Review
Targeted therapy for malignant gliomas

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Abstract

The identification of markers that are associated with tumour but not normal tissue has allowed the development of highly-specific targeted therapies. Monoclonal antibodies, either alone or linked to radioisotopes or toxins, have provided a powerful tool for research, as well as the basis for promising therapeutic agents with less side effects than standard radiotherapy or chemotherapy. A new class of drugs, the tyrosine kinase inhibitors, which interfere with the function of key molecules in cancer-promoting pathways, have had a dramatic effect in haematological malignancy and are being trialled in solid tumours, including glioma. Although the problem of achieving specific, high-level delivery of these various agents to tumours in the brain remains a major issue, encouraging early results with some targeted agents support the attractive theoretical principles of this new paradigm. Further work to identify new molecular targets and to develop agents exploiting them, is needed, as well as confirmation of their safety and efficacy by clinical trials.

Introduction

Brain and central nervous system cancer accounted for 3% of cancer-related deaths in Victoria (Australia) in 1999.1 Although not as common as cancer of the lung, breast or colon, Australia-wide in 2001 brain cancer of all grades was the third worst type of cancer in terms of survival post-diagnosis, with only 23.8% of patients alive after 5-years.2 The associated neurological disability and their propensity to affect a younger population make these tumours particularly devastating. The most malignant type of glioma, glioblastoma multiforme (GBM), despite advances in surgery, chemotherapy and radiotherapy, still has a dismal prognosis, with a median survival of generally less than 12 months. Because mortality is related to failure of local control of disease effective adjuvant treatments are needed.

The advent of targeted therapies has relied on a vastly expanded understanding of the molecular basis of cancer and glioma development. Gliomas arise from clonal expansion of cells that have accumulated mutations that either enhance (oncogenes), or abrogate (tumour suppressors) the function of certain genes (Fig. 1). Primary, or de novo, glioblastomas, usually have amplification of the epidermal growth factor receptor (EGFR/ErbB1) and loss of genes controlling the cell cycle, such as the INK4A-ARF locus, or cell survival pathways such as PTEN. Secondary glioblastomas, on the other hand, which are thought to arise by progression from lower grade lesions, commonly have upregulation of the platelet-derived growth factor receptor (PDGFR) and its ligands, together with loss of p53.[3], [4] High grade gliomas are also associated with increases in vascular endothelial growth factor (VEGF),5 which is critical for angiogenesis, a hallmark of GBM being prominent neovascularisation. Over-activity of growth factor/receptor pathways is therefore a key feature of gliomagenesis. These receptors are tyrosine kinase transmembrane proteins that are phosphorylated upon ligand binding and couple directly to a number of now well-characterised downstream pathways (Fig. 2) such as the Ras-Mitogen-Activated Protein Kinase (MAPK) pathway, which is the major signalling cascade for mitogenesis and the phosphoinositol-3-kinase (PI3K)-Akt pathway, which inhibits apoptosis.6 Receptors also regulate a range of molecules involved in cell adhesion and motility, processes critical to invasion and metastasis. These pathways appropriated by the cancer cell are often those that are activated during embryogenesis, a period of major cell proliferation, migration and apoptosis, which are normally quiescent in the adult.

The potential benefit of high tumour-specificity is the reduction of the effects of conventional DNA-damaging agents on normal tissues. Focused techniques such as stereotactic radiosurgery and less toxic chemotherapeutic agents and dose regimens, have meant that these side effects have been lessened, but the dream of a ‘magic bullet’ postulated by the German Nobel Laureate Paul Ehrlich at the turn of the century, still remains elusive.

