Glioblastoma multiform GBM is a heterogeneous group of primary neoplasm resistant to conventional therapies. Due to their infiltrative nature it not fully isolated by aggressive surgery, radiation and chemotherapy showing poor prognosis in glioma patients. Unfortunately, diagnosed patients die within 1. Last few decades different TMZ conjugated strategy is developed to overcome the resistance and enhance the chemotherapy efficacy. The main aim of this review is to introduce the new promising pharmaceutical candidates that significantly influence the therapeutic response of the TMZ in context of targeted therapy of glioblastoma patients. It is hoped that this proposed strategy are highly effective to overcome the current resistance limitations of TMZ in GBM patients and enhance the survival rate of the patients.
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Glioblastoma multiforme GBM is the most common and aggressive malignant primary brain tumour in humans and has a very poor prognosis. The existing treatments have had limited success in increasing overall survival. Thus, identifying and understanding the key molecule s responsible for the malignant phenotype of GBM will yield new potential therapeutic targets.
The treatment of brain tumours faces unique challenges, including the presence of the blood brain barrier BBB , which limits the concentration of drugs that can reach the site of the tumour.
Nevertheless, several promising treatments have been shown to cross the BBB and have shown promising pre-clinical results. This review will outline the status of several of these promising targeted therapies. GBM patients have a poor prognosis with a 1-year survival rate of However, despite this classification, the majority of GBM patients receive identical treatments, and few targeted therapies currently exist, contributing to the poor outcomes typically experienced by GBM patients. This review will outline the current treatment options for GBM and discuss some of the more recent developments in targeted therapies being investigated for the treatment of GBM.
The treatment of brain tumours faces unique challenges, most notably the presence of the blood brain barrier BBB , a highly selective semipermeable barrier that separates blood from the brain. The BBB is comprised of the endothelial cells of capillaries, astrocytes surrounding the capillary, and pericytes embedded in the capillary basal lamina. Physiochemical properties including molecular weight, lipophilicity and charge affect the ability of a molecule to cross the BBB 9.
The current treatment pipeline begins with surgical resection of the tumour, if applicable and safe to do so, followed by radiotherapy and concomitant chemotherapy 12 , The initial therapeutic approach for GBM is surgery, where maximal resection is associated with longer progression-free survival PFS and overall survival OS Resection is not a curative approach; hence, patients typically undergo radiotherapy and chemotherapy as an adjunct Radiotherapy, at a total dose of 60 Gy, is administered as either primary treatment or following surgery 16 , both resulting in improvements to PFS and OS.
However, despite this increase in survival with radiotherapy and temozolomide, tumour progression and recurrence typically occur 17 , 18 , due to the development of resistance to temozolomide 19 , Once GBM recurrence occurs, therapeutic options for patients are limited 21 , Recently, tumour treating fields TTFields; Optune , which deliver electric fields to the tumour location to disrupt cancer cell division, have emerged as an FDA-approved treatment for both recurrent and newly diagnosed GBM However, the identification of new targets to facilitate the development of novel targeted therapies is warranted.
GBM is an invasive tumour with hallmarks of neoangiogenesis and intratumour heterogeneity, contributing to the poor prognosis observed A variety of genetic and epigenetic alterations have been identified in GBM that influence patient prognosis Table 1. Drugs targeting many of these commonly observed alterations have been investigated as potential targeted therapies for GBM.
EphA3 is highly expressed on the tumour-initiating cell population in glioma, maintains tumour cells in a less differentiated and stem cell-like state, and its expression mediates the tumourigenic potential in GBM cells in vitro 26 , suggesting that EphA3 may be a potential target for the treatment of GBM Table 2. A small molecule inhibitor of the EphA3 receptor, GLPG, has demonstrated superior tumour reduction in UMG and U87MG subcutaneous xenograft models when compared to radiotherapy alone, however, GLPG was not as effective as treatment with radiotherapy and concomitant temozolomide Whilst GLPG did not exhibit improved benefit over the current therapies, additional strategies for targeting EphA3 are being examined.
Taken together, these studies indicate that EphA3 receptor inhibitors may be promising treatments for EphA3 receptor-amplified GBM, including recurrent disease, however, this remains to be tested in the clinic. Binding of a ligand to the ligand-binding site of these receptors induces receptor homo- or heterodimerisation, producing a conformational change that activates the intracellular tyrosine kinase domain.
This results in autophosphorylation of the cytoplasmic tail and induces a variety of downstream signalling pathways. The overexpression or mutation of EGFR leads to downstream signalling that impairs apoptosis, enhances proliferation, and angiogenesis. Small molecule tyrosine kinase inhibitors are the most widely studied EGFR inhibitors in GBM, and include erlotinib, gefitinib, and lapatinib.
