The British summer is here...

C&I Issue 14, 2007

While the summer sunshine may have been little in evidence at the time of writing this article, at least there is one reason to be cheerful about all of this year’s rain. With cases of skin cancer in the UK soaring by 200% in the past 25 years, according to figures from Cancer Research UK (CRUK), then many of us may be better advised to lower the risks by staying indoors.

Nearly 80 000 new cases of skin cancer are now reported every year in the UK and about 8000 people are diagnosed annually with malignant melanoma, the most serious and potentially life-threatening form of the disease.

Choosing to wear a sunscreen also helps to reduce the risks, but it is no guarantee of safety. While ‘there is actual evidence that sunscreens can significantly reduce the risk of the less dangerous non-melanoma skin cancer,’ says Dorothy Bennett, professor of cell biology at St George’s, University of London, and a Cancer Research UK scientist, ‘for melanoma different groups have found conflicting results. While some research groups find a protective effect, others see no particular differences and a few even report negative differences – more melanomas in people using sunscreens’.

Some people suggest this is because people who use sunscreen stay longer in the sun, or that the increased risk was seen only with older sunscreens that protected only against the shorter UVB wavelengths, and not the more penetrating UVA rays.

Beyond sunscreens
The market for complementary or ‘beyond sunscreen’ sun protection therapies, meanwhile, is hotting up. Consultancy firm Kline estimates global sales of sun protection products reached $4.4bn in 2006. Although uncommon in the developing world, skin cancer is the commonest form of cancer in the west, with almost half of people in developed countries now likely to develop precancerous skin lesions known as actinic keratoses (AKs) at some point in their lives.


  People with rare sun allergies, or who have undergone organ transplants, are also vulnerable, with fair-skinned transplant patients 60-100 times more likely to develop skin cancer than the rest of the general population (C&I 2007, 12, 11).

Protection and repair
Closest to the clinic potentially, although still several years away, are two new therapies aimed at harnessing the body’s own skin sun protection and repair systems. First of these is a product called Dimericine, developed as a type of after sun repair lotion by US firm AGI Dermatics. Currently in Phase II trials in kidney transplant patients, the active ingredient in Dimericine is a viral enzyme that homes in on the DNA base damaged by sunlight and makes a break at that site, signalling other cellular enzymes to remove and replace it.

‘What is novel about our approach is that it addresses a form of DNA damage that cannot be fixed by antioxidants,’ says Daniel Yarosh, ceo of AGI Dermatics. ‘Dimericine repairs damage that is induced directly by DNA absorbing sunlight. This reaction happens in 15 picoseconds and does not involve oxygen radicals – and cannot be stopped by antioxidants. It is a new approach to skin repair that is different from the widely available antioxidant formulations.’

A study of 30 people published in 2001 in The Lancet found the lotion reduced the incidence of AKs by 68% and basal cell carcinoma by 30%. Dimericine is also now in Phase III trials in people with a rare genetic disease called xeroderma pigmentosum, which predisposes them to skin cancer.

A second drug being developed by Australian company Clinuvel Pharmaceuticals, meanwhile, is designed to exploit the body’s own natural tanning ability to confer protection against sun damage. The drug CUV1647 is a synthetic analogue of the hormone a-MSH, which stimulates the production of the melanin pigment associated with skin darkening. Now in Phase III trials for two rare skin conditions, polymorphous light eruption or ‘sun poisoning’ and erythropoietic protoporphyria or ‘absolute sun intolerance’, Phase II trials in organ transplant patients are also due to start later this year.

Tanned and well pigmented skins are significantly less susceptible to sun damage, as seen by the very rare occurrence of skin cancers in Africa and other darker skinned populations, explains Philippe Wolgen, ceo of Clinuvel Pharmaceuticals, the company responsible for developing the drug. Even a 1% increase in melanin levels could have a ‘remarkable’ effect on a patient’s sun protection ability, he claims.

‘If we can show that CUV1647 works for these serious life-threatening applications, as is our current corporate objective, then we could run after the fast market for skin cancers more generally,’ Wolgen says.

Injected below the skin in the form of a rice-grain size implant, CUV1647 is slowly released into the body where it remains active for up to 90 days, after which another implant may be given. CUV1647 is 800-1000 times more potent than the natural hormone, and so promotes the production of melanin even at very low levels of sunlight such as indoors.

