other organisms. Bacteria become resistant to antibiotics by the overexpression of efflux pumps [Citation19], along with other mechanisms.

Other important mechanisms which tumour cells often use to become resistant include modification of drug-binding sites, use of alternate signalling pathways, acquisition of new mutations, higher expression of tumour-promoting genes, lower expression of tumour-suppressor genes, epigenetic alterations, drug inactivation, inhibition of transport, DNA damage repair, cell death inhibition, and tumour heterogeneity [Citation32,Citation77,Citation78]. For example, a major player in drug inactivation is the cytochrome p450, CYP6 system. Mutations and activation of the CIP system results in increased breakdown and excretion of chemotherapeutic agents [Citation99–102]. Another problem is the failure of phosphorylation to convert an inactive drug to its active form. In the case of nucleoside drug Cytarabine (ARAC), it remains in its inactive form because resistant cancer cells do not allow its phosphorylation.

Lower expression of the drug transporter is another example of mechanism for resistance, which decreases the uptake of the drug. Imatinib, a tyrosine-kinase inhibitor (BCR-ABL), used for chronic myeloid leukaemia (CML) [Citation103], uses this mechanism for resistance. Binding-site modification is common for resistance against small-molecule inhibitors, which are designed to target signalling molecules. EGFR and BRAF family inhibitors develop resistance in this manner. Alteration in the expression of signalling molecules is also involved in causing drug resistance. Some of the important signalling molecules are Transforming Growth Factor-beta (TGF-β), CD44, and HER-2 [Citation104–106]. Most of the drugs used in cancer therapy are targeted against specific signalling molecules. Often, they cause higher expression of anti-apoptotic proteins, such as BCL2, leading to survival of the cancer cells against chemotherapy [Citation107–109]. DNA damage repair mechanisms are more relevant to brain tumours. As we mentioned, temozolomide is the drug of choice for glioblastomas because it inhibits DNA replication. DNA damage caused by guanine alkylation could be repaired by the overexpression of the enzyme O6methylguanine DNA-methyltransferase (MGMT), which causes drug resistance [Citation110]. Intriguingly, over-expression of CD133 in glioblastoma cells is observed to cause resistance to radiation therapy [Citation111]. CD133 is one of the proteins that provides stem cell-like properties (STEMness). STEMness generates resistance to many types of standard cancer therapies. Epithelial–mesenchymal transition (EMT) also plays a significant role in drug resistance, in addition to its primary function of metastasis [Citation40]. While the expression of cell–cell adhesion molecules decreases, the expression of metalloproteinases increases [Citation112,Citation113]. Proteolysis caused by these enzymes helps tumour cells to dislodge [Citation112].

Glioblastoma (GBM) resistance after therapy includes most of the common known causes of drug resistance. Enrichment of CD133-positive cells (a marker of tumour stem cells) is achieved by the activation of DNA damage checkpoint kinases Chk1 and Chk2. Other reasons are oncogene activation including EZH2, NF-kB, and Notch [Citation110–115].

A new strategy to combat GBM is a combination therapy. In recent clinical trials, TMZ and an improved TMZ derivative which can pass BBB more efficiently are used. TMZ has been combined with the inhibitors of the signalling pathways mentioned above. In some other studies, radiation therapy is combined with TMZ. An elaborate description is available in recent reviews [Citation116,Citation117,Citation118]. The most important criteria for designing a combination therapy would be that they should have synergistic effect, individual drugs should be used in lower doses, and they should not generate toxicity. Another important criterion is that they or their metabolites should not antagonize each other downstream [Citation77].

One of the most important recent developments in cancer treatment is cancer immunotherapy. Checkpoint inhibitors PDL1 and CTLA-4 expressions are lower in tumour cells. This is one of the mechanisms by which tumours evade immunological surveillance. This lower expression makes it difficult for the T-cell, which express their ligands (PD1), to bind to the tumour cells [Citation119–122]. The use of antibodies to these proteins (PD1/PDL1 or CTLA-4 and combination) helps T-cells recognize the tumour cells and induce their death. This novel therapy is useful against melanoma and is in clinical trial against almost all other types of tumours, including brain tumours. CTLA-4 and PD-1 are two such immune checkpoint molecules; blocking both CTLA-4 and PD-1 molecules induces long-term survival [Citation123,Citation124]. Combination of anti-PD-1 antibodies and signalling inhibitors increased long-term survival in 15–40% GBM mice [Citation125] However, it has been observed that after prolonged use, cancer immunotherapy also becomes refractory [Citation122].

Tumour heterogeneity with differential expression of genes creates a situation in which some of the tumour cells will be eliminated by chemotherapeutic agents, whereas those who accrue drug resistance will survive and grow. Often when one target-specific drug develops resistance, the choice is to simply use another target-specific drug. However, eventually the second drug will also become refractory. Combination therapy, implementing two or more drugs, has been in use for the last two decades to avoid this major issue. Researchers believe that the simultaneous utilization of two or more drugs at lower doses will be more effective and will reduce the possibility of developing resistance [Citation32–34,Citation48,Citation77,Citation78,Citation80,Citation84,Citation126]. Unfortunately, while the combination of multiple drugs produced better outcomes, it did not unravel the quandary. One of the principal reasons is the choice of drugs. In many circumstances, target-specific and non-specific drugs are chosen randomly. While both drugs could potentially kill tumour cells, the targets and pathways that they act on could be antagonistic and possibly activate or deactivate other signalling pathways, causing more problems than they resolve. This antagonistic scenario develops further drug resistance, enhancement of tumour growth, and a boost in toxicity. Some of these topics are elaborately discussed in previous publications by the authors [Citation77,Citation78].

Sensitization

One vital question in regard to the treatment of brain tumours, as well as other cancer types, is how to sensitize drug-resistant cancer cells. Sensitization of resistant cancer cells could be achieved in two ways: to the same drug against which they developed resistance or to a different drug. It is well established that combination therapy can be extraordinarily successful and is one of the best current courses for treatment, however the common practice of random selection has created major problems. Usually, researchers choose a downstream target if the inhibitor against the upstream target becomes resistant. Another choice is to make new or modified inhibitors to the mutated target. But this option comes with an increased risk of toxicity. For example, if cancer cells are resistant due to RAF1 mutation, the downstream signalling molecules were chosen, such as MEK or MAP kinases [Citation127–131]. Often, researchers try to develop inhibitors to the altered signalling molecule that caused the cancer drug resistance. This approach is successful for only a brief amount of time but has not been found to be effective in the long term because of additional mutations.

We reason that the epigenetic alterations are one of the important mechanisms of cancer drug resistance along with cancer progenitor cell formation. Additionally, cancer progenitor/stem cells are not killed by contemporary therapies. These are the reasons that we rationalize that one of the ingredients of the combination therapy should be one or more types of epigenetic drugs [Citation45,Citation55,Citation68,Citation77,Citation79,Citation132–135]. Epigenetic drugs which are in the current use are either HDAC inhibitors (HDACi) and DNA methylation inhibitors (inhibitors of DNA methyltransferase or DNMT1, are usually AZA or new derivatives of AZA) [Citation135,Citation136]. Recent studies have developed inhibitors to specific HDACs. Other specific inhibitors include bromodomains and extra-terminal motif (BET) inhibitors and EZH2 inhibitors [Citation136,Citation137]. Sometimes both HDACi and DNA methylation inhibitors are used together with other types of drugs or separately.

