Authors: Sue Armstrong
p53 (32 page)
This makes sense, but it is only a hypothesis at present – there are no experimental data to prove it definitively. One source of confusion is the fact that, in the vast wealth of research
that is carried out on p53, there is so little consistency in the methodology that it is hard to compare results. ‘In experimental systems we have all kinds of effects,’ said Pierre
Hainaut. ‘You can always get an experimental system to behave as you would like it to, as an investigator! Now if you go to real life . . .’ Hainaut sat me down in front of the computer
in his study at his Lyon home and brought up a paper he was about to submit. It was an analysis of a number of clinical trials involving the use of a common chemotherapy drug, Cisplatin, in
lung-cancer cases. Overall, the effect of the drug was small, but he and his colleagues wanted to know whether the p53 status of an individual patient’s tumour influenced the outcome of
Cisplatin treatment. For their analysis they had before them the biggest data set of its kind. It contained information about the outcome of treatment, plus the p53 status of the tumours, for 1,200
cancer patients from four trials, conducted in Canada, the US and Europe.
The researchers found – unsurprisingly – that patients whose tumours had normal p53 did a lot better than those with mutant p53. But what did surprise them was that
patients with some specific mutants – but, crucially, not others – got dramatically worse after Cisplatin treatment. Their tumours spread aggressively and many patients
died even more quickly than they would likely have done with no treatment at all. Hainaut was not certain, at that point, whether it was the metastases that killed the people – he was
awaiting further information from a statistician – but that was his hunch.
Whatever the final cause of death turns out to be, knowing the p53 status of lung tumours will be useful in deciding who should receive Cisplatin therapy and who should not. ‘We are not
doing well with lung cancer,’ Hainaut reflected as he scrolled through his paper on the computer screen. ‘There are probably 1.5 million people in the world with this type of cancer.
Maybe 500,000 receive this treatment every year – and they receive it “blind”, because p53 is not being tested by mutation in these patients up front. Such a test would clearly
improve the outcome. It would be really worthwhile . . . That’s the lesson of our analysis.’
The situation Hainaut was describing was specific to lung cancer, with certain p53 mutations, treated with Cisplatin. But the lesson holds true more generally. What scientists have discovered
about p53 and its role in conventional therapy offers cancer specialists a tool for making more rational decisions about how best to treat their patients. This is especially true when p53 status is
part of a wider analysis of the genetic make-up of a tumour, because so many things besides this tumour suppressor have an impact on treatment. At present such tests are rarely offered in cancer
clinics, but things are changing fast. As full genome sequencing becomes ever easier, quicker and cheaper to perform – and as the new gene therapies that target the defects specific to an
individual patient’s tumour begin to reach the clinic – genetic analysis will become a routine part of diagnosis and treatment. Genetic analysis is an essential part, too, of the latest
strategies for cancer prevention.
THE BEST CHANCE OF SURVIVAL
Compared to new treatment ideas, prevention studies have a tough time attracting cancer-research funds. The science of prevention is not as sexy; it doesn’t offer the same rewards to Big
Pharma; and besides, it’s easier to get excited about tumours that are cured than about tumours that just don’t happen.
Nevertheless, Bert Vogelstein is not deterred. ‘We believe the major impact on cancer over the next half-century will come not from treating
advanced
cancers, but from preventing
cancer – in particular from detecting tumours at a very early stage,’ he said. ‘Virtually all cancers are treatable by surgery, without the need for any chemotherapy or radiation,
if they’re caught early enough. That’s definitely true for colon, but it’s also true for many other tumours. It’s an underlying principle.’
For a number of years now, Vogelstein’s lab at Johns Hopkins has been busily engaged in developing tools to look for evidence of early cancers. They are focusing their efforts on detecting
biomarkers – bits of mutant DNA sloughed off by cancer cells that might be swilling around in a sea of normal DNA molecules in the blood, urine, stools or sputum, bearing witness to the
presence of furtive disease. ‘The best marker, the best gene, is obviously p53, because it’s mutant in more tumours than any other gene – that’s the bedrock of this
test,’ explained Vogelstein.
The body fluid in which a biomarker is found is often a good indicator of where the tumour is developing: urine suggests bladder cancer, for example, stool suggests colon cancer and sputum
suggests lung. By late 2012, Vogelstein’s team had investigated more than 700 cancers, starting with advanced tumours, to see if they could find free-floating biomarkers. ‘In advanced
cancers of most tumour types – that is breast, colon, pancreas, lung – you can detect well over 90 per cent of them in the blood,’ he commented. For advanced colon cancer the
researchers’ detection rate in stool samples is close to 100 per cent, and even in relatively early, pre-metastatic cancers it is 85–90 per cent. ‘This test is starting to rival
colonoscopy in sensitivity,’ said Vogelstein. He reckons that even in blood samples, his team has more than a 50/50 chance of detecting colon cancer before it has spread. ‘And if you
can detect even 50 per cent of cancers at a stage when they’re curable that would be massive.’