Erlotinib inhibits anchorage-independent growth of GBM cells in vitro in an EGFR expression-dependent manner and induces greater levels of apoptosis in more malignant GBM phenotypes The tumour-initiating cell population, which is resistant to radiotherapy 99 , is sensitive to erlotinib in a phosphatase and tensin homolog PTEN and Akt dependent manner 59 , suggesting that erlotinib may eliminate this population in vivo.
Further, treatment with erlotinib was shown to reduce tumour burden in two GBM patient-derived xenograft PDX models Indeed, erlotinib was not effective as a monotherapy in recurrent GBM patients and was only marginally beneficial following radiotherapy for non-progressive GBM patients Despite a limited number of complete and partial responses in a Phase II study in first-relapse GBM, the 6-months PFS and median survival was similar to that previously reported for patients undergoing chemotherapy 64 , suggesting that erlotinib may be useful in this setting.
However, due to the non-randomised nature of this trial, these results must be interpreted cautiously. By contrast, improved survival In contrast to erlotinib, gefitinib exhibits anti-tumour activity independent of the expression level of EGFR Gefitinib inhibits GBM cell migration 65 , reduces proliferation of human glioma tumour-initiating cells in vitro 59 and enhances survival in an intracranial GBM mouse xenograft model in vivo Taken together, these pre-clinical studies indicate that gefitinib may be clinically beneficial.
However, despite gefitinib reaching high concentrations in GBM tumour tissue fold higher compared to plasma and the significant dephosphorylation of EGFR achieved 66 , limited clinical effects have been observed in Phase II trials. Although tumour immunotherapy has shown some success for the treatment of melanoma and haematological cancers, the applicability to GBM presents more of a challenge. Pre-clinical studies have shown that treatment with cetuximab alone and in combination with radiotherapy increases survival in vivo 69 and can also completely eliminate tumours in EGFR-amplified PDX models A phase II trial examining cetuximab treatment in patients with recurrent high-grade glioma showed that cetuximab was well-tolerated, but exhibited limited activity in this patient population With the largely disappointing clinical results for EGFR inhibitors, additional targets are being investigated, including vascular endothelial growth factor VEGF , which is highly expressed in glioma cells.
High VEGF expression is directly associated with the poor prognosis and malignancy of gliomas 51 — 53 , Following this interaction, VEGF mediates angiogenesis and cell proliferation. Under hypoxic conditions, hypoxia-inducible transcription factors translocate to the nucleus which activate VEGF leading to increased angiogenesis in an attempt to counteract hypoxia Several VEGF inhibitors have been examined for the treatment of GBM, including the small molecule inhibitors, tivozanib, and pazopanib.
Phase II studies of tivozanib 77 and pazopanib 78 in recurrent glioblastoma showed that these inhibitors exhibited limited anti-tumour activity and did not prolong PFS in this patient population. These trials highlight the limitations of anti-VEGF monotherapy.
Bevacizumab, a humanised monoclonal antibody against VEGF, blocks angiogenesis and thereby reduces tumour growth in a variety of GBM mouse models as a monotherapy and when combined with radiotherapy 72 — These promising pre-clinical studies led to the clinical investigation and subsequent approval of bevacizumab for the treatment of recurrent GBM However, a meta-analysis of four clinical trials including patients demonstrated that the addition of bevacizumab to standard chemo-radiotherapy in the upfront setting only improves PFS, with no improvement in OS, but with an increase in the number of treatment-related adverse events Of note, a decline in neurocognitive function is more frequently observed following bevacizumab treatment, as bevacizumab impairs hippocampal synaptic plasticity and decreases dendritic spine number and length The modest treatment responses combined with the increased treatment-related adverse events raises concerns about the suitability of the use of bevacizumab as a treatment for GBM.
A variety of multi-RTKs inhibitors have been examined both pre-clinically and clinically Table 2. These promising pre-clinical studies led to the initiation of clinical trials. However, whilst imatinib was well-tolerated in recurrent GBM patients, it exhibited limited anti-tumour activity Subsequent Phase III trials have examined imatinib in combination with hydroxyurea, rather than as a monotherapy This trial showed that there was no PFS benefit to the addition of imatinib to hydroxyurea, or hydroxyurea alone.
Further, a recent study has demonstrated that imatinib treatment can increase GBM cell migration and invasion in vitro , providing further potential insight as to why imatinib has failed in clinical trials for GBM.