Agents that have been investigated in the treatment of malignant gliomas include monoclonal antibodies, tyrosine kinase and other small molecule inhibitors, ligand conjugates and antisense oligonucleotides.7 This review will give an overview of these as well as some of the newer agents in clinical development (Table 1). Adoptive immunotherapy and gene therapy are not dealt with, but have been reviewed extensively elsewhere.[8], [9], [10]

Section snippets

Monoclonal antibodies: general considerations

The advent of hybridoma technology in 1975 allowed monoclonal antibodies (MAbs) to be produced in large scale.11 More than two decades of development has led to the therapeutic promise of MAbs being realised. Four Mabs are now in clinical use for haematogenous malignancies: the archetype being Rituximab (Rituxan, IDEC Pharmaceutical Corp, San Diego, CA), which is an anti-CD20 MAb used in Non-Hodgkin’s lymphoma and B-cell chronic lymphocytic leukaemia with response rates of up to 50%.[12], [13]

Immunoconjugates

MAbs are an ideal way to deliver effector agents to the tumour and have been conjugated with radioisotopes, toxins and chemotherapeutic drugs. Radioisotopes can emit either α-particles, β-particles or gamma rays; β-particles distribute energy over a longer range whereas α-particles have a higher energy but shorter range profile. β-emitting isotopes such as 131iodine (I) and 90yttrium (Y)19 have generally been used for intravascular use because their longer half-life suits slower uptake into the

Toxicity

Because MAbs are of murine origin, human anti-mouse antibodies (HAMAs) occur in a significant number of patients. Severe allergic reactions are rare, however, a major therapeutic efficacy issue is rapid elimination of the murine antibody from the circulation. Production of ‘humanised’ chimeric antibodies, composed of the constant region of the human Ig and the variable (antigen-recognising) part of the murine MAb has been facilitated by recombinant DNA technology and have a significantly longer

Delivery techniques and problems

Delivery can be by intravenous, intraarterial or local routes. Intravascular delivery requires the macromolecule to cross the blood–brain barrier (partially deficient in tumours) and be taken up into the tumour mass by diffusion and convection. These processes are limited by the high interstitial pressure within the tumour and the large size of conjugated molecules, resulting in slow transfer through the tumour. Heterogeneity in both the tumour vascular supply and the pattern of antigenic

Monoclonal antibodies: glioma therapy

Mahaley and Day were the first to attempt to use antibodies to target gliomas. They produced radiolabelled polyclonal antibodies by immunising rabbits with glioma tissue and were able to demonstrate localisation to tumours on imaging after intra-arterial injection, but only in low quantities.34 Large scale production of MAbs meant that specific glioma-associated antigens could be identified, along with the isolation of the antibody that had the highest affinity to the corresponding antigenic

Target I: epidermal growth factor receptor

EGFR (ErbB1/HER1) is a member of the Class I receptor tyrosine-kinases. It binds epidermal growth factor (EGF), transforming growth factor alpha (TGFα) and other ligands and is important for maintaining many epithelial tissues. EGFR is now recognised as an oncogene in many cancers, notably non-small cell lung carcinoma (NSCLC) and head and neck squamous cell carcinoma (HNSCC). The EGFR gene is amplified in 40–50% of glioblastomas and overexpressed in up to 90%; this is correlated with shorter

Target II: tenascin

Tenascin was first identified as the antigen of MAb 81C6, produced by fusing hybridoma cells with spleen cells of mice immunised with the U251 MG human glioma cell line.35 Tenascin is an extracellular matrix glycoprotein which is expressed in a high proportion of glioblastomas but not in normal brain. It is located in association with the perivascular matrix and may play a role in promoting angiogenesis[60], [61] as well as invasion.62 Like many tumour markers, its expression is heterogeneous

Tyrosine kinase inhibitors

A new class of small-molecule orally available drugs known as tyrosine kinase inhibitors (TKIs) work by mimicking ATP, thus reversibly blocking the binding site for ATP in the tyrosine kinase domain of growth factor receptors and preventing the phosphorylation of tyrosine substrates. TKIs have been shown to enhance apoptosis, reduce invasion and overcome resistance to radiotherapy and chemotherapy.

