Republished with permission from Personalize My Medicine, a Patient Worthy partner organization. 

Written by Eleanor Doherty

Glossary

Antibody, Antidepressant, Antigen, Apoptosis, Astrocyte, CAR-T Cell Therapy, Atypia, Clinical Trial, CNS, Dendritic Cell Vaccine, Epidermal Growth Factor, Ex-Vivo, Glioblastoma Multiforme, Glioma, Immunotherapy, Metastasis, Mitotic Activity, Monoclonal Antibody, Necrosis, Neuron, Neurotransmitter, Oncology, Oncolytic Virotherapy, Prognosis, Radiotherapy, Stem Cell, Surgical Resection, Tumor, Vaccine Therapy, Vascular Endothelial Growth Factor

 

Abbreviations

BBB, blood-brain barrier; CAR-T, chimeric antigen receptors; CNS, central nervous system; CRISPR, clustered regularly interspaced short palindromic repeats; DC, dendritic cell; EGFR, epidermal growth factor receptor; EGFRvIII, EGFR variant III; GBM, Glioblastoma; HER-2, human epidermal growth factor receptor-2; HSPPC-96, heat shock protein-peptide complexes-96; IDH, isocitrate dehydrogenase; MAO, monoamine oxidase; MAOI, monoamine oxidase inhibitor; OV, oncolytic virotherapy; PDGFRA, platelet-derived growth factor receptor alpha (a); RTK, receptor tyrosine kinase; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor receptor

 

Introduction

Formerly known as glioblastoma multiforme (GBM), glioblastoma is the most common and aggressive malignant primary brain tumor that occurs in adults. Glioblastoma accounts for 57% of all gliomas and 48% of all primary malignant central nervous system (CNS) tumors. In contrast, only 2-3% of all malignancies in the pediatric population are diagnosed as being glioblastoma [1, 2]. Glioblastomas are pleomorphic, meaning that the tumors can be of various sizes and the cells that make up these tumors can take a variety of shapes. However, most glioblastomas originate from glial cells, which are the most abundant cell type found in the human brain, constituting 90% of brain cells. Glial cells retain their capacity for cell division throughout a person’s life [3]. They are characterized histologically by necrosis (cell death resulting in tissue death), vascular proliferation, cellularity, and mitotic activity. Approximately 82% of malignant gliomas are comprised of glial cells [4]. These cells are highly invasive and grow without clear margins. However, they do not usually metastasize (spread to other areas of the body) and tend to remain within the CNS [5].

 

 

Figure 1 Location and prevalence of glioblastomas in the central nervous system (CNS)

The majority of glioblastomas arise in the frontal, temporal, and parietal lobes of the brain. While brain stem glioblastomas are rare in adults, they are the most common type of pediatric glioblastoma [2]. Diagram created with Biorender.com.

 

The symptoms of glioblastoma can vary greatly in different people. Headaches are the main complaint and are present in approximately 50% of patients at the time of their diagnosis. Seizures are also a common complaint at the time of diagnosis and are reported in approximately 20-40% of cases. Other common signs symptoms include, but are not limited to, optic nerve swelling (papilledema), cognitive difficulties, aphasia, personality changes, urinary incontinence, gait imbalance, incontinence, sensory loss, and visual disturbances [4, 5]. The majority of glioblastomas are diagnosed following the presentation of symptoms and diagnosis is subsequently confirmed by neuroimaging. Neurologic workups, which assess motor and sensory skills, hearing and speech, vision, balance, and coordination are carried out if a patient presents with cognitive and neurologic deficits.

Despite being one of the most common primary malignant brain tumors, glioblastoma continues to be associated with an extraordinarily high mortality rate and presents an enormous challenge to current neuro-oncology research. Currently, glioblastoma is not only incurable, but also results in severe neurologic morbidity. Glioblastoma tumors exhibit a high degree of heterogeneity both intra- and intertumor. This means that there are differences between the characteristics of cancer cells within a single tumor. This heterogeneity contributes to both drug resistance and tumor recurrence. Following a diagnosis of glioblastoma, the median survival rate with the current treatment of surgical resection, radiation, and chemotherapy is around 12-18 months [6]. The five-year survival rate for glioblastoma is one of the lowest for all cancer types (just 6%), confirming the aggressiveness of this cancer [7]. The poor prognosis is believed to be largely due to the infiltrative nature of the tumor [8]. Numerous innovative approaches are currently being investigated to develop effective treatments for glioblastoma. This article will summarize the progress that has been made to date, with the main types of treatment approaches currently being researched.