In acute myeloid leukaemia patients (AML) prior use of HDACi followed by all-trans retinoic acid (ATR) provided better outcomes [Citation138]. This example shows simultaneous administration of the combination therapy ingredients is not effective in all circumstances. Thus, the timing of the introduction of epigenetic drug ATR is important. Another study showed that platinum drug resistance in ovarian cancer is caused by the over-expression of RGS10 gene [Citation139]. This gene is epigenetically regulated. The higher expression was reversed using both HDACi and DNMT inhibitors [Citation139]. This re-expression RGS10 gene makes the platinum drug-resistant ovarian cancer cells sensitive to the original drug.

One recent study showed that the development of breast cancer could be reduced by inhibiting the formation of cancer stem cells [Citation140]. Treating breast cancer cells with both HDACi and DNMT1 inhibitors reduced the tumourigenicity of breast cancer stem cells [Citation141]. This raises a possibility that the use of epigenetic drugs in combination with conventional therapies is expected to have a better outcome in paediatric tumours. The reasoning for this comes from a recent study which has shown that the formation of paediatric brain tumours is principally an epigenetic event in the absence of sequential mutations [Citation18,Citation92].

Another example where a specific HDAC type of inhibitors produced better outcomes was observed in diffuse pontine gliomas [Citation137]. The use of BET and extra-terminal motif inhibitors in combination with EZH2 inhibitors produced better growth inhibitory effects [Citation137]. Other studies have shown that the combination of HDACi with other cytotoxic agents enhanced cell growth inhibition and cell death in many types of cancer cells including neuroblastoma, breast cancer, and ovarian cancer [Citation80,Citation124,Citation142–144].

Another way epigenetic drugs allow sensitization of tumour cells is by overexpressing known targets. For example, triple negative breast cancers lack oestrogen receptors (ER), progesterone receptors (PR), and HER2 expression. Treatment with HDACi increased the expression of oestrogen receptors, which can be targeted by oestrogen specific drug tamoxifen. HDACi also produced more than additive growth inhibition in combination therapy against triple negative breast cancer cells. This inhibition was achieved by the re-expression of epigenetically silent tumour suppressor genes [Citation80]. Similarly, HDACi increases the expression of checkpoint inhibitors: PDL-1 and CTLA-4, which can then be targeted by their antibodies, thus enhancing the efficacy of cancer immunotherapy [Citation122]. HDACi inhibitors have also been shown to regulate DNMT1 in cancers by interfering with ERK signalling [Citation25]. A study has shown that the combination of HDACi with retinoic receptor inhibitors increased the efficacy in neuroblastoma cells [Citation144].

These studies suggest that epigenetic alterations are mediated by the signalling process by the effect of external and internal milieu. Recent evidence suggests that epigenetic drugs also regulate important signalling molecules by modifying them in cells or by regulating their expression [Citation25].

There is a notion that a combination of only epigenetic drugs will result in a better outcome. Clinical trials based on this idea did not produce encouraging results in the long run. We believe that the combination of epigenetic drugs with traditional therapy is the better choice [Citation18–20,Citation22,Citation33,Citation40,Citation48,Citation68,Citation77,Citation132,Citation133]. Epigenetic drugs can halt the formation of and kill cancer progenitor cells, while also being able to sensitize cancer cells resistant to chemo therapies. However, they are inefficient at killing the fully developed tumour cells. The concept of combination therapy, which includes epigenetic drugs (HDACi, DNA methylation inhibitors, targeted histone modification inhibitors such as EZH2 inhibitor, or a combination of them), is described in .

Figure 4. Comparison of Standard Chemotherapy with Combination Therapy. a) Standard Chemo Therapy. (I) Standard chemotherapy, (II) Epigenetic Drug therapy, and (III) Combination therapy with epigenetic Drugs. b) Combination Therapy (I) Surgery, Radiation, Chemo Therapy, Standard therapy, (II) Epigenetic Drug therapy, and (III) Combination therapy with Epigenetic Drugs.

Figure 4. Comparison of Standard Chemotherapy with Combination Therapy. a) Standard Chemo Therapy. (I) Standard chemotherapy, (II) Epigenetic Drug therapy, and (III) Combination therapy with epigenetic Drugs. b) Combination Therapy (I) Surgery, Radiation, Chemo Therapy, Standard therapy, (II) Epigenetic Drug therapy, and (III) Combination therapy with Epigenetic Drugs.

depicts the differences in the outcome of combination therapies compared to standard treatments and only epigenetic drug treatments. This analysis predicts a better outcome for combination therapy including epigenetic drugs. Standard chemotherapies () reduce tumour growth, but they do not stop cancer progenitor cell formation or kill cancer progenitor cells. Nor do they eliminate the possibility of developing drug resistance. The scenario is better if the standard chemotherapy is combined with surgery and radiation () which will be more effective in reducing the tumour. But again, they do not stop cancer progenitor cell formation or kill cancer progenitor cells. Nor do they eliminate the possibility of developing drug resistance. Only epigenetic drug treatment ( II), when used as a single agent or in combination with other epigenetic drugs partially reduce tumour growth but will be able to stop further cancer progenitor cell formation and will reduce development of drug resistance. Usually, they are not that effective at reducing tumours rapidly. However, when epigenetic drugs are used with other therapies in combination, the outcome is expected to be that all three variables are inhibited (). The outcome will possibly be better as described in when multiple standard therapies will be combined with epigenetic drugs (). However, this outcome will depend on doses and on the time of administration of individual players, which will vary from patient to patient.

depicts the probabilities of futuristic modalities. No direct evidence is available for each step described. However, indirect evidence supports this notion as described in this article that epigenetics plays a significant role in the initiation and progression of brain tumour but more prominently in paediatric brain tumours. In addition, cancer stem cells are resistant to traditional therapies.

Conclusions

This commentary on brain tumours compares the differences between paediatric and adult types in terms of origin, development, location, therapy, drug resistance, and sensitization. Paediatric brain tumours differ from adult brain tumours based on the developmental origin, likelihood of metastatic behaviour, and overall prognoses. Adult brain tumours are observed to be more metastatic, worsening the prognosis, most commonly in glioblastomas. Metastatic brain tumours are diverse, more heterogeneous, and have origins both in the brain and from elsewhere in the body. In that context, adult metastatic brain tumours could be treated similarly to those found throughout the body. However, brain tumours are more difficult to treat because of their location and the blood–brain barrier (BBB). Development of new ways to deliver drugs to the brain will be extremely important for an effective combination therapy. Because the blood-tumour barrier (BTB) is more permeable than the BBB, it provides hope that future drug delivery development can infiltrate these tumours.

