DEVELOPING NEW CANCER DRUGS
Clearly, a massive body of biological research underpins cancer research. There have been huge advances made in the last 50 years, particularly the unravelling of the structure of DNA and the so-called ‘central dogma’ of biology. Previous generations of cancer drugs were developed largely by observing the effects of chemicals on cells, looking for drugs that were particularly effective at killing cancer cells. This research produced the chemotherapy drugs that appeared in large numbers in the 1970s and 1980s. Although new chemotherapy agents are still being produced, there is a sense of diminishing returns from more recent drugs compared to the huge advances of previous decades.
More recent research has focused on the evolving knowledge of the molecular signatures of cancer in relation to targeted small molecules and monoclonal antibodies. The human genome was sequenced in the late 20th century. The initial sequencing technology was cumbersome and slow, and the first complete sequence took many years to complete. Having completed this task, and with the overall structure of the human genome now known, it has become possible to sequence the genomes of specific cancers and to compare the cancer DNA to the patient’s normal DNA extracted from their blood cells. This now takes teams in specialized laboratories a few weeks and costs are falling rapidly. The technology, time required, and costs are likely to improve dramatically over the next few years such that it will soon be possible to individually determine the DNA sequence of each patient’s cancer as part of the diagnostic workup. For the time being, this work is experimental, and remarkable results are emerging from this new field of study.
The human cell contains around 21,000 genes arranged in 23 chromosomes. Research comparing the DNA sequence of the entire 21,000 genes with the normal DNA of the patients has now been done for a number of cancers, and the results illustrate how small the line is between normal and cancerous cells. On average, experiments of this sort reveal abnormalities in around 40 to 60 genes. Put another way, if we picture the human genome as a library of 23 books (the chromosomes) each of around 1,000 pages (genes), there will be a total of 40 to 60 typographic errors in the entire cancer cell version of the ‘library’. Furthermore, many of these genetic ‘typos’ will not actually alter the ‘sense’ of the gene – the protein produced will retain normal function. The number of key drivers of the cancer process boils down to around 12 pathways. The genes mutated or misfiring in cancers studied in this way all belong to one of these pathways and appear to be present in all cancers studied. This work points the way to the next stage of cancer drug development. The recent round of small molecules and monoclonals have largely (but not entirely) focused on single molecules such as HER2 being targeted by Herceptin. This recent whole genome work highlights the need to target pathways of multiple genes rather than single members. Drug screens in the future are likely to focus on this aspect of cancer biology, in tandem with whole genome screens to pinpoint the key mutated genes in particular cancers. It also opens the possibility that the drugs of tomorrow will be known to work in the presence of particular genetic signatures. Therefore, linking whole genome sequencing to diagnosis points the way to one of the ‘holy grails’ of cancer medicine – the personalized selection of drug therapies.