PDGFR inhibitors

The first TKI to enter into clinical use, imatinib (STI-571, GleevecTM, Novartis Pharmaceuticals Corp., East Hanover, NJ), received approval from the United States FDA in May 2001 as an oral treatment for chronic myeloid leukemia (CML) and in February 2002 for treatment of gastrointestinal stromal tumour (GIST), a rare form of stomach cancer. Imatinib has activity against the related tyrosine kinases Bcr-Abl, Abl, c-Kit and PDGFRβ but not against EGFR.67 The Bcr-Abl fusion oncoprotein is a

EGFR inhibitors

Gefitinib (ZD1839, IressaTM, AstraZeneca, London, UK) is a selective inhibitor of the EGFR tyrosine kinase. In vitro experiments confirm its ability to promote apoptosis,79 inhibit angiogenesis,[80], [81] and induce cell cycle arrest.82 In addition it has synergistic effects when combined with radiotherapy and/or chemotherapy.[81], [83]

Clinical trials with gefitinib in NSCLC have shown mixed results. Phase II trials (IDEAL-1 and 2) in 426 patients with NSCLC who had failed chemotherapy showed

VEGFR inhibitors

The concept of targeting tumour neovasculature, first suggested by Folkman over 30 years ago, has led to anti-angiogenic agents becoming a mainstay of research in cancer therapy.94 Advantages of this approach include the tumour-specific nature of neovasculature and the ease of intravascular delivery. However, anti-angiogenic agents are only expected to be cytostatic, because they are aimed at limiting the tumour nutrient supply rather than killing tumour cells directly. Ongoing therapy would

Ligand-based approaches

Ligands are the body’s natural receptor-targeting molecules and, being peptides of short to medium molecular weight, lend themselves to the engineering of fusion proteins with toxin components. Many ligand-toxin combinations have been investigated to date in the laboratory but this form of targeting is still in an early developmental stage; further clinical trials are expected in the near future.

EGFR ligands

A TGFα-PE40 fusion protein, which targets EGFR, was found to be cytotoxic to glioblastoma cell lines and to cause tumour reduction in nude mice with subcutaneous human glioblastoma xenografts when given continuously intra-peritoneally over 7 days.100 TGFα has also been combined with PE38 and shown to be effective given intra-tumourally.101 This effect, however, depended on EGFR expression, which is heterogeneous and could be abolished by the presence of high EGF levels.101

In boron neutron

Transferrin

The transferrin (Tf) receptor is essential for iron transport into growing cells and is expressed in glioma tissue and normal endothelium, but not in normal brain. A conjugate of a point mutated DT and human transferrin, Tf-CRM107 specifically and effectively kills glioblastoma cells in culture that express the TfR,[104], [105] as well as human gliomas in nude mice by intratumoural infusion.106 One clinical study has been completed, which examined eighteen patients with recurrent malignant

Interleukins

Perhaps more promisingly, the IL-13 receptor (IL-13R) has recently been found to be extremely specific for malignant glioma. An engineered mutant IL-13 ligand binds the glioma-associated IL-13R but not that of normal tissue.109 IL-13 has been combined as a fusion protein with the first 389 amino acids of the DT and observed to induce tumour regression110 and an agent fusing IL-13 to a PE variant, PE38QQR, is now undergoing clinical trials. Similarly, the IL-4 receptor is expressed in

Antisense oligonucleotides

Small nucleotide strands (15–21 base pairs) can bind to their complementary mRNA sequences and interfere with protein translation, thus inhibiting a particular molecule extremely specifically. This strategy has been used in the last decade to induce growth inhibition in cultured glioma cell lines and in in vivo studies, but has not been tested in a clinical trial. Various molecules thought to be important in gliomagenesis have been targeted experimentally by antisense oligomers including basic

Farnesyl transferase

Ras is another signalling molecule that has been implicated in many cancers, most harbouring activating mutations. Ras is modified by the enzyme farnesyl transferase, before moving to the inner cell membrane where it is activated by many processes including phosphorylation of receptor kinases. Ras itself activates the cascade leading to MAP kinase activation. The Ras proto-oncogene is not mutated in astrocytomas, however the levels of activated Ras-GTP have been shown to be increased, probably

Conclusions

In the last decade, the appealing concept of targeted therapy has suffered both triumphs and setbacks. Although the promise of antibody therapy has been realised to some extent with agents like Herceptin in breast cancer, monotherapy for glioma with intravascular ‘naked’ monoclonal antibodies was generally ineffective because of the inability to concentrate therapeutic amounts in the tumour. Current work with radio-isotope conjugated MAbs has preferentially utilised local delivery techniques

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