We have postulated previously that the formation of cancer-progenitor cells from predisposed cells is an epigenetic event [Citation20,Citation33,Citation34,Citation40,Citation48,Citation77] []. This event occurs by the combination of histone modifications and DNA methylation [Citation33,Citation34,Citation48] which turns on and off many genes. A recent study supports this notion that H3K4me3 works as a pulse in turning on and off genes [Citation145]. It remains to be determined whether H3K27me3 at the enhancer region works in a similar manner. Both of these two histone modifications work in a different manner. H3K4me3 binds to the unmethylated promoter regions and promotes gene transcription, whereas H3K27me3 binds to the unmethylated enhancer regions but inhibits transcription. Recent studies with both paediatric and adult brain tumours suggest that epigenetic alterations, in terms of histone modifications and DNA methylation, play an essential role in carcinogenesis. We have proposed that a combination therapy using epigenetic drugs could have a more promising outcome for many types of cancers [Citation68,Citation77,Citation132,Citation133]. In this article, we described how this combination will be beneficial to both paediatric and adult brain tumours. This is a more relevant choice for paediatric brain tumours, as recent studies have shown that epigenetics plays a significant role in the development of paediatric brain tumours [Citation18,Citation86,Citation89,Citation90,Citation92]. TERT methylation cohort study from the preserved tissues and MGMT methylation studies will provide the possibility of assessing the progression of brain tumours and could be developed as clinical biomarkers as well [Citation92,Citation146]. Future studies will reveal how many of the epigenetic alterations occurred in the developing child and how many epigenetic changes were inherited from parents. Thus, it will be rewarding to assess the epigenetic status and markers of parents of paediatric brain tumour patients and compare them with that of other patients. These types of studies could be performed by studying the preserved tissues as performed in the TERT study [Citation92] These types of studies will determine the molecular development of paediatric brain tumours and will help in improved diagnosis, prognosis, and treatment.

It is extremely important to understand how and why drug selection is important for effective combination therapy. This type of combination can reduce the production of cancer progenitor cells, kill cancer progenitor cells, and sensitize cancer drug-resistant cells. However, some necessary questions include the timings of drugs (administered simultaneously or separately?), duration of the combination therapy, whether the epigenetic drugs should be reduced to a lower dose after apparent tumour remission to attempt to inhibit further cancer progenitor cell formation, and whether the lower dose will prevent development of further drug resistance in tumour cells. Researchers often question whether higher doses of epigenetic drugs may cause alterations in the regulation of many unrelated genes, in turn producing unwanted consequences. With this concern in mind, introducing epigenetic drugs, combined with standard chemotherapy, allows for a lower dosage, significantly decreasing unwanted side effects. Another important aspect is the simultaneous or staggered timing of epigenetic drugs in the combination in order to achieve optimum efficacy [Citation77]. As we move towards personalized medicine, these treatment regimens will vary from patient to patient and must be decided upon an individual basis.

Abbreviations

MET =

Mesenchymal-epithelial transition
EMT =

Epithelial-mesenchymal transition
c-Src =

Proto-oncogene tyrosine-protein kinase sarcoma
Raf =

Rapidly Accelerated Fibrosarcoma
MAP =

Mitogen-Activated Protein kinase
HER-2 =

Human Epidermal Growth Factor Receptor 2
FGF =

Fibroblast Growth Factor
CIP =

Drug metabolism
CTCF =

CCCTC binding factor
CNS =

Central Nervous System
ASD =

Autism Spectrum Disorder
HAR =

Human Accelerated Regions
CpG =

Cytosine Phosphate Guanine
HGE =

Human Gain Enhancers
DNMT =

DNA methyltransferase
BBB =

Blood-brain barrier
BTB =

Blood-tumour barrier
TGF-β =

Transforming Growth Factor beta
H3K4me3 =

Trimethylated Histone 3 Lysine-4
H3K9me3 =

Trimethylated Histone 3 Lysine-9
H3K27me3 =

Trimethylated Histone 3 Lysine-27
HDAC =

Histone Deacetylases
EGFR =

Epidermal Growth Factor Receptor
GBM/GB =

Glioblastoma
MGMT =

O6-methylguanine-DNA methyltransferase
IDH =

Isocitrate Dehydrogenase

Authors’ contribution

SS conceived the concept of the paper. SS, TD, HR, and WC contributed to the development of the manuscript.

Acknowledgments

In an elaborate discussion, like this article, we try to cite as many relevant references as possible. Unfortunately, it is not possible to cite all applicable sources.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

The author(s) reported that there is no funding associated with the work featured in this article.