 

Risk Factors, Causes & Hallmarks

Glioblastoma is characterized by molecular heterogeneity. This means that there can be many differences between tumors from different patients or even between the cells and proteins found in different tumors in a single glioblastoma patient [2]. For the majority of glioblastoma cases, the cause is unknown. However, there are several risk factors associated with the disease. The most significant associated risk factors include increasing age and exposure to ionizing radiation [1, 2]. Several rare hereditary autosomal genetic syndromes have been associated with an increased risk of glioma and glioblastoma, though this association is seen in less than 1% of cases and is usually associated with secondary glioblastomas that have evolved from an initial glioma. These syndromes include neurofibromatosis, Li-Fraumeni, Cowden, Turcot, tuberous sclerosis, and familial schwannomatosis. In contrast, there is a reduced incidence of glioma in individuals who have atopic diseases such as asthma, eczema, and hayfever [1, 4].

Glioblastoma is a grade IV glioma which differs from lower-grade glioma in that it is characterized by rapid growth, necrosis, and microvascular proliferation (Figure 2). Grade IV gliomas emerge either as a primary glioblastoma, as a secondary glioblastoma originating from a lower grade brain tumor such as a grade II or III glioma, or as a result of a mutation in the isocitrate dehydrogenase (IDH) gene [2, 9].

 

 

Figure 2 The pathological and molecular features of glioblastoma

Glioblastoma tumors typically present with a necrotic center, increased cell density, cell atypia/abnormality, and the growth of new capillaries (angiogenesis), forming a highly vascularized mass. Diagram created with Biorender.com.

 

The most significant prognostic molecular marker for glioblastoma is the presence of the isocitrate dehydrogenase 1 or 2 (IDH1 or IDH2) genes. IDH can be wild type (IDH-wild type) meaning there is no mutation, or can be mutant (IDH-mutant), meaning there is a mutation within the IDH gene. IDH-mutant glioblastoma is associated with a better overall survival rate than IDH-wild type glioblastoma. Since 2016, the WHO classification of tumors in the CNS includes IDH status for the diagnosis of glioblastoma. Wherever possible, it is recommended that glioblastoma be classified as either IDH-wild type or IDH mutant, as this classification is thought to be more accurate for prognosis than the histologic grade of the tumor [10]. Where it is not possible to classify, the subgroup ‘glioblastoma, not otherwise specified’ may be used for diagnosis. IDH-wild type glioblastoma is typically defined as a primary glioblastoma and is identified in approximately 90% of glioblastoma patients. IDH-wild type normally occurs in older patients and requires more aggressive treatment, whereas IDH-mutant glioblastoma is a secondary glioblastoma that arises from anaplastic astrocytoma. IDH-mutant glioblastoma occurs in approximately 10% of patients and is more prominent in younger patients with a median diagnosis age of 44 years. This diagnosis typically results in a better prognosis. Histologically, glioblastoma is characterized by astrocytic tumors with focal necrosis (the death of living cells and tissue) and/or microvascular proliferation (abnormal vascular structure). Within IDH-wild type glioblastoma, there are further specific histologic variations. However, treatment options are not usually changed based on these histologic variants. In addition to IDH mutation status, there are other epigenetic and genetic changes resulting in the pathogenesis of the IDH subcategories. IDH-wild type glioblastomas tend have abnormally high levels of epidermal growth factor receptor (EGFR), PTEN deletions, and TERT promoter mutations. In addition, MGMT promoter methylation is present in approximately 30-50% of IDH-wild type glioblastomas, which are more responsive to treatment with either temozolomide or other alkylating chemotherapies [1]. Furthermore, there are two histopathologic variants of primary glioblastoma, namely, gliosarcoma, and giant cell glioblastoma. Giant cell glioblastoma tends to present with a high frequency of TP53 mutations, with EGFR mutations being less common [2].