Researchers working on the problem of liver cancer in West Africa have found biomarkers in the blood that can be used to screen for the disease before symptoms arise. In this region, you will
recall, liver cancer is often associated with aflatoxin contamination of food crops, and DNA molecules released into the blood from a diseased liver show the characteristic fingerprint mutations in
the p53 gene. Elsewhere, too, scientists are exploring the possibilities of using the presence of mutant p53 in body fluids to screen for early cancers.
***
Such screens have still to be widely validated and refined before they reach the clinic. However, many scientists working on the front line of p53 believe we are on the
threshold of a golden age in cancer prevention and cure. In coming years we should expect to see:
• gene therapy become routine treatment for cancer as researchers perfect the technique for modifying viruses as delivery vehicles (dozens of people with diverse
genetic disorders have already been treated successfully);
• more widespread use of genetic analysis of tumours, and the status of p53 being used to determine the best course of treatment and to predict outcomes and
long-term prognosis;
• a dramatic decrease in side effects of cancer therapy as treatment becomes more accurately and exclusively targeted at tumour cells, and as strategies such as
cyclotherapy are used to protect the body’s normal cells;
• a variety of p53-based drugs for use in different circumstances that are able to manipulate the tumour-suppressor pathway to kill cancer cells.
‘I’m very, very optimistic,’ said Gerard Evan. ‘I think we’re going to see dramatic shifts in our ability to treat and contain human cancers over the next 10, 15,
20 years.’ And he added, perhaps provocatively, ‘My daughter is 22 and my son is 21, and I can pretty confidently say they will never, ever have to worry about dying from
cancer.’
Note: these thumbnail biographies do not include all the people mentioned in this book, but are intended as an aide-memoire to some key players whose names appear frequently
and sometimes out of context.
EVAN
,
GERARD
A scientist with Cancer Research UK (CRUK), now based at Cambridge University as Professor of Biochemistry. An early enthusiast for the use of mouse models to find out how
things work in living organisms, he is renowned as an original thinker whose work frequently challenges mainstream thinking. We meet him first in
Chapter 1
, making the provocative comments about
the rarity of cancer.
HAINAUT
,
PIERRE
Based at the World Health Organization’s International Agency for Research on Cancer (IARC) in Lyon, France, for many years, Hainaut ran the mutant p53 database – a
detailed record of all the different mutants appearing in the literature and how they behave. A natural-born detective, he has a special interest in tracing the distribution and pattern of disease
caused by mutant p53 among people throughout the world.
HALL
,
PETER
A Professor of Pathology and close colleague of one of p53’s discoverers, David Lane, at Dundee University, Scotland, in the 1990s. p53 has been one of Hall’s main
research interests. Especially renowned for the maverick experiment he cooked up with Lane in a Dundee pub to test the effects of radiation on p53 in living organisms.
KNUDSON
,
ALFRED
The US-based cancer geneticist who first hypothesised the presence in our cells of genes whose job is to protect us from cancer. The ‘two-hit’ hypothesis of 1971,
which grew out of Knudson’s work with children with the eye tumour retinoblastoma, changed forever the way in which cancer biologists viewed the process of tumour formation.
LANE
,
DAVID
A central character in the story of p53 as one of four people who, working entirely independently, discovered the gene in 1979. Lane was then at the ICRF (Imperial Cancer
Research Fund, now known as Cancer Research UK) in London. At Dundee University in the 1990s, he built one of the largest communities of scientists working on p53 anywhere in the world.
Responsible, among many other things, for dubbing p53 ‘Guardian of the Genome’.
LEVINE
,
ARNIE
The Princeton-based scientist who discovered p53 independently but at the same time as David Lane and two others in 1979. Levine’s lab has been a hub of p53 research ever
since and has been involved in many of the most important discoveries about the function of the gene.
OREN
,
MOSHE
One of the first people, in 1984, to make a clone – an exact replica – of p53 from which endless copies could be made for research. Among many other important
contributions to the field, Oren also discovered p53’s role in apoptosis (cell suicide) and, along with Arnie Levine and Carol Prives, helped to uncover the mechanism that keeps the powerful
p53 under strict control in our cells.
PRIVES
,
CAROL
A Columbia University-based scientist who, in collaboration with Bert Vogelstein, discovered that p53 works as a master switch in our cells, turning other genes on and off in
response to signals. Involved also, along with Moshe Oren and Arnie Levine, in discovering the mechanism that keeps the powerful p53 itself under strict control in our cells. Prives is among a
number of key researchers at the core of the p53 community.
ROTTER
,
VARDA
Based at the Weizmann Institute in Israel, Rotter was one of the earliest researchers to recognise that p53, when mutated, does not simply lose the ability to function as a
tumour suppressor; very often the mutant acts to promote the growth of a tumour. Rotter is famed for having stuck to her guns, even when her analysis was challenged by some of the best brains in
the community, and today hers is the mainstream view.