References

  • Azzarelli R, Simons B, Philpott A. The developmental origin of brain tumors: a cellular and molecular framework. Development. 2018;145(10):dev162693. doi: 10.1242/dev.162693 PMID: 29759978.
  • Abou-Antoun T, Hale J, Lathia J, et al. Brain cancer stem cells in adults and children: cell biology and therapeutic implications. Neurotherapeutics. 2017;14(2):372–22. doi: 10.1007/s13311-017-0524-0 PMID: 28374184; PMCID: PMC5398995]
  • Stratakis CA, Tichomirowa MA, Boikos S, et al. The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes. Clin Genet. 2010;78(5):457–463. doi: 10.1111/j.1399-0004.2010.01406.x PMID: 20507346; PMCID: PMC3050035
  • Onilude OE, Lusher ME, Lindsey JC, et al. APC and CTNNB1 mutations are rare in sporadic ependymomas. Cancer Genet Cytogenet. 2006;168(2):158–161. doi: 10.1016/j.cancergencyto.2006.02.019 PMID: 16843107
  • Bai J, Shi J, Li C, et al. Whole genome sequencing of skull-base chordoma reveals genomic alterations associated with recurrence and chordoma-specific survival. Nat Commun. 2021;12(1):757. doi: 10.1038/s41467-021-21026-5 PMID: 33536423; PMCID: PMC7859411.
  • Snuderl M, Kannan K, Pfaff E, et al. Recurrent homozygous deletion of DROSHA and microduplication of PDE4DIP in pineoblastoma. Nat Commun. 2018;9(1):2868. doi: 10.1038/s41467-018-05029-3 PMID: 30030436; PMCID: PMC6054684.
  • Hollander MC, Blumenthal GM, Dennis PA. PTEN loss in the continuum of common cancers, rare syndromes and mouse models. Nat Rev Cancer. 2011;1111(4):289–301. doi: 10.1038/nrc3037 Erratum in: Nat Rev Cancer. 2011 Jun;11(6):458. PMID: 21430697; PMCID: PMC6946181.
  • Kehrer-Sawatzki H, Farschtschi S, Mautner VF, et al. The molecular pathogenesis of schwannomatosis, a paradigm for the co-involvement of multiple tumour suppressor genes in tumorigenesis. Hum Genet. 2017;136(2):129–148. doi: 10.1007/s00439-016-1753-8 Epub 2016 Dec 5. PMID: 27921248; PMCID: PMC5258795.
  • Guha A, Vicha A, Zelinka T, et al. Genetic variants in patients with multiple head and neck paragangliomas: dilemma in management. Biomedicines. 2021;9(6):626. doi: 10.3390/biomedicines9060626 PMID: 34072806; PMCID: PMC8226913
  • Domingues P, González-Tablas M, Otero Á, et al. Genetic/Molecular alterations of meningiomas and the signaling pathways targeted. Oncotarget. 2015;6(13):10671–10688. doi: 10.18632/oncotarget.3870 PMID: 25965831; PMCID: PMC4484411.
  • Yang I, Nagasawa DT, Kim W, et al. Chromosomal anomalies and prognostic markers for intracranial and spinal ependymomas. J Clin Neurosci. 2012;19(6):779–785. doi: 10.1016/j.jocn.2011.11.004 Epub 2012 Apr 18. PMID: 22516549; PMCID: PMC3615711
  • Smith JS, Perry A, Borell TJ, et al. 19q as predictors of survival in oligodendrogliomas, astrocytomas, and mixed oligoastrocytomas. J Clin Oncol. 2000;18(3):636–636. doi: 10.1200/JCO.2000.18.3.636
  • Watanabe T, Nobusawa S, Kleihues P, et al. IDH1 mutations are early events in the development of astrocytomas and oligodendrogliomas. Am J Pathol. 2009;174(4):1149–1153. doi: 10.2353/ajpath.2009.080958 Epub 2009 Feb 26. PMID: 19246647; PMCID: PMC2671348
  • Turkalp Z, Karamchandani J, Das S. IDH mutation in glioma: new insights and promises for the future. JAMA Neurol. 2014;71(10):1319–1325. doi: 10.1001/jamaneurol.2014.1205
  • Richardson S, Hill RM, Kui C, et al. Emergence and maintenance of actionable genetic drivers at medulloblastoma relapse. Neuro Oncol. 2022;2424(11):153–165. doi: 10.1093/neuonc/noab178
  • Zhang X, Zhang Z. Oncohistone mutations in diffuse intrinsic pontine glioma. Trends Cancer. 2019;5(12):799–808. doi: 10.1016/j.trecan.2019.10.009 Epub 2019 Nov 9. PMID: 31813457; PMCID: PMC6986369.
  • Lewis NA, Klein RH, Kelly C, et al. Histone H3.3 K27M chromatin functions implicate a network of neurodevelopmental factors including ASCL1 and NEUROD1 in DIPG. Epigenet Chromatin. 2022;15(1):18. doi: 10.1186/s13072-022-00447-6 PMID: 35590427; PMCID: PMC9121554
  • Cancer M, Hutter S, Holmberg K, et al. Humanized stem cell models of pediatric medulloblastoma reveal an Oct4/mTOR axis that promotes malignancy. Cell Stem Cell. 2019;25(6):855–870. doi: 10.1016/j.stem.2019.10.005 PMID: 31786016.
  • Willbanks A, Leary M, Greenshields M, et al. The evolution of epigenetics: from prokaryotes to humans and its biological consequences. Genet Epigenet. 2016;8:25–36. doi: 10.4137/GEG.S31863 PMID: 27512339].
  • Lapinska K, Faria G, McGonagle S, et al. Cancer progenitor cells: the result of an epigenetic event? Anticancer Res. 2018;38:1–6. doi: 10.21873/anticanres.12184 PMID: 29277749.
  • Romani M, Pistillo MP, Banelli B. Epigenetic Targeting of Glioblastoma. Front Oncol. 2018;8:448. doi: 10.3389/fonc.2018.00448 PMID: 30386738.
  • Moyon S, Liang J, Casaccia P. Epigenetics in NG2 Glia cells. Brain Res. 2016;1638(Pt B):183–198. doi: 10.1016/j.brainres.2015.06.009 PMID: 26092401.
  • Mack S, Hubert C, Miller T, et al. An epigenetic gateway to brain tumor cell identity. Nat Neurosci. 2016;19(1):10–19. doi: 10.1038/nn.4190 PMID: 26713744
  • Orozco J, Knijnenburg T, Manughian-Peter A, et al. Epigenetic profiling for the molecular classification of metastatic brain tumors. Nat Commun. 2018;9(1):4627. doi: 10.1038/s41467-018-06715-y PMID: 30401823
  • Sarkar S, Abujamra A, Loew J, et al. Histone deacetylase inhibitors reverse CpG methylation by regulating DNMT1 through ERK signaling. Anticancer Res. 2011;31(9): 2423–2432. PMID: 21868513.
  • Campos-Sanchez E, Martínez-Cano J, Del Pino Molina L, et al. Epigenetic deregulation in human primary immunodeficiencies. Trends Immunol. 2019;40(1):49–65. doi: 10.1016/j.it.2018.11.005
  • Orozco JIJ, Knijnenburg TA, Manughian-Peter AO, et al. Epigenetic profiling for the molecular classification of metastatic brain tumors. Nat Commun. 2018 Nov 6;9(1):4627.
  • Chen KY, Bush K, Klein RH, et al. Reciprocal H3.3 gene editing identifies K27M and G34R mechanisms in pediatric glioma including NOTCH signaling. Commun Biol. 2020;3(1):363. doi: 10.1038/s42003-020-1076-0
