Cancer

By Joseph Milton, FT science intern

The successful mapping of two cancer genomes has enabled scientists to track the genetic evolution of skin and lung tumours for the first time, providing a catalogue of all the mutations invloved in the cancers. It has been hailed as a breakthrough which could revolutionise treatment and testing for these cancers.

The genomic maps of lung cancer and melanoma, a skin cancer, produced by researchers at the Wellcome Trust Sanger Institute in Cambridgeshire and published in Nature this week, track the DNA mutations that have accumulated in diseased cells through the course of the patients’ lives, revealing the histories of the cancers as they developed in the patients.

Mike Stratton, who led the melanoma study said: ”It’s like doing archaeological excavation. You’ve got traces and imprints of all these processes that have been operative for decades before the cancer arose.”

The researchers were able to trace the replication of every error found in the genome – from a healthy, pristine cell in the embryo, through naturally occurring mutations happening in the body during growth, to cancerous cells, severely damaged by cigarette smoke and ultraviolet light.

In the melanoma patient, tumour cells exposed to sunlight showed a very high proportion of a particular type of mutation, a kind of “signature” of UV damage. But as the cancer developed inside the patient’s body, shielded from exposure to sunlight, the proportion of these UV “signatures” started to decrease.

The scientists found more than 23,000 DNA mutations in the cancerous cells of a 55 year old smoker, and more than 33,000 in cells of a malignant melanoma sampled from a 45 year old man. Most of these mutations are harmless but occassionally a damaging mutation will occur in an important gene, leading to cancer.

The teams also found evidence of DNA repair mechanisms – cells fighting back against the cancer. They could tell this was taking place becuase many more mutations were seen in non-functional areas of DNA between genes than were found in active genes, suggesting that repair mechanisms prioritise important functional areas of DNA over non-functional regions.

The project has been lauded in the press, including in this paper, as the first time cancer genomes have been sequenced in full.

But this is not the first time that cancer development has been tracked by sequencing the genome, then looking at the progression and patterns of DNA mutations. In October Canadian scientists at the BC Cancer Research Centre, Vancouver, led by Samuel Aparicio, published a paper in Nature looking at the history of mutation in breast cancer genomes.

Clive Cookson

More promising cancer research has been revealed on the last day of the British Science Festival in Guildford.

This time it’s a possible treatment for cachexia, the debilitating weight loss and muscle wasting that afflicts about half of all cancer patients. It is particularly severe in gastro-intestinal and lung cancer, and is responsible for an estimated 25 per cent of cancer mortality. No specific treatments for cachexia are available.

Michael Tisdale and colleagues at Aston University in Birmingham have discovered a molecule produced by tumours, called proteolysis inducing factor or PIF for short, which triggers muscle loss.

PIF has a “receptor” on the surface of muscle cells, which can be blocked with an antibody. That stops the molecule getting into the muscles and prevents cachexia.

The project is still at an early stage. Lab tests have shown that antibodies block the action of PIF linked in tissue culture. The researchers are now looking for the best humanised antibody, which might be ready to start clinical trials within three years.

The Aston team has licensed the treatment for development by Halsa Pharmaceuticals, based in Texas. “We went round several British biotech companies but they were not interested,” said Prof Tisdale.

In fact one British company, Ark Therapeutics, has a cachexia candidate in clinical trials – a more conventional “small molecule” drug called Vitor, developed originally to treat high blood pressure. It counteracts the effects of muscle wasting by stimulating mitchondria (the cell’s microscopic power packs) to produce more energy and reduces the breakdown of muscle proteins.

But if the Aston treatment works – a big if for an approach that has not even for tested in animals let alone people – it will be a more direct attack on the underlying cause of cachexia.

Oncologists would welcome any specific cachexia treatment, which could prolong and improve the lives of millions of cancer patients.

Clive Cookson

An interesting clinical trial is under way at Leicester and Loughborough universities, to see whether chemotherapy can be tailored more closely to the needs of the individual patient.

Barry Sharp of Loughborough, the project leader, outlined the move towards “personalised chemotherapy” at the British Science Festival in Guildford.

Compounds based on platinum (cisplatin, carboplatin and oxaliplatin) are used in about 65 per cent of chemotherapy. All patients receive a standardised treatment regime based on their body size and kidney function, although response to the drugs varies substantially.

The aim is to develop a test that clinicians can use before and after dosing, to personalise the regime to maximise benefit and minimise side effects.

Thirty people are taking part in the pilot trial. Researchers take 20ml blood samples and use mass spectroscopy to quantify how much of the administered drug has bound to the target DNA.

They hope to see how the drug dose is distributed through the cells and thereby predict both efficacy and side effects.

If it turns out that test results correlate well with clinical data, then clinicians could for the first time make decisions about dosing on the basis of numerical data from an objective test.

As Dr Sharp says, the benefits to patients in terms of improving effectiveness and reducing harm from platinum chemotherapy are potentially huge.

But at least five years more work will be needed before clear clinical guidelines emerge.

Clive Cookson

Whether to screen middle-aged men for prostate cancer is one of the most controversial issues in oncology.

Screening through the PSA blood test, which detects raised levels of “prostate specific antigen” associated with the disease, can reveal the presence of cancer before symptoms appear, enabling doctors to treat it early through surgery or radiation. In principle this should improve the prospects of a cure.

However the side-effects of treatment are often unpleasant, including impotence and incontinence. And prostate cancers often grow extremely slowly, causing no trouble till the patient dies of other causes.

Now the New England Journal of Medicine has published the results of two huge clinical trials of prostate cancer screening, which were supposed to give doctors better guidance about whether to give the PSA test to symptomless men.

Unfortunately the results are somewhat contradictory. But the overall conclusion seems to be that screening may save a small number of lives but will expose far larger numbers to unnecessary treatment and psychological stress.

A European study of 162,000 men, observed for an average of nine years, found a 20 per cent reduction in mortality among those given the PSA test. For every life saved, however, 1,400 men were screened and 48 men received treatment following a positive result. A US study of 77,000 men, followed for seven years, resulted in more detections of disease but no survival benefit from screening.

John Neate, chief executive of the UK-based Prostate Cancer Charity, says the research “highlights the critical importance of the development of a scientific test that can identify aggressive forms of prostate cancer and differentiate them from slow growing forms of the disease. Such a test would enable treatment to be focused on men for whom prostate cancer poses a serious risk to their health and avoid the over treatment of men with the harmless, slow growing forms of the disease.”

Until a much improved test is available, the middle-aged writer of this blog will decline any invitation to be screened for prostate cancer.

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Clive Cookson, the FT's science editor, picks out the research that everyone should know about, in fields from astronomy to zoology. He also discusses key policy issues, from R&D funding to science education. He'll cover the weird and wonderful, as well as the serious side of science.

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