Gene therapy of glioblastoma multiforme

K K Jain MD (Dr. Jain is a consultant in neurology and has no relevant financial relationships to disclose.)
Originally released December 16, 1997; last updated August 13, 2016; expires August 13, 2019

Overview

There is no satisfactory method for treating glioblastoma multiforme. Gene therapy is 1 of the promising innovative approaches. This article describes several methods of gene therapy applicable to brain tumors. Most of the initial clinical trials were with herpes simplex virus–thymidine kinase gene therapy, but it did not succeed in completely eliminating the tumor, which is a requirement for cure. Among the newer approaches, oncolysis by genetically modified bacteria appears to be the most promising approach.

Key points

 

• Several gene therapy approaches for brain tumors have been investigated in preclinical studies.

 

• Clinical trials have shown that gene therapy can be carried out safely but did not increase survival of the patients with glioblastoma multiforme.

 

• Some gene therapy strategies such as RNA interference may enhance the effect of concomitant chemotherapy.

 

• Innovative strategies for glioblastoma that are promising include targeted gene therapy delivered by nanoparticles.

Historical note and terminology

Historical aspects, nomenclature, and biology of glioblastoma multiforme are described in malignant astrocytomas. There was no remarkable development in the treatment of glioblastoma multiforme for nearly half a century, until the first clinical trial of the herpes simplex virus, thymidine kinase, and ganciclovir gene therapy system in glioblastoma multiforme (Oldfield and Ram 1993). At the end of 1998, after completion of phase 3 clinical trials, this gene therapy approach was discontinued from further development because it failed to show efficacy. Various innovations employed to treat this condition are listed in Table 1 and some of these are linked to gene therapy. The number of current research projects to find a cure for glioblastoma multiforme exceeds 100, but thus far, none of these has succeeded in curing this disease. This article includes recent advances in gene therapy, as well as antisense therapy, considered to be a form of gene therapy.

Table 1. Innovative Therapies for Glioblastoma Multiforme

New chemotherapeutic agents

 

Innovations for the delivery of chemotherapy

 

• Intraoperative local chemotherapy with fibrin glue containing anticancer agents
• Magnetic cationic microsphere delivery system for anticancer drugs
• Chemotherapeutic agents incorporating biodegradable polymer wafers
• Stereotactic implantation of microspheres containing anticancer drugs
• Lipid-coated microbubbles as a delivery vehicle for taxol

Strategies to overcome the blood-tumor barrier for delivery of chemotherapy

 

• Intra-arterial chemotherapy
• Use of nanoparticles
• Bradykinin analogue RMP-7

Chemotherapy sensitization

 

• Use of thermosensitive liposomes and localized hyperthermia
• Photodynamic therapy for chemosensitization

Innovations of radiotherapy

 

• Boron neutron capture therapy
• Brachytherapy: implantation of interstitial radiation-emitting seeds into the tumor
• Radiosurgery: enhancing effects of ionizing radiation

Corticotropin-releasing factor for peritumoral edema

 

Inhibition of tumor growth

 

• Receptor tyrosine kinases as a signal blocker to hinder the growth of gliomas
• Telomerase inhibition
• Antiangiogenesis therapy
• Polyinosinic-polycytidylic acid given intramuscularly
• Thalidomide, systemic administration
• Targeting epidermal growth factor receptor-mediated metabolic pathway

Local destruction of tumor

 

• Injection of interleukin-4 fusion toxin binds with high affinity to interleukin-4 receptors in tumor
• tumor necrosis factor-alpha
• interleukin-13

Prevention of local extension of tumor to the normal brain

Immunotherapy

 

• Recombinant interleukin-2 and lymphokine activated killer cells
• Monoclonal antibodies
• Radiolabeled antibodies injected directly into the tumor
• Recombinant immunotoxins specific for epidermal growth factor receptor
• Biodegradable polymer implants containing immunotoxins
• Brain tumor vaccines

Gene therapy

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