  • Johnson DR, Guerin JB, Giannini C, et al. 2016 updates to the WHO brain tumor classification system: what the radiologist needs to know. Radiographics. 2017;37(7):2164–2180. doi: https://doi.org/10.1148/rg.2017170037
  • Tomasetti C, Marchionni L, Nowak M, et al. Only three driver gene mutations are required for the development of lung and colorectal cancers. Proc Natl Acad Sci USA. 2015;12(vol 1):118–123. doi: 10.1073/pnas.1421839112 PMID: 25535351
  • Hanahan D, Weinberg R. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. doi: 10.1016/j.cell.2011.02.013 PMID: 21376230
  • Sarkar S, Horn G, Moulton K, et al. Cancer development, progression, and therapy: an epigenetic overview. Int J Mol Sci. 2013;14(10):21087–21113. doi: 10.3390/ijms141021087 PMID: 24152442
  • Byler S, Sarkar S. Do epigenetic drug treatments hold the key to killing cancer progenitor cells? Epigenomics. 2014;6(2):161–165. doi: 10.2217/epi.14.4 PMID: 24811783
  • Longacre M, Snyder NA, Housman G, et al. A comparative analysis of genetic and epigenetic events of breast and ovarian cancer related to tumorigenesis. Int J Mol Sci. 2016;17(5):759. doi: 10.3390/ijms17050759 PMID: 27213343
  • Reilly KM. Brain tumor susceptibility: the role of genetic factors and uses of mouse models to unravel risk. Brain Pathol. 2009 Jan;19(1):121–131. doi: 10.1111/j.1750-3639.2008.00236.x
  • Barnholtz-Sloan J, Sloan AE, Land S, et al. Somatic alterations in brain tumors. Oncol Rep. 2008 Jul;20(1):203–210. doi: 10.3892/or.20.1.203 PMID: 18575738.
  • Tiong KL, Yeang CH. Explaining cancer type specific mutations with transcriptomic and epigenomic features in normal tissues. Sci Rep. 2018;8(1):11456. doi: 10.1038/s41598-018-29861-1
  • Kennedy SR, Zhang Y, Risques RA. Cancer-associated mutations but no cancer: insights into the early steps of carcinogenesis and implications for early cancer detection. Trends Cancer. 2019;5(9):531–540. doi: 10.1016/j.trecan.2019.07.007 PMID: 31474358.
  • Platten M, Bunse L, Wick A, et al. A vaccine targeting mutant IDH1 in newly diagnosed glioma. Nature. 2021;592(7854):463–468. doi: 10.1038/s41586-021-03363-z
  • Heerboth S, Housman G, Leary M, et al. EMT and tumor metastasis. Clin Transl Med. 2015;4(1):1–13. doi: 10.1186/s40169-015-0048-3 PMID: 25852822
  • Perkins A, Liu G. Primary brain tumors in adults: diagnosis and treatment. Am Fam Physician. 2016;93(3):211–217. PMID: 26926614.
  • Grant R. Overview: brain tumor diagnosis and management/Royal College of physicians guidelines. J Neurol Neurosurg Psychiatry. 2004;75(Suppl 2):ii18–23. doi: 10.1136/jnnp.2004.040360 PMID: 15146035
  • McFaline-Figueroa J, Lee EQ. Brain Tumors. Am j med. 2018;131(8):874–882. doi: 10.1016/j.amjmed.2017.12.039 PMID: 29371158.
  • Samorodnitsky E, Ghosh E, Mazumder S, et al. Methylation by DNMT1 is more efficient in chronic lymphocytic leukemia cells than in normal cells. J Proteomics Bioinform. 2014;S10–004. doi: 10.4172/jpb.S10-004
  • Sarkar S, Goldgar S, Byler S, et al. Demethylation and re-expression of epigenetically silenced tumor suppressor genes: sensitization of cancer cells by combination therapy. Epigenomics. 2013;5(1):87–94. doi: 10.2217/epi.12.68 PMID: 23414323.
  • Hnisz D, Brian J, Abraham BJ, et al. Super-enhancers in the control of cell identity and disease. Cell. 2013;155(4):934–947. doi: 10.1016/j.cell.2013.09.053 PMID: 24119843
  • Tang F, Yang Z, Tan Y, et al. Super-enhancer function and its application in cancer targeted therapy. NPJ Precis Oncol. 2020;12(4):2. PMID: 32128448. doi: 10.1038/s41698-020-0108-z
  • Byler S, Goldgar S, Heerboth S, et al. Genetic and epigenetic aspects of breast cancer progression and therapy. Anticancer Res. 2014;34(3):1071–1077. PMID: 24596345.
  • Won H, Huang J, Opland C, et al. Human evolved regulatory elements modulate genes involved in cortical expansion and neurodevelopmental disease susceptibility. Nat Commun. 2019;10(1):2396. doi: 10.1038/s41467-019-10248-3 PMID: 31160561.
  • Doan R, Bae B, Cubelos B, et al. Mutations in human accelerated regions disrupt cognition and social behavior. Cell. 2016;167(2):341–354.e12. doi: 10.1016/j.cell.2016.08.071 PMID: 27667684
  • Tan AC, Ashley DM, López GY, et al. Management of glioblastoma: State of the art and future directions. CA Cancer J Clin. 2020;70(4):299–312. doi: https://doi.org/10.3322/caac.21613
  • Miao R, Xia L, Chen H, et al. Improved classification of blood-brain-barrier drugs using deep learning. Sci Rep. 2019;9(1):8802. doi: 10.1038/s41598-019-44773-4 PMID: 31217424.
  • Tiwary S, Morale J, Kwiatkowski S, et al. Metastatic brain tumors disrupt the blood-brain barrier and alter lipid metabolism by inhibiting expression of the endothelial cell fatty acid transporter Mfsd2a. Sci Rep. 2018;8(1):8267. doi: 10.1038/s41598-018-26636-6 PMID: 29844613.
  • Arvanitis C, Ferraro G, Jain R. The blood–brain barrier and blood–tumour barrier in brain tumours and metastases. Nat Rev Cancer. 2020;20(1):26–41. doi: 10.1038/s41568-019-0205-x PMID: 31601988
  • Pardridge W. Drug transport in the brain via the cerebrospinal fluid. Fluids Barriers CNS. 2011;8(1):7. doi: 10.1186/2045-8118-8-7 PMID: 21349155.
  • El-Habashy SE, Nazief AM, Adkins CE, et al. Novel treatment strategies for brain tumors and metastases. Pharm Pat Anal. 2014 May;3(3):279–296. doi: 10.4155/ppa.14.19 PMID: 24998288; PMCID: PMC4465202.
  • Pathan SA, Iqbal Z, Zaidi SM, et al. CNS drug delivery systems: novel approaches. Recent Pat Drug Deliv Formul. 2009;3(1):71–89. doi: 10.2174/187221109787158355
  • Costantino L, Tosi G, Ruozi B, et al. Chapter 3 - colloidal systems for CNS drug delivery. Prog Brain Res. 2009;180:35–69. Highlights the novel colloidal carrier systems used to effectively deliver molecular therapeutics across the BBB into the brain. It provides a comprehensive overview of the novel pharmaceutical nano-formulations in efficiently targeting the problematic CNS.
  • Kuo Y-C, Lin P-I, Wang C-C. Targeting nevirapine delivery across human brain microvascular endothelial cells using transferrin-grafted poly(lactide-co-glycolide) nanoparticles. Nanomedicine (Lond). 2011;6(6):1011–1026. doi: 10.2217/nnm.11.25
