Gliomas are an aggressive form of brain tumour thought to be derived from astrocytes. Worldwide, 80,000 people are diagnosed with gliomas annually. Glioma cells are highly invasive, and quickly infiltrate surrounding tissue so that the tumour is already malignant upon diagnosis. These cancers are therefore inoperable, and usually fatal, with more than half of all patients dying within 18 months of diagnosis.
Complex cellular and molecular mechanisms underly the aggressiveness of glioma tumours. As it grows, the tumour pushes healthy cells aside, squeezing them against the inside of the skull and preventing the brain from functioning properly, sometimes causing behavioural changes and paralysis. Glioma cells secrete metalloproteases which degrade extracellular matrix proteins; the cells also undergo dramatic changes in shape and volume, allowing them to migrate through narrow gaps between healthy cells.
Because chemotherapy has unwanted side-effects and kills healthy tissue around the tumour, researchers have been trying to develop alternative forms of therapy. The aim of targeted therapies, as their name implies, is to target cancerous cells while leaving surrounding cells unaffected. One type of targeted therapy which looks promising is based on the venom of the yellow Israeli scorpion, Leiurus quinquestriatus. The venom is among the most toxic of all scorpion venoms; it contains histamine, enzymes, enzyme inhibitors and the potent neurotoxins chlorotoxin and charbydotoxin, which specifically target low-conductance glioma-chloride chloride channels (GCC) and high-conductance calcium-gated potassium channels, respectively.
Invasion of surrounding tissue by a glioma tumour apparently requires efflux of chloride ions from the cancerous cells. This efflux is mediated by GCC. Chlorotoxin, a 36-amino acid peptide, selectively binds to GCC with high affinity, inhibiting its function and preventing the migration and invasion of glioma cells. (Other GCC inhibitors, such as tamoxifen, have the same effect.) Recombinant, synthetic and fluorescently labelled forms of chlorotoxin retain the properties of the natural molecule; chlorotoxin conjugated to nanoparticles has been used to help in the detection of gliomas by neuroimaging.
The knowledge that GCC appears to be expressed only by glioma and meningioma cells, and that chlorotoxin selectively binds to and blocks GCC, has encouraged researchers to develop chlorotoxin-based therapies.
TransMolecular, Inc., a Birmingham, Alabama-based biotechnology company, has developed TM-601, a synthetic version of the chlorotoxin peptide bound to the radioactive isotope iodine-131. Upon injection into the bloodstream, TM-601 homes in on glioma cells, delivering its cargo of radioactive atoms. These atoms then decay, destroying the cancerous cells in the process, while leaving adjacent healthy cells unaffected. Another possibile therapy is attaching the synthetic chlorotoxin to chemotherepeutic agents such as samporin.
According to Matthew A. Gonda, CEO of TransMolecular Inc., TM-601 acts like a “smart missile” because the glioma cells it targets divide rapidly, and therefore have properties similar to those of invertebrate cells. Invertebrates, which constitute the prey of the scorpion, have rapidly dividing cells, which gives those organisms the capacity for quick regeneration of damaged tissue. Hence, scorpion venom evolved to attack rapidly dividing cells.
In August 2003, TransMolecular Inc. received fast track designation from the Food and Drug Administration (FDA) for its compound. Because of a lack of effective treatment for glioma, the FDA will facilitate the the development and review of applications for the approval of TM-601. There is, therefore, a danger that the drug will be approved before its safety is fully evaluated.
In the first round of clinical trials, 18 patients with high-grade gliomas were given a single dose of TM-601; all of them were still alive 18 months after the trial, a considerable improvement on the 2-4 months they would normally be expected to live after being diagnosed with high-grade gliomas.
The company began enrolling patients for phase II clinical trials using TM-601 in 2004. The trial is being conducted at multiple sites accross the U.S., and will evaluate the tolerability, effectiveness and safety of multiple doses of TM-601. So far, no side-effects have been observed; the drug is removed from the body in sweat and urine after 72 hours.