 

Current Standard Therapies

In 2005, the current standard of care for glioblastoma was the Stupp protocol which involves surgical resection, chemotherapy with temozolomide, and radiotherapy [10]. This protocol is still used today. Maximal safe surgical resection is the standard initial approach for the majority of primary CNS tumors. It not only results in significant reduction of tumor volume and improved overall survival, but also allows for tumor genotyping and accurate histological diagnosis. However, with resection there is a risk of causing neurologic deficits and it is rare that all of the cancerous cells can be removed using surgery alone [1, 7]. Therefore, post-surgical treatment is normally given in order to prevent a recurrence. Numerous challenges remain when it comes to treating glioblastoma. Due to the invasiveness of this cancer and its ability to spread in healthy brain tissue, it is still difficult to treat using radiotherapy and surgical resection. Tumor recurrence and therapeutic resistance to chemotherapy options are the main reasons for the poor prognosis of glioblastoma. There have been few advances in the treatment of glioblastoma using chemotherapy as the concentration of chemotherapeutics needed to be effective the tumor also affects healthy tissue throughout the body. While there is a risk of therapeutic resistance with the use of temozolomide, no other drugs have shown efficacy in clinical trials [11]. Ultimately, the Stupp protocol only provides a means to prolong survival and alleviate symptoms. Currently, there is no accepted care for recurrent glioblastoma. There are some potentially promising early results from clinical trials that are mainly based on molecular profiling and immunotherapy.

 

 

Figure 3 Current therapies and recent advances

A diagram of the current therapies discussed above and some of the recent advances in glioblastoma treatment including peptide vaccines, monoclonal antibodies, tyrosine kinase inhibitors, dendritic cell vaccines, oncolytic virotherapy, and CAR-T cell therapy. Diagram created with Biorender.com.

 

Recent Advances & Future Therapies

There are many obstacles to overcome when it comes to treating glioblastoma. As previously mentioned, these tumors tend to be highly heterogeneous, vascularized, and invasive. The blood-brain barrier (BBB) presents a further challenge. An important consideration in drug development is the permeability of small molecules. This is critical as the BBB not only prevents small molecule transport, but BBB active transporters work to clear foreign particles that manage to pass through the protective layers [7]. These obstacles are the reason for the slow progression in therapeutic advancement for the treatment of glioblastoma. However, progress is still being made, and there is more hope with every new discovery. So far, therapeutic advances have increased the median survival rate from four months to >15 months and the overall one-year survival rate in the US from 34.4% (2000 – 2004) to 44.6% in (2005 – 2014) [1]. Following treatment with first-line therapy according to the Stupp protocol, tumor cell subclones with distinct features can emerge. These may include a deficiency in DNA mismatch repair (MMR), a higher mutation rate (as seen in 10% of recurrent post-temozolomide glioblastoma), DNA hypermutation associated with DNA alkylating agents, or oncogene amplification on extrachromosomal DNA common in sporadic adult glioblastoma. Analysis of tumor samples before and after diagnosis, and at recurrence, demonstrates that 80% of copy-number variants remained unchanged between the primary tumor and the tumor at recurrence. Genetic profiling has exponentially increased our understanding of the molecular pathogenesis of glioblastoma and offers potential for the development of genotype-directed therapies [2].

 

 

Figure 4 The six hallmarks of cancer

Cancer cells are essentially ‘immortal’ as tumor cells are able to subvert cellular pathways that are associated with apoptosis. Apoptosis is a type of programmed cell death in which damaged cells are broken down and recycled. This process is vital for cell turnover and cancer prevention, as without apoptosis, cells may begin to divide uncontrollably giving rise to the formation of a tumor. Cancer cells are also able to evade growth suppressors. This allows tumors to grow uncontrollably with unlimited replicative potential. They are also capable of proliferation without stimulation. As the tumor grows, it requires more nutrients and oxygen. Tumor-induced angiogenesis leads to the formation of new capillaries from existing vessels. As the tumor grows, it invades the surrounding healthy tissue and can metastasize to other areas of the body. The molecular characteristics of tumors can serve as potential targets for the development of novel cancer therapies, which are discussed below.

