08 November 2010
Professor Emeritus, University of NottinghamAppeared in BioNews 583
BBC Radio 4, Wednesday 3 November 2010
About 15 years ago, I formed the view we should be less ambitious about improving 'Public Understanding of Science' because we should not expect the public to understand genetic principles in detail. Better, I thought, to give a grounding in core science skills. Then people could build on this basic knowledge while coming to terms with what had happened if they were diagnosed with cancer or inherited disease, or gave birth to a baby with a congenital abnormality.
The BBC 'Frontiers' programmes on Radio Four are excellent examples of informing the wider public. Topics covered in the last 18 months have ranged from synthetic biology to graphene and from stem cells to future vaccines. This week's programme, the first in a new series, tackled a new approach to the management of disseminated malignant melanoma. As many recent radio and TV programmes have done, the encouraging results were attributed to knowledge gained from sequencing the human genome.
The programme concentrated on PLX4032, a new treatment for metastatic melanoma. This synthetic agent was designed using a different strategy from the selective cell killing approaches of conventional chemotherapies. PLX4032 development was an excellent example of logical thought and clear insights, founded on accurate, reproducible observations. Frontiers explained how this was done.
About eight years ago, a UK team discovered that a gene, BRAF, was mutated in tumour tissue of about 70% of melanomas and in lesser proportions of other cancers. The melanoma finding was soon confirmed; it transpired that the BRAF gene was mutated in as many as 81% of melanomas.
The previous best treatment for disseminated melanoma was dacarbazine, a powerful cell-toxic drug, which prolongs survival in up to 20% of affected people. Being toxic to all growing cells, dacarbazine leads to the whole gamut of dangerous side effects. In contrast, PLX4032 has fewer side effects because it targets the BRAF changes in melanoma cells not present in normal ones. Early trials indicate patients who benefited from PLX4032 showed a response within a week.
Professor Mike Stratton, joint head of the Cancer Genome Project, explained how BRAF mutations led to unrestrained growth of melanoma cells. These mutations duped tumour cells into keeping on growing; the BRAF gene function was stuck in the 'on' position. PLX4032 targeted only cells with that mutation, causing cell death in BRAF positive ones. We heard from a patient whose intrathoracic melanoma was 7cm in diameter; the tumour shrank within a few weeks. We also heard that PLX4032 is effective when administered orally.
There are limitations, of course. There are many examples of drug resistance in cancer therapy and one problem is the possibility that clones of melanoma cells without the BRAF mutation might develop during PLX4032 treatment. The vacuum created by the demise of BRAF positive cells might therefore enhance growth of resistant ones. Despite this caveat, however, the researchers were unanimous this was a 'foot in the door' towards effective cancer treatment; one clinical researcher felt we were 'halfway there'.
Frontiers included musings on whether this was a 'penicillin moment': a drug as effective as the first use of penicillin against staphylococcal infection in 1941. I hoped not because that treatment ran out after five days and the patient relapsed. One researcher felt it was more an 'AZT moment': that drug slowed the progression of HIV disease by inhibition of HIV virus replication. PLX4032 is analogous to AZT because it slows disease progression by inhibiting replication of BRAF positive melanoma cells.
I think we need to pass to members of the public a sense of proportion about the human genome. They should know treatments will only be successful when therapy is targeted to abnormal cells and when a gene's action causes progress of a disease. We have about 27,000 genes and within each there is the possibility of hundreds of pathogenic mutations. I'd like to call this excellent Frontiers programme a 'PLX4032 moment' - when the public received balanced, accurate genetic information.