Following the failure of imatinib in clinical trials, additional multi-RTK inhibitors have been studied. In pre-clinical models, sunitinib treatment induced apoptosis in vitro , and improved survival in an intracerebral GBM mouse model Further, sunitinib treatment delayed tumour growth and increased survival in a PDGFF-driven mouse model, both as a monotherapy and in combination with low dose radiotherapy By contrast, a Phase II trial and systematic review of the literature indicated that compared to conventional chemotherapy or bevacizumab, sunitinib has limited clinical activity in recurrent GBM as a monotherapy 86 or when combined with temozolomide or radiotherapy and temozolomide as a first-line treatment of patients with GBM More than 50 PI3K inhibitors have been designed and are under investigation as treatments for a range of cancers.
However, single agent efficacy in Phase II trials in recurrent glioblastoma has been minimal The lack of clinical efficacy was explained by incomplete blockade of the PI3K pathway in the tumour tissue. Whilst buparlisib showed minimal single-agent efficacy, the study of other PI3K inhibitors that achieve more-complete pathway inhibition may still be warranted. Sonolisib is an irreversible wortmannin analogue that demonstrates a more persistent inhibitor effect on PI3K than wortmannin.
Sonolisib inhibits invasion and angiogenesis in GBM cell lines in vitro and extends survival benefit in orthotopic xenograft models in vivo 91 , Despite these promising pre-clinical results, the response rate to sonolisib in a Phase II study in patients with recurrent GBM was low, and the study did not meet its primary endpoint HGF is overexpressed in 1.
Additionally, amuvatinib MP is a small molecule inhibitor that acts on multiple tyrosine kinases, including MET, has been shown to radiosensitise GBM cell lines both in vitro and in vivo Table 2 Another small molecule inhibitor of MET kinase activity, crizotinib, inhibits the growth, sphere-forming capacity and expression of stem cell markers in a subcutaneous xenograft model of GBM using the U87MG cell line However, in a subcutaneous xenograft model using Mayo39 and Mayo59 GBM cell lines, crizotinib was only effective at reducing tumour burden and vascular density when used in combination with the EGFR inhibitor erlotinib GBM is an often-fatal disease and the standard treatment options available to patients are only minimally effective.
There is a growing body of evidence suggesting that a personalised therapeutic approach for the stratification of GBM patients to novel treatment regimens is necessary if survival rates for GBM patients are to improve. This highlights that a better understanding of the basic biology of GBM is required so that additional targets can be identified.
Indeed, promising pre-clinical effects have been observed with EphA3 inhibitors, however, it remains to be seen whether this translates into the clinic. Whilst PI3K inhibitors have exhibited limited effects in clinical trials, they did not completely inhibit the PI3K pathway.
Despite the promising outlook for personalised therapeutic approaches to treating GBM patients, the identification of therapeutics that can cross the BBB, whilst maintaining therapeutic concentrations, remains a challenge and is often not reported.
Further, although targeted therapies show limited efficacy as single agents, the combination of several targeted therapies may be of benefit to GBM patients.
Thus, additional research is urgently required to identify therapeutic targets in GBM and to design novel therapeutic strategies for the treatment of GBM. OT and JB drafted the manuscript and reviewed the literature. KS formulated the idea. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Cancer statistics, CA Cancer J Clin. Iacob G, Dinca EB. Current data and strategy in glioblastoma multiforme. J Med Life. PubMed Abstract Google Scholar. Increasing incidence of glioblastoma multiforme and meningioma, and decreasing incidence of Schwannoma — : findings of a multicenter Australian study. Surg Neurol Int. Neuro Oncol. Survival benefit of glioblastoma patients after FDA approval of temozolomide concomitant with radiation and bevacizumab: a population-based study.
The site navigation utilizes arrow, enter, escape, and space bar key commands. Up and Down arrows will open main level menus and toggle through sub tier links. Enter and space open menus and escape closes them as well. Tab will move on to the next part of the site rather than go through menu items. Glioblastoma multiforme GBM also called glioblastoma is a fast-growing glioma that develops from star-shaped glial cells astrocytes and oligodendrocytes that support the health of the nerve cells within the brain. GBM is often referred to as a grade IV astrocytoma.
Current promising treatment strategy for glioblastoma multiform: A review
Glioblastoma multiforme is a central nervous system tumor of grade IV histological malignancy according to the WHO classification. Monoclonal glioblasttoma can also inhibit activity of integrins [ 69 ]. Cases of glioblastoma in infants and children are also reported. Glioblastoma multiforme cells are polygonal to spindle-shaped with acidophilic cytoplasm and indistinct cellular borders.