Introduction to glioblastoma

Glioblastoma is a highly aggressive type of brain cancer. It affects astrocytes of brain neurons in the central nervous system (CNS). They can even spread rapidly to invade other healthy tissue. Symptoms include nausea, dizziness, blurred vision or even loss of balance. The severity of symptoms will depend on the glioblastoma stage and the affected brain regions.¹ Glioblastoma stems from mutations of genes that regulate cell division. This causes cells to divide uncontrollably, leading to tumour formation. Like most cancers, the risk of developing glioblastoma increases with age and exposure to environmental factors like smoking and radiation.²

Standard treatments for glioblastoma include surgery where most of the brain tumour is removed from the patient. This is then followed by radiation to kill cancer cells. Surgery is also often complemented with oral chemotherapy. The patient will take medications like temozolomide daily to slow down tumour growth. Temozolomide is the main anti-cancer drug used to treat brain cancers. Evidence has shown that taking this drug alongside radiotherapy increases the average survival of patients.³ Nevertheless, there are various limitations to conventional therapies. There is a high risk of tumour recurrence associated with surgical procedures as the tumour is not completely removed. Patients will often have to undergo follow-up surgeries. Besides, radiotherapy causes damage to both cancerous and healthy tissue. It is also ineffective in killing all cancer cells in large glioblastoma tumours, especially when it has metastasised to other parts of the CNS.⁴

What is targeted therapy?

Given the limitations of conventional treatments, there is a need for targeted therapy for the treatment of glioblastoma. This is when drugs are used to precisely target cancer cells without harming healthy tissue around the tumour. This can be combined with chemotherapy, radiotherapy or surgery for a higher efficacy.⁵ Targeted therapy either makes use of drugs that are small molecule inhibitors,  monoclonal antibodies, or immunotherapy agents. They target molecules that are involved in cancer cell survival or proliferation.⁶

Types of targeted therapies for glioblastoma and their targets

Monoclonal antibodies

Tumour growth requires a large supply of nutrients and oxygen that is delivered via blood vessels to the tumour site. This is also necessary for the metastasis of cancer cells to other parts of the CNS. To achieve this, the vascular endothelial growth factor (VEGF) secreted by cancer cells plays an important role in the vascularisation (formation of new blood vessels) of gliomas. Many monoclonal antibodies (mAbs) have been developed to target VEGF, so they are classified as antiangiogenic drugs. A common drug is Bevacizumab which is also used in the treatment of other cancer types. This drug binds to VEGF to prevent it from binding to its receptor. This inhibits cell proliferation and migration. Bevacizumab has shown the highest survival ratio compared to other drugs like Brivarib and Tandutinibi.⁷

Small molecule inhibitors

By understanding the mechanisms and cellular signalling pathways associated with glioblastoma formation and spread, researchers have developed small molecule inhibitors that block specific enzymes or pathways. There are over 200 clinical trials that are testing the efficacy of this drug group. One of the most common targets is the epidermal growth factor receptor (EGFR) that regulates cell growth and differentiation in normal cells. In glioblastoma, the EGFRs are often mutated and are highly expressed in cancer cells, activating pathways that cause cancer cells to produce large quantities of growth factors. This causes high cancer cell proliferation and survival. Hence, EGFR tyrosine kinase inhibitors like erlotinib, lapatinib and gefitinib have been developed. Furthermore,  some drugs inhibit molecules that are involved in the dysregulated pathways stimulated by the EGFRs. For example,  PI3K inhibitors like idelalisib work by preventing cell apoptotic escape and uncontrolled growth.⁸

Immunotherapy approaches

Another targeted therapy is immunotherapy. It aims to stimulate the body’s immune response against cancerous cells. With the advancement of bioengineering, chimeric antigen receptor (CAR) T-cell therapy has been widely used in cancer therapy. This is when a patient’s T cells are extracted and genetically modified to express certain receptors that complement antigens on cancer cells. This reduces the change of immune response rejection as the patient’s T cells are used while increasing the release of cytokines that have an antitumour response. CAR T cells also stimulate T cell activation to fight off cancer cells. However, the challenge lies in the harvesting and modification of these T cells as they require a lot of time, especially when they are unique to each patient.⁹ Furthermore, isocitrate dehydrogenase (IDH) enzymes are involved in various cell metabolic processes, including the Krebs cycle in aerobic respiration. Mutations of the IDH gene are often associated with glioblastoma as it leads to oxidative damage of cells. Thus, IDH inhibitors are used to treat brain cancer and other malignancies by suppressing the enzyme’s activity.¹⁰

Gene therapy

Since glioblastoma is associated with various gene mutations that lead to the formation of faulty proteins like IDH enzyme and EGFR, gene therapy has been proposed as a treatment option. It can repair or replace defective genes. It can be used to increase the expression of tumour suppressor genes or suppress oncogenes. For example, there are gene therapies that deliver the normal wild-type P53 gene using viral vectors. The P53 gene is responsible for suppressing tumour growth. Promising progressions in the development of gene therapy for glioblastoma can be seen from 2005 onwards. An emerging technique is the CRISPR or Cas9 which can precisely edit certain sections of defective genes.¹¹ 

