Understanding DNA Defects Is Route To Better Cancer Therapy

Cancer is at its root a disease of the genes. Whether a tumour affects the lungs, brain or breast, it is the result of a cell that has acquired the capacity to divide unchecked because of mutations in its DNA.

These mutations can be inherited, they can be the result of environmental carcinogens such as cigarette smoke or they can accumulate through errors copied during cell division — all three routes, indeed, are often involved.

This genetic background to all cancers offers an exciting route to better therapy, because the precise pattern of DNA defects that drives a tumour will influence its growth, its spread and the way it responds to treatment.

Drugs such as Herceptin, for breast cancer, are already taking healthcare towards more personalised medicine. Herceptin is highly effective but only against breast tumours with a particular genetic profile, and it must be prescribed accordingly.

Oncologists will be able to select the most appropriate treatment for almost any patient by sequencing the DNA of his or her tumour, and then using the combination of drugs that is likely to be most effective.

Two major hurdles stand in the way, however. The first is the cost of sequencing the genome of a tumour — about $50,000 (£31,362), although this will likely drop to about $1,000 within two years.

The second is a lack of understanding about which mutations and combinations of mutations drive tumours, and how they affect susceptibility to drugs. This is where projects such as the drug database at St George’s, University of London, will be pivotal.

The aim is to help researchers to “mix and match” drugs and cancer mutations, to determine combinations of defects that predict whether a given medicine is likely to work.

Last year, The Times revealed the launch of a similar initiative from the Sanger Institute near Cambridge and Massachusetts General Hospital in Boston. It will examine 1,000 colonies of cancer cells with known genetic defects, which will be exposed to 400 chemical agents to identify which colonies are susceptible to which drugs.

Such studies also have the potential to “rescue” drugs that have failed clinical trials for broad-spectrum use, either because they do not work for enough patients, or cause serious side-effects for a minority.

Some of these may prove to be both safe and effective for patients with a particular genetic profile. It is interesting to note that one “rescued” drug — thalidomide — is among those on the St George’s database.

What is happening now for cancer is also likely, in the longer term, to change the way that many other medical conditions are treated. Cancer may be the most obvious common disease with a genetic root, but it is far from the only one: disorders such as type 2 diabetes and heart disease also have a strong genetic component, and the DNA you inherit also affects the way your body metabolises drugs.

As more of these genetic variations become understood, doctors will increasingly start to practise “pharmacogenomics” for all manner of diseases, precribing drugs and other treatments according to their patients’ DNA profiles. The days when computerised tools like the St George’s database are used routinely in healthcare are probably not far off.  By Mark Henderson, The Times.