  • Kazantsev AG, Outeiro TF. Editorial [hot topic: drug discovery for CNS disorders: from bench to bedside (guest editor: Tiago Fleming Outeiro)]. CNS Neurol Disord Drug Targets. 2010;9(6):668. doi: 10.2174/187152710793237395
  • Lockman PR, Mittapalli RK, Taskar KS, et al. Heterogeneous blood-tumor barrier permeability determines drug efficacy in experimental brain metastases of breast cancer. Clin Cancer Res. 2010;16(23):5664–5678. doi: 10.1158/1078-0432.CCR-10-1564
  • Hirano A, Matsui T. Vascular structures in brain tumors. Hum Pathol. 1975;6(5):611–621. doi: 10.1016/S0046-8177(75)80045-1
  • Hiesiger EM, Voorhies RM, Basler GA, et al. Opening the blood-brain and blood-tumor barriers in experimental rat brain tumors: the effect of intracarotid hyperosmolar mannitol on capillary permeability and blood flow. Ann Neurol. 1986;19(1):50–59. doi: 10.1002/ana.410190110
  • Gerstner ER, Fine RL. Increased permeability of the blood-brain barrier to chemotherapy in metastatic brain tumors: establishing a treatment paradigm. J Clin Oncol. 2007;25(16):2306–2312. doi: 10.1200/JCO.2006.10.0677
  • Bronger H, Konig J, Kopplow K, et al. ABCC drug efflux pumps and organic anion uptake transporters in human gliomas and the blood-tumor barrier. Cancer Res. 2005;65(24):11419–11428. doi: 10.1158/0008-5472.CAN-05-1271
  • Meegan M, O’Boyle N. Special issue “anticancer drugs”. Pharmaceuticals (Basel). 2019;12(3):134. doi:10.3390/ph12030134 PMID: 31527393.
  • Sanchez-Vega F, Mina M, Armenia J, et al. Oncogenic signaling pathways in the cancer genome atlas. Cell. 2018;173(2):321–337.e10. doi:10.1016/j.cell.2018.03.035 PMID: 29625050.
  • Housman G, Byler S, Heerboth S, et al. Drug resistance in cancer: an overview. Cancers. 2014;6(3):1769–1792. doi: 10.3390/cancers6031769 PMID: 25198391.
  • Brennan CW, Verhaak RGW, Mckenna A, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;85(155):462–477. doi: 10.1016/j.cell.2013.09.034
  • Furnari FB, Cloughesy TF, Cavenee WK, et al. Heterogeneity of epidermal growth factor receptor signalling networks in glioblastoma. Nat Rev Cancer. 2015;15:302–310. doi: 10.1038/nrc3918
  • Libermann TA, Nusbaum HR, Razon N, et al. Amplification, enhanced expression and possible rearrangement of EGF receptor gene in primary human brain tumours of glial origin. Nature. 1985;313:144–147. doi: 10.1038/313144a0
  • Krauth J. Comments on the paper by Möller et al. (1989): problems in single-case evaluation. Eur Arch Psychiatry Neurol Sci. 1990;239(6):391–394. discussion 395–397. doi: 10.1007/BF01734548
  • Akhavan D, Cloughesy TF, Mischel P. S. mTOR signaling in glioblastoma: lessons learned from bench to bedside. Neuro Oncol. 2010;12:882–889. doi: 10.1093/neuonc/noq052
  • Liu X, Chen X, Shi L, et al. The third-generation EGFR inhibitor AZD9291 overcomes primary resistance by continuously blocking ERK signaling in glioblastoma. J Exp Clin Cancer Res. 2019;38:219. doi:10.1186/s13046-019-1235-7
  • Gao M, Fu Y, Zhou W, et al. EGFR activates a TAZ-driven oncogenic program in glioblastoma. Cancer Res. 2021;81(13):3580–3592. doi: 10.1158/0008-5472.CAN-20-2773
  • Chen C, Cheng CD, Wu H, et al. Osimertinib successfully combats EGFR-negative glioblastoma cells by inhibiting the MAPK pathway. Acta Pharm Sin. 2021;42:108–114. doi:10.1038/s41401-020-0418-2
  • Leary M, Heerboth S, Lapinska K, et al. Sensitization of drug resistant cancer cells: a matter of combination therapy. Cancers. 2018;10(12):483. doi: 10.3390/cancers10120483 PMID: 30518036
  • Raymond E, Faivre S, Chaney S, et al. Cellular and molecular pharmacology of oxaliplatin. Mol Cancer Ther. 2002;1(3):227–235. PMID: 12467217.
  • Mataga M, Rosenthal S, Heerboth S, et al. Anti-breast cancer effects of histone deacetylase inhibitors and calpain inhibitors. Anticancer Res. 2012;32(7):2523–2529. PMID: 22753709.
  • Lapinska K, Housman G, Byler S, et al. The effects of histone deacetylase inhibitor and calpain inhibitor combination therapies on ovarian cancer cells. Anticancer Res. 2016;36(11):5731–5742. doi: 10.21873/anticanres.11156 PMID: 27793894
  • Weaver B, Bement W. How Taxol/paclitaxel kills cancer cells. Mol Biol Cell. 2014;25(18):2677–2681. doi: 10.1091/mbc.E14-04-0916 PMID: 25213191.
  • William D, Walther M, Schneider B, et al. Temozolomide-induced increase of tumorigenicity can be diminished by targeting of mitochondria in in vitro models of patient individual glioblastoma. PLoS One. 2018;13(1):e0191511. doi: 10.1371/journal.pone.0191511 PMID: 29352318.
  • Barbuti AM, Chen ZS. Paclitaxel through the ages of anticancer therapy: exploring its role in chemoresistance and radiation therapy. Cancers (Basel). 2015;7(4):2360–2371. doi: 10.3390/cancers7040897 PMID: 26633515
  • Zhou J, Kang Y, Chen L, et al. The drug-resistance mechanisms of five platinum-based antitumor agents. Front Pharmacol. 2020;11:343. doi: 10.3389/fphar.2020.00343 PMID: 32265714; PMCID: PMC7100275.
  • Hegi ME, Diserens AC, Gorila T, et al. MGMT gene silencing and benefit from temozolomide in glioblastoma. N Engl J Med. 2005;352(10):997–1003. doi: 10.1056/NEJMoa043331
  • Esteller M, Hamilton SR, Burger PC, et al. Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res. 1999;59(4): 793–797. PMID: 10029064.
  • Bady P, Kurscheid S, Delorenzi M, et al. The DNA methylome of DDR genes and benefit from RT or TMZ in IDH mutant low-grade glioma treated in EORTC 22033. Acta Neuropathol. 2018;135(4):601–615. doi: 10.1007/s00401-018-1810-6
  • Xu W, Yang H, Liu Y, et al. Oncometabolite 2-hydroxyglutarate is a competitive inhibitor of αketoglutarate-dependent dioxygenases. Cancer Cell. 2011;19:17–30. doi:10.1016/j.ccr.2010.12.014
  • Duncan CG, Barwick BG, Jin G, et al. A heterozygous IDH1R132H/WT mutation induces genomewide alterations in DNA methylation. Genome Res. 2012;22:2339–2355. doi:10.1101/gr.132738.111