Monoclonal Antibodies & Tyrosine Kinase Inhibitors

Monoclonal antibodies are a type of laboratory-produced protein that can bind to specific targets such as antigens on the surface of cancer cells. They can be used as substitutes for naturally produced antibodies. Monoclonal antibodies can act in a variety of ways including blocking immune system inhibitors, attacking cancer cells directly, flagging cancer cells for the immune system to attack, triggering cell-membrane destruction, preventing blood vessel growth, delivering radiation treatment or chemotherapy, and blocking cell growth. Monoclonal antibodies are the preferred type of immunotherapy for the treatment of glioblastoma patients, with nearly 25% of clinical trials for glioblastoma focused on this type of treatment [6]. These antibodies are designed to block the tumorigenic mechanisms exhibited by malignant cells, which suppress antitumor immune responses. They are commonly used in chemotherapy protocols designed for the treatment of glioblastoma that aim to to improve antiangiogenic processes and improve immunotherapy. As glioblastomas are highly vascularized tumors (meaning they produce new capillaries which increase blood flow to the tumor and promote tumor growth), the anti-angiogenic properties of monoclonal antibodies are particularly attractive as they prevent the growth of these new blood vessels and slow down the growth of the tumor [12]. The EGFR variant III (EGFRvIII) is the most frequently occurring mutation in glioblastomas and is therefore an ideal target for the development of monoclonal antibodies. Clinical trials for glioblastoma targeting EGFRvIII are currently focused on monoclonal antibodies such as panitumumab, nimotuzumab, and cetuximab, which bind to the extracellular EGFR domain [13]. The monoclonal antibody, bevacizumab, a humanized antibody targeting VEGF-A, is the most commonly used antibody therapy currently being used to treat glioblastoma[14]. It was approved by the US FDA for recurrent glioblastoma in 2009 [10]. Bevacizumab is preferred for the treatment of glioblastoma due to its antiangiogenic properties [1].

Tyrosine kinases are enzymes and important mediators in signaling cascades (a series of biochemical reactions) involved in cell growth, differentiation, apoptosis and metabolism. They have recently been shown to be implicated in the pathophysiology of cancer. Receptor tyrosine kinase (RTK) signaling is one of the three major signaling pathways involved in glioblastoma [9].  As previously mentioned, mutations in the EGFR are one of the most commonly observed changes in glioblastoma (~45% of patients). Furthermore, mutations in vascular endothelial growth factor (VEGF) and VEGF receptor (VEGFR), as well as platelet-derived growth factor receptor a (PDGFRA) and human epidermal growth factor receptor-2 (HER-2) are commonly found in glioblastoma patients [11, 14]. Tyrosine kinase inhibitors (TKIs) are small molecule drugs that are used to treat a range of different cancers such as non-small cell lung cancer, melanoma, and breast cancer. They act by blocking receptor signaling, which leads to the inhibition of cell proliferation, growth, and angiogenesis. Therefore, TKIs are being considered as potential drugs to treat glioblastoma. They are widely accessible to healthcare providers and may be administered orally [11]. Human epidermal growth factor receptor 2 (HER2) is a transmembrane tyrosine kinase receptor that is overexpressed in approximately 80% of glioblastomas. In a phase I clinical trial using HER-2 targeting CAR-T cells, the median overall survival was 11.1 months from the time of the first infusion and 24.5 months from the time of diagnosis, compared to an average of four months survival with no treatment [14].

 

Peptide Vaccines

Peptide vaccines, which are also called epitope vaccines, are composed of peptides that mimic the epitopes (antigenic determinants) of particular antigens that trigger immune responses. The use of peptide vaccines to treat cancer is a promising new approach in cancer immunotherapy. These vaccines can induce cancer-specific cytotoxic T-lymphocytes in tumors that are able to kill cancerous cells. A peptide vaccine that targets the mutant EGFRvIII, called rindopepimut, may be a viable treatment option for patients with EGFRvIII positive glioblastoma [1]. This mutation is expressed in 20% to 40% of patients with glioblastoma [1, 15]. To date, numerous peptide vaccines have been shown to be effective in several phase II clinical trials and have improved overall patient survival to 12 to 21.8 months. However, due to the high level of heterogeneity across different types of glioblastoma tumors, there is a need for alternative vaccine approaches to target multiple tumor neoantigens. A peptide vaccine incorporating heat shock protein-peptide complex 96 (HSPPC-96) has been shown to elicit a tumor-specific peripheral immune response in 91% of patients in a phase I clinical trial of high-grade glioma patients. In a multicentrer phase II clinical trial in patients with recurrent glioblastoma, patients’ overall survival was significantly increased by a median of 42.6 weeks [14].

 

Dendritic Cell Vaccines

Dendritic cells (DC) are known as being accessory cells of the immune system. These cells  present antigens to T cells as antigenic peptides. Dendritic cell vaccines are another immunotherapeutic approach that is being used to deliver tumor antigens to CD4+ and CD8+ T cells to stimulate an immune response. DC vaccines present a huge breakthrough in the evolution of personalized medicine as they are able to target either specific or multiple tumor antigens. After harvesting dendritic cells  from patients, the cells are stimulated to encourage an immune response by loading them with tumor antigens before being injected back into the patient. In a phase I/II clinical trial with sixteen glioblastoma patients, a novel DC vaccine known as DCVax-L prepared from tumor lysate produced a median survival of 525 days [14].