Challenges and limitations of targeted therapy

Tumor heterogeneity

As discussed earlier, glioblastoma is genetically diverse. There are various gene mutations on different chromosomes that are associated with the development of glioblastoma. For primary glioblastoma, it is often due to mutations in the EGFR gene and the murine double minute (MDM2) oncogene, while secondary glioblastoma is associated with tumour protein 53 (TP53) mutations.¹² This shows that different glioblastoma subtypes have different root causes and will have different biomarkers for diagnosis and treatment purposes. This explains why patients will each respond differently to the same medication provided. They must be classified based on genetic background to determine the best-targeted therapy.¹³

Blood-brain barrier

The blood-brain barrier (BBB) is composed of capillaries that are lined with endothelial cells held together by tight junctions. Cellular junctions found between the endothelial cells allow the BBB to act as a filter to prevent the entry of foreign substances and many macromolecules like proteins into the brain through passive diffusion. However, the BBB allows essential nutrients to pass through to the brain via various transport methods. This means that different drugs will have different permeability across the BBB; this will affect the drugs’ bioavailability in the brain’s target site. Less permeable drugs will have a lower concentration at the target site, reducing their efficacy in reducing brain tumour volume. To this day, the BBB is still a major biological barrier for many treatments for brain conditions. Overall, it can be said that small lipophilic molecules will be more permeable.¹⁴

Drug resistance

Similar to chemotherapy, a major limitation of targeted therapy is the development of drug resistance over time. This is due to the mutations, heterogeneity and immune evasion that are set up by different molecular mechanisms and pathways in glioblastoma. In the same tumour mass, there can be the existence of cancer cells of different glioblastoma subtypes with different genetic profiles. Hence, the therapeutic response may vary among patients. Furthermore, mutated proteins like abnormal RTK and EGFR receptors can affect multiple signalling pathways, contributing to the development of drug resistance and low patient survival rates. Thus, it may be more effective to prescribe a combination of targeted therapies to improve the clinical efficacy of therapeutic agents.¹⁵

Side effects

There are some side effects caused by targeted therapy. However, since targeted therapy does not usually harm healthy cells and tissues, the side effects are usually less severe compared to conventional treatments. For instance, as mAbs are proteins, they may stimulate an immune response from the body, potentially causing allergic reactions like fever and chills. The side effects could also be related to the antigens that they target. Targeting VEGF to prevent angiogenesis can lead to high blood pressure and poor wound healing.¹⁶ On the other hand, immunotherapy may stimulate autoimmune complications that can affect different organs. Focusing on neurological complications, this adverse response can lead to fatigue or more severe issues like peripheral neuropathy and meningtis.¹⁷

Future directions and emerging therapies

Personalized medicine

As we mentioned glioblastoma has many subtypes and patients can have very different responses and tolerances to targeted therapies, it is important to tailor them based on an individual’s genetic profile. This allows clinicians to identify the root cause and affected molecular pathways to administer the most suitable medication for better overall survival. With the advancements in Genome-Wide Studies (GWS), healthcare professionals can characterise brain tumour profiles more effectively. Studies have demonstrated higher overall survival of combination or personalised therapy for different glioblastoma subtypes.¹⁸

Nanotechnology-based drug delivery

Many studies are testing the application of nanotechnology-based drug delivery systems for glioblastoma, as seen in other cancer types. Nanoparticles are less than 100nm in diameter and are used to overcome many biological barriers. In glioblastoma, the most notable advantage of nanoparticles is their ability to cross the BBB to deliver therapeutic agents to the tumour microenvironment. Nanoparticles can vary in characteristics like size, composition and surface charge depending on their clinical application. ¹⁹ Silica metal nanoparticles, polymeric micelles, dendrimers and liposomes are examples of nanoparticles used for glioblastoma. Their modifiable properties allow them to improve the absorption, permeability and bioavailability of drugs. To cross the BBB, nanoparticles are designed to do so via diffusion via lipophilic pathways or through transport proteins found on endothelial cells of the BBB.²⁰

New molecular targets

Despite some side effects from small molecule inhibitors, it is worth doing further research on their clinical applications as they can pass through the BBB relatively well compared to other therapeutic agents. This is because they have a simple structure. Some molecules with great attention include PI3K inhibitors and EGFR inhibitors as they have high BB penetration. Scientists can modify their structures to optimise these compounds. Other molecules that can act as a good target are the cyclin-dependent kinases like CDK4 and CDK6 that regulate cell cycle and cell division.²¹

Summary

Overall, targeted therapies like small molecule inhibition, immunotherapy and gene therapy are more promising than traditional treatments as they target specific molecules or proteins involved in various molecular and signalling pathways. They can be used to target cancer cell proliferation, growth and division. Studies have demonstrated high clinical efficacy such as higher patient survival rates. However, there remain challenges like low blood-brain barrier penetration, drug resistance, and side effects. Thus, continued research is vital to understand the complex mechanism of glioblastoma and to test the efficacy of combined treatments for patients with different glioblastoma subtypes and genetic profiles.