  • Turcan S, Rohle D, Goenka A, et al. IDH1 mutation is sufficient to establish the glioma hypermethylator phenotype. Nature. 2012;483:479–483. doi:10.1038/nature10866
  • Louis DN, Perry A, Reifenberger G, et al. The 2016 World Health Organization classification of tumors of the central nervous system: a summary. Acta Neuropathol. 2016;131(6):803–820. doi: 10.1007/s00401-016-1545-1
  • Castelo-Branco P, Choufani S, Marck S, et al. Methylation of TERT promoter and risk stratification of childhood brain tumors: an integrative genomic and molecular study. Lancet Oncol. 2013;14(6):534–542. doi: 10.1016/S1470-2045(13)70110-4
  • Bardella C, Al-Dalahmah O, Krell D, et al. Expression of Idh1(R132H) in the murine subventricular zone stem cell niche recapitulates features of early gliomagenesis. Cancer Cell. 2016;30(4):578–594. doi: 10.1016/j.ccell.2016.08.017
  • Lu C, Ward P, Kapoor G, et al. IDH mutation impairs histone demethylation and results in a block to cell differentiation. Nature. 2012;483(7390):474–478. doi: 10.1038/nature10860
  • Al-Emran A, Marzese DM, Menon DR, et al. Commonly integrated epigenetic modifications of differentially expressed genes lead to adaptive resistance in cancer. Epigenomics. 2019;11(7):732–737. doi: 10.2217/epi-2018-0173 PMID: 31070054.
  • Abolhoda A, Wilson A, Ross H, et al. Rapid activation of MDR1 gene expression in human metastatic sarcoma after in vivo exposure to doxorubicin. Clin Cancer Res. 1999;5(11): 3352–3356. PMID: 10589744.
  • Thomas H, Coley HM. Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting P-glycoprotein. Cancer Control. 2003;10(2):159–165. doi: 10.1177/107327480301000207 PMID: 12712010
  • Michael M, Doherty MM. Tumoral drug metabolism: overview and its implications for cancer therapy. J Clin Onc. 2005;23(1):205–229. doi: 10.1200/JCO.2005.02.120 PMID: 15625375.
  • Plastaras J, Guengerich F, Nebert D, et al. Xenobiotic-metabolizing cytochromes P450 convert prostaglandin endoperoxide to hydroxyheptadecatrienoic acid and the mutagen, malondialdehyde. J Biol Chem. 2000;275(16):11784–11790. doi: 10.1074/jbc.275.16.11784 PMID: 10766802
  • Shen H, He M, Liu H, et al. Comparative metabolic capabilities and inhibitory profiles of CYP2D6.1, CYP2D6.10, and CYP2D6.17. Drug Metab Dispos. 2007;35(8):1292–1300. doi: 10.1124/dmd.107.015354 PMID: 17470523
  • Rodriguez-Antona C, Ingelman-Sundberg M. Cytochrome P450 pharmacogenetics and cancer. Oncogene. 2006;25(11):1679–1691. doi: 10.1038/sj.onc.1209377 PMID: 16550168.
  • Thomas J, Wang L, Clark RE, et al. Active transport of imatinib into and out of cells: Implications for drug resistance. Blood. 2004;104(12):3739–3745. doi: 10.1182/blood-2003-12-4276 PMID: 15315971
  • Brunen D, Willems S, Kellner U, et al. TGF-β: an emerging player in drug resistance. Cell Cycle. 2013;12(18):2960–2968. doi: 10.4161/cc.26034 PMID: 23974105.
  • Ravindranath AK, Kaur S, Wernyj RP, et al. CD44 promotes multi-drug resistance by protecting P-glycoprotein from FBXO21-mediated ubiquitination. Oncotarget. 2015;6(28):26308–26321. doi: 10.18632/oncotarget.4763 PMID: 26299618.
  • Hori A, Shimoda M, Naoi Y, et al. Vasculogenic mimicry is associated with trastuzumab resistance of HER2-positive breast cancer. Breast Cancer Res. 2019;21(1):88. doi: 10.1186/s13058-019-1167-3 PMID: 31387614.
  • Yang X, Zheng F, Xing H, et al. Resistance to chemotherapy-induced apoptosis via decreased caspase-3 activity and overexpression of antiapoptotic proteins in ovarian cancer. J Cancer Res Clin Oncol. 2004;130(7):423–428. doi: 10.1007/s00432-004-0556-9 PMID: 15156398.
  • Wilson T, Johnston P, Longley DB. Anti-apoptotic mechanisms of drug resistance in cancer. Curr Cancer Drug Targets. 2009;9(3):307–319. doi: 10.2174/156800909788166547 PMID: 19442051.
  • Stover E, Baco M, Cohen O, et al. Pooled genomic screens identify anti-apoptotic genes as targetable mediators of chemotherapy resistance in ovarian cancer. Mol Cancer Res. 2019;17(11):2281–2293. doi: 10.1158/1541-7786.MCR-18-1243 PMID: 31462500
  • Maier P, Spier I, Laufs S, et al. Chemoprotection of human hematopoietic stem cells by simultaneous lentiviral overexpression of multidrug resistance 1 and O(6)-methylguanine-DNA methyltransferase(P140K). Gene Ther. 2010;17(3):389–399. doi: 10.1038/gt.2009.133 PMID: 19865182
  • Bao S, Wu Q, McLendon RE, et al. Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 2006;444:756–760. doi: 10.1038/nature05236 PMID: 17051156.
  • Farahani E, Patra H, Jangamreddy J, et al. Cell adhesion molecules and their relation to (cancer) cell stemness. Carcinogenesis. 2014;35(4):747–759. doi: 10.1093/carcin/bgu045 PMID: 24531939.
  • Quintero-Fabian S, Arreola R, Becerril-Villanueva E, et al. Role of matrix metalloproteinases in angiogenesis and cancer. Front Oncol. 2019;9:1370. doi: 10.3389/fonc.2019.01370 PMID: 31921634.
  • Labelle M, Hynes RO. The initial hours of metastasis: the importance of cooperative host–tumor cell interactions during hematogenous dissemination. Cancer Discov. 2012;2(12):1091–1099. doi: 10.1158/2159-8290.CD-12-0329 PMID: 23166151.
  • Flavahan WA, Drier Y, Liau BB, et al. Insulator dysfunction and oncogene activation in IDH mutant gliomas. Nature. 2016;529(7584):110–114. doi: 10.1038/nature16490 Epub 2015 Dec 23. PMID: 26700815; PMCID: PMC4831574.
  • Venere M, Horbinski CM, Crish JF, et al. The mitotic kinesin KIF11 is a driver of invasion, proliferation, and self-renewal in glioblastoma. Sci Transl Med. 2015;7(304):304ra143. doi: 10.1126/scitranslmed.aac6762
  • Ghosh D, Nandi A, Bhattacharjee A. Combination therapy to checkmate glioblastoma: clinical challenges and advances. Clin Trans Med. 2018;7(1):33. doi: https://doi.org/10.1186/s40169-018-0211-8
  • George SL, Falzone N, Chittenden S, et al. Individualized 131I-Mibg therapy in the management of refractory and relapsed neuroblastoma. Nucl Med Commun. 2016;37(5):466–472. doi: 10.1097/MNM.0000000000000470 PMID: 26813989; PMCID: PMC4819901.
  • Kayano D, Kinuya S. Current consensus on I-131 MIBG therapy. Nucl Med Mol Imaging. 2018;52(4):254–265. doi: 10.1007/s13139-018-0523-z Epub 2018 May 3. PMID: 30100938; PMCID: PMC6066492