 

 

Figure 5 The process of creating dendritic cell (DC) vaccines

Dendritic cells (DCs) are harvested from the patient, loaded with maturation factors and tumor-specific antigens ex-vivo, and returned to the patient as a cellular vaccine. Diagram created with Biorender.com.

 

CAR-T Cell Therapy

Chimeric antigen receptor (CAR-T) cell therapy is a form of adoptive T cell therapy that makes use of the patient’s own T cells. These cells are engineered to express chimeric antigen receptors (CARs) for the targeting of cancerous cells, as they are able to bind to specific proteins such as neoantigens (malignant cell surface antigens) present on the surface of cancer cells, [6]. You can read more about CAR-T cell therapy here. The IL13Ra2 receptor is overexpressed in over 50% of glioblastoma patients and is a reliable indicator of poor prognosis and decreased patient survival. IL13Ra2 CAR-Ts have been studied in phase I clinical trials and show a reduction in IL13Ra2 expression in glioblastoma tissue as well as both partial and complete tumor remission in patients. As previously mentioned, EGFRvIII is a mutation commonly found in glioblastoma. Furthermore, CAR-Ts that target HER-2 currently under development and have shown increased overall survival in patients. Multi-targeted CAR-Ts are currently under preclinical development. A trivalent CAR-T specific to IL13Ra2, HER2 and EGFRvIII is also currently being developed [6].

 

Oncolytic Virotherapy

Oncolytic virotherapy (OV) is used to specifically target cancerous cells by using either engineered or natural viruses to trigger inflammation and immune responses in cancerous tissue. For treating glioblastomas, these viruses are delivered directly into resected cavities within the tumor during surgery. Viruses such as adenovirus, poliovirus, and herpes simplex virus (HSV) have been successfully used as vehicles to deliver cancer therapies. Viruses are used as they are small particles that are capable of infiltrating human cells.  When delivered via an OV, the virus triggers an immune response directed towards cancerous cells avoiding damage to healthy tissues. Several oncolytic virotherapies are currently under development for glioblastoma. The polio-rhinovirus chimera (PVS-RIPO) is a live attenuated poliovirus vaccine and human rhinovirus chimera that is used to target the poliovirus receptor CD155 that is overexpressed on tumor cells. In a phase I clinical trial, 61 grade IV malignant glioma patients who received intratumor PVS-RIPO had an overall survival rate of 21% at 24 and 36 months post-treatment, and two patients lived for more than seventy months with treatment. DNX-2401, which is a replication-competent adenovirus, is another OV that is being investigated as a treatment for glioblastoma. In a phase I clinical trial, 37 recurrent glioblastoma patients received intratumoral DNX-2401, either using a biopsy needle or a permanent catheter. Approximately 20% of patients who received DNX-2401 via biopsy needles survived for more than three years following treatment, with three of these patients showing dramatic tumor reduction (>95%). This was the first clinical trial that demonstrated the successful effects of OV on glioblastoma. Furthermore, a combination therapy of the monoclonal antibody pembrolizumab and OV DNX-2401 is currently under investigation. Overall, virotherapy trials for recurrent glioblastoma have shown improved two year and three year survival rates compared to non-OV clinical trials [14].

 

Antidepressants

An antidepressant is a type of medication that is primarily used to treat depression, though may also be prescribed for psychiatric disorders such as generalized anxiety disorder and post-traumatic stress disorder. While it is unknown precisely how antidepressants work, it is believed they increase levels of certain neurotransmitters in the brain. Several different classes of antidepressant have been found to have antitumor properties. These include tricyclic antidepressants (TCAs), selective-serotonin-reuptake inhibitors (SSRIs), and monoamine oxidase inhibitors (MAOIs). Examples of TCAs include amitriptyline, imipramine, clomipramine, and doxepin. While these TCAs are involved in five different neurotransmitter pathways, their main action is to block the reuptake of the neurotransmitters, norepinephrine and serotonin. Neurotransmitters are chemical messengers that carry signals throughout the body via the nervous system to communicate with cells such as muscle cells or glands. TCAs are commonly prescribed for the treatment of mood disorders, anxiety disorders, chronic pain, and personality disorders.  Amitriptyline and imipramine are TCAs that target mitochondria and inhibit gene expression within the inflammatory pathway in order to support balance between inflammatory mediators. These drugs are also glycolysis inhibitors. It is thought that they may support immunotherapies by decreasing tumor invasiveness and improving the function of immune cells as glycolysis is the first step in the break-down of glucose to produce energy. Imipramine has also been found to cause autophagy (the breakdown of damaged cells) in glioma cells by blocking the PI3K/AKT/mTOR signaling pathway. Clomipramine, a TCA commonly used to treat obsessive-compulsive disorder, has been found to induce apoptosis in cancer cells as well as decrease chemoresistance. Doxepin is commonly used to treat anxiety, depression, and insomnia and has been found to be an inhibitor of cellular respiration in tumor cells. Like other TCAs, it induces apoptosis.

