Genentech and the sonic hedgehog

Decades ago, ranchers who moved their sheep up to the high-altitude summer pastures of the Californian Sierra found lambs were being stillborn with gross deformities, including a distorted skull with a single eye, a forebrain with the hemispheres are fused into a single mass, and lacking a medulla, a collapsed chest without lungs, and a long proboscis-like nose.

Dr Neil Watkins, a University of Western Australia PhD, who now works at Johns Hopkins University, in Baltimore, Maryland, told the Lorne Cancer Conference the problem was eventually traced to a toxic, steroid-like alkaloid in California's corn lily, Veratrum californicum, that chemists dubbed cyclopamine, after the one-eyed giant Cyclops, of Greek mythology.

Watkins said cyclopamine was discovered too long ago to be patentable, but big US life sciences company Genentech is developing a synthetic anti-cancer compound that will mimic its ability to shut down the Hedgehog signalling pathway, which is involved in repairing injuries to epithelial tissues, including the skin.

In vertebrates, knockout mutations in the homologous Sonic Hedgehog gene or its receptor, Patched, activate the pathway and trigger uncontrolled cell growth, resulting in a wide range of epithelial cancers, including basal cell carcinoma of the skin, and cancers of the lung, breast, colon, esophagus, and pancreas, and the medulla of the brain.

Hedgehog and Patched are highly conserved genes with a central role in laying out the body plan of all animals, from Drosophila fruit flies to mammals. They establish the polarity of the early embryo -- which ends will develop as the head and thorax, as well as having a role in bilateral symmetry and the development of branched structures like the lungs and kidneys.

In the fruit fly, knockout mutations of the Hedgehog gene, or mutations that spontaneously activate its receptor, Patched, result in wingless flies an undifferentiated head and thorax, completely covered in coarse hairs -- hence, \'Hedgehog\'. The mutations are dominant -- only one copy of the gene needs to be mutant in cancerous cells.

The vertebrate version, Sonic Hedgehog, results in a completely dorsalised embryo -- the underside skull structures fail to develop, the brain develops as a unstructured lump, with no cerebellum.

Watkins' JHU research group is studying the genes in the cell-repair pathways regulated by Sonic Hedgehog in mice -- knockout mutations of the gene or its receptor result in identical foetal deformities to those seen in lambs.

As long as the Hedgehog protein remains bound to the Patched receptor, the pathway is inhibited.

Watkins said the leading Hedgehog researcher, JHU researcher Dr Phil Beachy, had published convincing evidence that the Patched protein is a transporter for a small, as yet unidentified molecule that represseses a downstream gene, Smoothin. While smoothin is expressed, the epithelial tissue-repair mechanisms remain inactive

Watkins said lung cancer was now the leading cause of death in the US, and there is an alarming, rapid rise in the aggressive and deadly Hedgehog-activated small-cell carcinoma, in women in their early 40s who have never smoked. Women cancer patients outnumber men by around two to one.

For Watkins, the most likely explanation is passive smoking. His research is partly funded by a huge damages award by a US association of air hostesses who successfully sued the tobacco companies.

He said his team is interested in the effect of Hedgehog-pathway mutations that inappropriately and permanently switch on localised tissue-repair mechanisms, causing cancer.

Epithelial tissues in organs like the bowel, lung, bladder and oesophagus are subject to rapid turnover and repair because of they are more directly exposed to physical injury and toxins -- or damaging ultraviolet radiation, in the case of the skin.

"One of the current theories of cancer is that the involvement of primitive stem cells or progenitor cells is fundamental property of all cancers," Watkins said. "Every cancer has a way of recruiting one of the many cell-growth and division pathways -- cancer has an embryonic phenotype. "We're lucky enough to work on a pathway that is very simple. It has just three ligands and two receptors, one of which is smoothin, and all three versions of Hedgehog converge on that one molecule. That makes it much easier to deal with pharmacologically.

"We were also fortunate enough to realise that activation of the Hedgehog pathway is a very common event in adults, and causes a diverse range of cancers."

Watkins said cyclopamine appears to be an inactive analogue of the as-yet unidentified, cholesterol-like molecule that represses smoothin. Smoothin, rather than its transporter, Patched is the target for Genentech's prototype anti-cancer drug.

Smoothin's attraction as a drug target is that one molecule of Patched's mystery signalling molecule can shut down 50 smoothin molecules, so an inactive analogue should work at low dosage, minimising any side effects.