Immunotherapy goals
Further along the disease pathway, researchers are also looking to halt the progression of melanoma to its more dangerous malignant form by harnessing the body’s immune system. Currently, the ‘most exciting’ of these immunotherapies, says CRUK’s Bennett, is being done by researchers at the National Cancer Institute (NCI), part of the National Institutes of Health (NIH) in Washington, US. Last year NCI researchers, led by Steven Rosenberg, reported in a paper in Science (2006, 314, 126) on an immune therapy treatment able to reverse the symptoms of advanced melanoma in two of 17 patients involved in the trial, so effectively curing them of the disease.

To carry out the treatment, Rosenberg and colleagues withdrew small samples of normal infection-fighting white blood cells or lymphocytes from patients, and infected them with a virus in the laboratory. By using the virus as a delivery vehicle to transport new so-called T-cell receptor genes into cells, the researchers were able to decorate the outer surface of the lymphocytes with the encoded receptor proteins.

On re-introducing the cells back into patients, the proteins acted as homing devices by seeking out and attaching to certain molecules found on the exterior of tumour cells, whereupon the tumour cells could be destroyed.

Speaking after the publication appeared last year, NIH director Elias Zerhouni commented: ‘These results represent the first time gene therapy has been used successfully to treat cancer. Moreover, we hope it will be applicable not only to melanoma, but also for a broad range of cancers, such as breast and lung cancer.’

Causes and mechanisms
In fact, the basic mechanisms behind the development of most cancers are surprisingly similar, Bennett says. Cancers form following a series of genetic changes called ‘clonal evolution’, involving mutations at several important genes that gradually lead to the development of the disease via several successive sets of cells or clones, all derived from the same ‘grandparent’ cell.

In the case of skin cancer, she explains, ‘huge numbers of genetic changes are involved in advanced melanoma. Not all of these individual mutations are needed for the growth of malignant melanomas, but a certain critical set are needed, possibly as few as four, and you could potentially interfere with any one of them to halt disease progression.’

One of the most important of these potential targets, scientists believe, is the BRAF gene, found to be mutated in 70% of all melanomas, and also in about 70-80% of skin moles – one of the most susceptible sites for skin cancer progression. Alteration to the BRAF gene occurs at a very early stage during the clonal evolution process, a team of scientists at CRUK, the Institute of Cancer Research and The Wellcome Trust, has recently discovered.

‘It’s clear that BRAF mutation occurs early on during the genesis of the disease so it is possible that cleverly used BRAF inhibitors could have a preventative function,’ says Richard Marais of CRUK. The team has recently formed an alliance with GSK to develop small molecule drugs to block the damaged BRAF proteins produced by the faulty gene, he adds. Although still at the early research stage, a small number of tests are already under way with ‘off the shelf’ compounds that may be inhibitors of these proteins to investigate if the idea could work.

Next along the pathway of clonal evolution, Bennett explains, is the p16 gene associated with the body’s natural defence mechanism against cancer involving a process known as cell senescence. Damage to this p16 gene is the second commonest type of cancer mutation after the notorious p53 gene mutations, she continues. In normal healthy individuals, the p16 gene effectively acts as the messenger signal that tells cells that are dividing too much to stop. For those people unlucky enough to inherit mutated p16 genes, this signal is disrupted, leaving them especially susceptible to melanoma skin cancer as well as several other cancers.

Although the details of Bennett’s current work to restore p16 gene function are still secret, Bennett notes that ‘Our previous work helped to show the importance of p16 and cell senescence as a defence against melanomas/cancers. For example, skin moles contain a lot of p16 – they seem to be potential melanomas that were blocked by cell senescence. Considering moles are hundreds of times commoner than melanoma, that’s how efficient this blocking process is.’

However promising the research, actual therapies for preventing skin cancer are still a long way off the clinic. It will be 2010 at the earliest before any of these is approved for use, and even then they will only be available on prescription. In the meantime, the best advice for the rest of us remains the same. Either stay out of the sun or slip on a shirt, slop on some sunscreen and slap on a hat, ideally with both UVA and UVB protection.

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