SSRIs are thought to have immunomodulatory properties and improve the efficiency of immunotherapies, similarly to amitriptyline and imipramine. SSRIs act by blocking the reuptake of serotonin, and are commonplace in the treatment of depression and anxiety. An SSRI known as Citalopram has been shown to have pro-apoptotic effects on glioma cells and may have anti-inflammatory effects in glioblastoma with chronic inflammation, though this is yet to be confirmed. Fluoxetine is currently the ‘gold standard’ in neuro-oncology research for antidepressant treatment in glioblastoma. This drug has been proven to decrease chemoresistance, increase T-cell mediated tumor immunity, and have anti-proliferation and pro-apoptotic effects. Furthermore, a study of rat and human cell lines has demonstrated that fluoxetine alongside temozolomide induces apoptosis in glioma cells and increases the sensitivity of temozolomide through MGMT expression. Fluvoxamine has been found to suppress cell migration in human malignant glioma cell lines and potentially increase the numbers of natural killer cells in cancer patients.

Monoamine oxidases (MAOIs) act by inhibiting the activity of monoamine oxidases (MAO-A and B), which leads to the prevention of neurotransmitter breakdown resulting in increased neurotransmitter levels in the brain. They are used for neuropsychiatric conditions such as Parkinson’s disease, atypical depression, and treatment-resistant depression. It is thought that this class of antidepressants may be beneficial in the treatment of glioblastoma as MAO-A is often overexpressed in gliomas. A study by Kushal et al in 2016 found that MAO-A inhibitors reduce the resistance of cells to temozolomide and therefore may be useful in combinational therapy. Tranylcypromine is a non-selective MAO-A and MAO-B inhibitor that has been shown to reduce drug resistance in several cancers including glioblastoma. While this drug can increase the sensitivity of glioblastoma cells to temozolomide, this sensitivity is dependent on oxygen levels in the tumor microenvironment. A 2017 study by Lee et al found that a combination of tranylcypromine and a histone deacetylase inhibitor could induce apoptosis in glioblastoma cells. Finally, another benefit of these antidepressants is the reduction of depression and anxiety in glioblastoma patients. Depression is common in cancer patients [8].

 

CRISPR-Cas9

CRISPR (clustered regularly interspaced short palindromic repeats) is a revolutionary gene editing technology that has recently been applied to the development of glioblastoma gene therapy. The method involves Cas9 (CRISPR-associated protein 9) binding to the target DNA and precisely cutting it in order to edit the base pairs of a gene. It is hoped that CRISPR-Cas9 nanocapsules may lead to an effective means of glioblastoma gene therapy. This particular nanocapsule, non-invasive and tumor cell targeting, may prove to be both effective and safe. So far, it has been shown to be effective in crossing the BBB and to have excellent gene editing efficiency, exceptional tumor targeting, limited off-target effects, and high intracellular environment responsive release capability. As CRISPR technology is still relatively new, further research is needed to fully evaluate its safety and efficacy. However, these efforts to develop nanocapsules for the treatment of glioblastoma represent a significant advance towards a treatment and potential cure for this lethal disease [16].

 

Other Recent Advances

More recently, a research group at the University of Michigan Rogel Cancer Center identified a key gene in gliomas, ZMYND8, that increases the resistance of the cancer to radiotherapy. The identification of this gene holds great promise for creating strategies to combat radiotherapy resistance and increasing survival outcomes for glioma patients in the future [17]. Moreover, researchers in the United States have used a new type of cell therapy to create a dual-action vaccine to both eliminate primary tumors and prevent tumor recurrence. This vaccine has been trialed in mouse models of glioblastoma with outstanding results, bringing the hope for the potential cure of this disease all the more closer [18]. Finally, urine analysis to detect tumor-related extracellular vesicles is being developed by researchers in Japan. They found the presence of extracellular vesicles CD31/CD63 in the urine of brain cancer patients with unique RNA and proteins. In the future, it may become possible to diagnose brain cancers, including glioblastoma earlier by detecting these extracellular vesicles in urine [19].