  • Stanculeanu DL, Daniela Z, Lazescu A, et al. Development of new immunotherapy treatments in different cancer types. J Med Life. 2016;9(3): 240–248. PMID: 27974927.
  • Oiseth SJ, Aziz MS. Cancer immunotherapy: a brief review of the history, possibilities, and challenges ahead. J Cancer Metastasis Treat. 2017;3(10):250–261. doi: 10.20517/2394-4722.2017.41
  • Waldman AD, Fritz JM, Lenardo MJ. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol. 2020;20(11):651–668. doi: 10.1038/s41577-020-0306-5 PMID: 32433532
  • Bai R, Chen N, Li L, et al. Mechanisms of Cancer Resistance to Immunotherapy. Front Oncol. 2020;10:1290. doi: 10.3389/fonc.2020.01290 PMID: 32850400.
  • Fecci PE, Ochial H, Mitchell D, et al. Systemic CTLA-4 blockade ameliorates glioma-induced changes to the CD4(+) T cell compartment without affecting regulatory T-cell function. Clin Cancer Res. 2007;13(7):2158–2167. doi: 10.1158/1078-0432.CCR-06-2070
  • Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264. doi: 10.1038/nrc3239
  • Zeng J, See AP, Phallen J, et al. Anti-PD-1 blockade and stereotactic radiation produce long-term survival in mice with intracranial gliomas. Int J Radiat Oncol Biol Phys. 2013;86(2):343–349. doi: 10.1016/j.ijrobp.2012.12.025
  • Patel K, Kollory A, Takashima A, et al. MicroRNA let-7 downregulates STAT3 phosphorylation in pancreatic cancer cells by increasing SOCS3 expression. Cancer Lett. 2014;347(1):54–64. doi: 10.1016/j.canlet.2014.01.020 PMID: 24491408
  • Lawlor E, Thiele C. Epigenetic changes in pediatric solid tumors: promising new targets. Clin Cancer Res. 2012;18(10):2768–2779. doi: 10.1158/1078-0432.CCR-11-1921 PMID: 22589485.
  • Clark P, Treisman D, Ebben J, et al. Developmental signaling pathways in brain tumor-derived stem-like cells. Dev Dyn. 2007;236(12):3297–3308. doi: 10.1002/dvdy.21381 PMID: 18000980
  • Hertzman Johansson C, Egyhazi Brage S. BRAF inhibitors in cancer therapy. Pharmacol Ther. 2014;142(2):176–182. doi: 10.1016/j.pharmthera.2013.11.011 PMID: 24325952.
  • Griffin M, Scotto D, Josephs DH, et al. BRAF inhibitors: resistance and the promise of combination treatments for melanoma. Oncotarget. 2017;8(44):78174–78192. doi: 10.18632/oncotarget.19836 PMID: 29100459.
  • Heerboth S, Lapinska K, Snyder N, et al. The use of epigenetic drugs in diseases: an overview. Genet Epigenet. 2014;6:9–19. doi: 10.4137/GEG.S12270 PMID: 25512710.
  • Sarkar S, Longacre M, Tatur N, et al. Histone deacetylases (HDACs): function, mechanism, & inhibition. Encycl Anal Chem, R.A. Meyers (Ed.). 2014;1–9. doi: 10.1002/9780470027318.a9365
  • Rankin AM, Forman L, Sarkar S, et al. Enhanced cytotoxicity from deoxyguanosine-enriched T-oligo in prostate cancer cells. Nucleic Acid Ther. 2013;23(5):311–321. doi: 10.1089/nat.2013.0420 PMID: 23971906
  • Sarkar S, Faller D. Telomere-homologous G-rich oligonucleotides sensitize human ovarian cancer cells to TRAIL-induced growth inhibition and apoptosis. Nucleic Acid Ther. 2013;23(3):167–174. doi: 10.1089/nat.2012.0401 PMID: 23634944.
  • Bender CM, Pao MM, Jones PA. Inhibition of DNA methylation by 5-Aza-2′-deoxycytidine suppresses the growth of human tumor cell lines. Cancer Res. 1998;58(1): 95–101. PMID: 9426064.
  • Zhang Y, Dong W, Zhu J, et al. Combination of EZH2 inhibitor and BET inhibitor for treatment of diffuse intrinsic pontine glioma. Cell Biosc. 2017;7(1):56. doi: 10.1186/s13578-017-0184-0 PMID: 29118968.
  • Thurn KT, Thomas S, Moore A, et al. Rational therapeutic combinations with histone deacetylase inhibitors for the treatment of cancer. Future Oncol. 2011;7(2):263–283. doi: 10.2217/fon.11.2 PMID: 21345145
  • Blagitko-Dorfs N, Jiang Y, Duque-Afonso J, et al. Epigenetic priming of AML blasts for all-trans retinoic acid-induced differentiation by the HDAC class-I selective inhibitor entinostat. PLoS One. 2013 October;8(10):| e7525. doi: 10.1371/journal.pone.0075258
  • Cacan E, Ali MW, Boyd NH, et al. Inhibition of HDAC1 and DNMT1 modulate RGS10expression and decrease ovarian cancer chemoresistance. PLoS One. 2014;9(1):e87455. doi: 10.1371/journal.pone.0087455 PMID: 24475290.
  • Pathania R, Ramachandran S, Mariappan G, et al. Combined inhibition of DNMT and HDAC blocks the tumorigenicity of cancer stem-like cells and attenuates mammary tumor growth. Cancer Res. 2016;76(11):3224–3235. doi: 10.1158/0008-5472.CAN-15-2249 PMID: 27197203
  • Sarkar S, Faller D. T-oligos inhibit growth and induce apoptosis in human ovarian cancer cells. Oligonucleotides. 2011;21(1):47–53. doi: 10.1089/oli.2010.0259 PMID: 21281128
  • Frew AJ, Lindemann RK, Martin BP, et al. Combination therapy of established cancer using a histone deacetylase inhibitor and a TRAIL receptor agonist. Proc Natl Acad Sci USA. 2008;105(32):11317–11322. doi: 10.1073/pnas.0801868105 PMID: 18685088
  • Bensaid D, Blondy T, Deshayes S, et al. Assessment of new HDAC inhibitors for immunotherapy of malignant pleural mesothelioma. Clin Epigenetics. 2018;10(1):79. doi: 10.1186/s13148-018-0517-9 PMID: 29946373
  • Almeida VR, Vieira IA, Buendia M, et al. Combined treatments with a retinoid receptor agonist and epigenetic modulators in human neuroblastoma cells. Mol Neurobiol. 2017;54(10):7610–7619. doi: 10.1007/s12035-016-0250-3
  • Wang H, Fan Z, Shliaha PV, et al. H3k4me3 regulates RNA polymerase II promoter-proximal pause-release. Nature. 2023;615(7951):339–348. doi: 10.1038/s41586-023-05780-8
  • Butler M, Pongor L, Su YT, et al. MGMT status as a clinical biomarker in glioblastoma. Trends Cancer. 2020;6(5):380–391. doi: 10.1016/j.trecan.2020.02.010 Epub 2020 Mar 27. PMID: 32348734; PMCID: PMC7315323.
Download PDF

Related research

People also read lists articles that other readers of this article have read.

Recommended articles lists articles that we recommend and is powered by our AI driven recommendation engine.

Cited by lists all citing articles based on Crossref citations.
Articles with the Crossref icon will open in a new tab.