BioEd Online

Cancer researchers have pinned down a tiny molecule that is capable of kick-starting the body’s own tumour-destroying systems, triggering cell death in cancerous but not healthy tissue in mice.

Called TIC-10, the molecule triggers the gene for a protein known as TRAIL (tumor necrosis factor-related apoptosis-inducing ligand). TRAIL has long been a target for cancer researchers investigating new kinds of drugs that would avoid the debilitating effects of conventional therapy.

“TRAIL is a part of our immune system: all of us with functional immune systems use this molecule to keep tumors from forming or spreading, so boosting this will not be as toxic as chemotherapy,” explains says Wafik El-Deiry, lead author of the study, which appears online today in Science Translational Medicine.

Experiments demonstrated that TIC-10 had potent effects against a variety of tumours including breast, lymphatic, colon and lung. it was especially effective at triggering cell suicide in glioblastoma, a kind of brain tumour which is notoriously difficult to treat.

This, says El-Deiory, owes to the fact that TIC-10 is a tiny molecule — much smaller than other kinds of proteins which have been explored as TRAIL-based drugs. So nimble is TIC-10, it can cross the blood-brain barrier, a membrane sheath covering the circulatory system of the brain. This barrier normally acts to prevent hazardous agents such as microbes from infecting the brain, but can also thwart anti-cancer drugs by blocking their entry. “We didn’t actually anticipate that this molecule would be able to treat brain tumours — that was a pleasant surprise,” says El-Deiry.

Moreover, it seems that this method activates the TRAIL gene not only in cancerous cells, but also in healthy ones, which has enormous potential to create a so-called “bystander effect,” which “It’s almost like TRAIL-plus — it does so much more,” he says.

Although the work was limited to mice, the authors are confident that a similar approach would work in humans. Others are sceptical, in part because TRAIL-based strategies have not lived up to past hype.

The potential for TRAIL as the harbinger of a new age in cancer therapy was first identified in the mid-1990s³. Early clinical trials for a variety of TRAIL-based therapies showed little toxicity, but were also not very successful, says oncologist Andrew Thorburn of the University of Colorado in Denver. “All the large clinical trials found no significant survival benefit to adding TRAIL-based therapeutics to standard treatments,” says Thorburn, who co-authored a review of TRAIL-based therapeutics last year⁴. Large biomedical research groups such as Roche shelved many of their TRAIL-based drugs.