Skin-deep screen: cheminformatics reveals melanoma lead

Focused skin cancer search

Cheminformatics has helped researchers home in on a single compound that could lead to a new approach to treating malignant melanoma. Laboratory tests show that the compound reduces the number of cell types formed by neural crest progenitor cells.

The rare, but usually lethal skin cancer known as malignant melanoma arises when cells originally derived from the embryonic neural crest go awry and melanocytes are transformed into tumour cells. Although squamous cell and basal cell carcinomas are commonly caused by exposure to ultraviolet light, either solar or artificial, the jury is still out on the underlying causes of melanoma. Indeed, there is no good evidence to suggest that reducing sun exposure reduces melanoma risk and it is possible that long-term sun exposure may have a protective effect against this risk; a similar benefit has been claimed for other forms of cancer, although this is not to advocate acquiring sunburn to ward off cancer as that comes with its own inevitable problems. It seems, however, that a genetic predisposition to melanoma is a major factor in its emergence.

Regardless of its cause, malignant melanoma is potentially lethal and in some cases is quick to metastasize, or spread, to other tissues. In the so-called post-genomic world there is evidence that inhibiting a protein expressed by the B-RAF cancer-causing genetic mutation can be successful in reducing symptoms and leading to life extension in patients carrying this mutation (about 80% of cases). This gene was found by spin-off research as part of the human genome project and represents one of the best known examples of the still gradually emerging area of pharmacogenomics.

Screening for skin cancer drugs

Given that the molecule found through the screening is so similar to leflunomide the team tested the latter to see if it could inhibit human melanoma growth in engrafted mice. They also combined it with a known B-RAF inhibitor made by Plexxikon, which is in late stage clinical trials for metastatic melanoma. The combined chemical attack decreased melanoma in the mice even at low doses of each drug with a 40 percent success rate. This drug combination may enter human clinical trials within a year, and it may be possible to use lower doses of each drug to decrease the risk of side effects and resistance.

The research was underpinned by the expertise of Leonard Zon of the Howard Hughes Medical Institute (HHMI) and the Children's Hospital Boston, Massachusetts on using zebrafish as a biological model of human disease. The zebrafish, a species found in the Ganges, shares many of its genes with humans and has become a model organism in Zon's laboratory. Moreover, it is a relatively simple task to modify this species to incorporate a human disease gene, such as the melanoma-related B-RAF gene.

Zon and 21 colleagues at HHMI and multiple institutions used a mutant zebrafish model to uncover two new proteins that promote melanoma development, which could represent new targets for drug therapy. A second set of experiments demonstrated that shutting down a protein involved in converting DNA to RNA can block the formation of stem cells that give rise to melanoma. Zon and colleagues recently published two Nature papers back to back outlining their research.

Using a "brute force" approach to analyze more than 2100 tumours in more than 3000 zebrafish, the researchers found just one gene, SETDB1, that accelerated melanoma growth. It made the cancer appear earlier, grow faster, and invade deeper into the muscle and spine. By screening 100 human melanoma cell lines, the team found that SETDB1 was also up-regulated in 70 percent of human tumours.

In the second paper, Zon worked with 19 coauthors, including HHMI's Sean Morrison at the University of Michigan, examined the embryos of the zebrafish that were genetically modified to be prone to developing melanoma. The embryos appeared normal, but by analyzing their gene expression, Richard White, a postdoctoral researcher in Zon's lab, discovered a set of 127 genes that are inappropriately expressed in melanomas and that predict which fish will get melanoma.