Conclusion

Glioblastoma is the most common and aggressive type of primary malignant brain tumor that is associated with high rates of mortality and morbidity. While the Stupp protocol, introduced in 2005, has increased overall survival for many patients, glioblastoma remains an incurable disease that presents numerous challenges to neuro-oncology research patients, their families, and healthcare professionals. Developing drugs to treat glioblastoma has been challenging due to the difficulties involved in developing methods to effectively deliver treatment across the BBB and tumor characteristics such as high invasiveness, heterogeneity, vascularity, and drug resistance. However, current and ongoing research in the development of targeted therapies, immunotherapies and pharmacotherapies, monoclonal antibodies, TKIs, peptide vaccines, DC vaccines, OVs, CAR-T cell therapy, antidepressants, and CRISPR-Cas9, provide hope that we may eventually be able to cure this devastating disease. There are hundreds of clinical trials and research projects studying glioblastoma currently underway worldwide, such as Project Rush, and the Glioblastoma Adaptive Global Innovative Learning Environment. Details of these are listed below, alongside the many other research projects and ongoing clinical trials, all of which demonstrate the hard work and hope in glioblastoma research. Finally, recent advances such as the identification of the gene ZMYND8, the development of the dual-action vaccine,  and the early detection of brain cancer through urine analysis are all indicators of the rapid progress in the field of glioblastoma research and for the hope of finding a cure to this deadly disease.

 

Further Resources

Below you will find a summary of prominent research organizations and research projects focusing on glioblastoma as well as a list of ongoing clinical trials across the world that are either currently recruiting applicants or are in the stages prior to recruitment.

 

Organizations & Research for Glioblastoma

The Glioblastoma Research Organization

The Lee Project, at the University of Texas’ MD Anderson Cancer Center, is funded by the Glioblastoma Research Organization. This project is focused on the directed evolution of vectors for glioblastoma treatment.

Project Rush is an ongoing collaboration with the Glioblastoma Research organization and Lenox Hill Hospital’s Department of Neurosurgery’s Brain Tumor Center. This project is researching the effectiveness of repeated super selective intra-arterial cerebral infusion of bevacizumab with radiation and temozolomide chemotherapy in comparison to radiation and temozolomide in patients with newly diagnosed glioblastoma.

Project Nate Roston is a project by the partnership of the Glioblastoma Research Organization and Cleveland Clinic. This project is exploring how diet and ageing effect the regulation of hydrogen sulfide production in the body and the impact of hydrogen sulfide on tumor suppression.

University College of London (UCL)

Glioblastoma Research Group – The University College of London (UCL) has a glioblastoma research group with a clinical trial programme.

Brain Research UK

Targeted Immunotherapy of Glioblastoma – Richard Baugh of the University of Oxford is currently researching targeted immunotherapies for the treatment of glioblastoma.

Delivering a New Combination Therapy for Glioblastoma – Professor Khuloud Al-Jamal at King’s College London University  (KCL) is currently researching combinational therapy strategies for glioblastoma with immunotherapy techniques and chemotherapy.

Global Coalition for Adaptive Research

GBM AGILE – (Glioblastoma Adaptive Global Innovative Learning Environment) is a clinical trial for the evaluation of multiple investigational treatments for glioblastoma.

Other Useful Links

• Normal Cells vs Cancer Cells
• The Cell Cycle and Cancer
• Glioma vs Glioblastoma
• Introduction to Glioblastoma
• Understanding Glioblastoma
• Diagnostic and Prognostic Markers of Glioblastoma
• Glioblastoma Survivor Story
• Cancer Research – Understanding Clinical Trials
• Global Clinical Trial Database
• The Glioblastoma Research Organization
• The Lee Project
• Project Rush
• Project Nate Roston
• Glioblastoma Research Group
• Brain Research UK
• Targeted Immunotherapy of Glioblastoma
• Delivering a New Combination Therapy for Glioblastoma
• Global Coalition for Adaptive Research
• GBM AGILE

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