VOGELSTEIN
,
BERT
Trained as a medical doctor at Johns Hopkins in Baltimore, Vogelstein’s experience treating children with cancer led him to molecular-biology research. The first person to
investigate p53 in human cancers, he has been involved in many key discoveries about the function of the gene, including its role as a tumour suppressor and a master switch.
WEINBERG
,
ROBERT
Eminent US scientist involved since the early days of the molecular-biology revolution in uncovering the genetic basis of cancer. Best known for his discoveries of the first
human oncogene (or cancer-promoting gene) and the first tumour suppressor. Weinberg has spent most of his working life at the Massachusetts Institute of Technology (MIT) and is the author, with
Doug Hanahan, of a seminal paper, ‘The Hallmarks of Cancer’, which defines the key characteristics of all cancer cells.
WYLLIE
,
ANDREW
Trained as a pathologist, Wyllie was a PhD student at Aberdeen University in Scotland when ‘programmed cell death’, or cell suicide, emerged from rarefied fields
into mainstream biology and was given the name ‘apoptosis’. His was one of two groups of researchers who simultaneously discovered that apoptosis is one of the programmes p53 is able to
trigger in response to cellular stress in real life, not just in cell cultures in Petri dishes.
Allele:
One of a pair of genes that occupy the same site on a chromosome. All genes come in pairs: you inherit one allele of each gene from your mother and one
from your father.
Antibody:
Antibodies are the soldiers of the immune system; they move freely in the blood, seeking out invaders such as bacteria and viruses and flagging them
up for destruction. Antibodies are tailor-made by the immune system to recognise and attach to specific targets, which makes them excellent tools for ‘finding’ target molecules in
researchers’ laboratory experiments.
Apoptosis:
Programmed cell death, or cell suicide.
Bacteriophage:
A virus which targets and infects bacteria.
Carcinogen:
A substance capable of causing cancer.
Carcinoma:
A type of cancer that starts in the epithelial cells that form the outer membranes of all the organs, tubes and cavities in our bodies, and include
our skin. At least 80 per cent of cancers are carcinomas (see also
sarcoma, leukaemia, lymphoma
).
Cell culture:
A laboratory process in which cells are maintained and grown outside the body in specially designed containers, such as test tubes and Petri
dishes, and under precisely controlled conditions of temperature, humidity, nutrition and freedom from contamination.
Cell line:
A cell culture developed from a single cell and therefore consisting of cells with a uniform genetic make-up.
Cell-cycle checkpoint:
The checkpoints mark the end of each phase in the multi-phase process of cell division. At each checkpoint, ‘quality
control’ has the chance to verify that the process has been accurately completed before allowing the cell to proceed to the next phase.
Checkpoint:
See
cell-cycle checkpoint
.
Codon:
A sequence of three consecutive nucleotides (the basic building blocks of
DNA
) on a gene that together form a unit. These units dictate
which amino acids are to be used to create the protein that will carry out the function of the gene.
Clone:
In the context of this book, a gene that is produced artificially from another gene, of which it is an identical copy.
DNA:
Deoxyribonucleic acid, the material inside the nucleus of the cells of living organisms that carries genetic information.
Expression:
The process by which an activated gene makes a protein or other product that carries out the function of that gene in the cell. If a gene is
‘over-expressed’, it implies there is an over-abundance of protein in the cell.
Gain of function:
An expression used in reference to a genetic mutation that changes the gene product (e.g. protein) in such a way that it gains a new and
abnormal function (see also
loss of function
).
‘Hallmarks of Cancer’:
A seminal paper written by Robert Weinberg and Doug Hanahan in 2000 that describes the six characteristics common to all
cancers, of whatever organ or origin. They revised the ‘Hallmarks’ in 2011, adding four more general principles.
Large T antigen:
The gene in the
DNA
of the monkey virus SV40 that is responsible for causing cancer in the cells of the host species it
infects.
Leukaemia:
Cancer of the white blood cells, which are a vital component of the immune system (see also
lymphoma
).
Loss of function:
An expression used in reference to a mutation that renders a gene useless – the mutant gene is either unable to make any protein or the
protein it makes has no function. In most, if not all, tumour-suppressor genes other than p53, mutation leads to ‘loss of function’.
Lymphoma:
Cancer originating in lymphoid tissue, a key component of the body’s immune system. Cancers of lymphocytes (lymphomas) and other white cells in
the blood (
leukaemia
) together account for about 6.5 per cent of all cancers.
Malignant:
In medical usage malignant means cancerous; able to spread to other parts of the body.
Metastasis:
The spread of cancer cells from the original site to other parts of the body (hence
metastases
: secondary cancers).
Mutagen:
A substance capable of causing mutation.
Mutant:
Something that has undergone mutation (see below).
Mutation:
A change of the
DNA
sequence within a gene or chromosome of an organism resulting in a new character or trait not found in the
parental type; or the process by which such a change occurs.
Nucleotide:
Nucleotides are the basic building blocks of
DNA
, which stack one on top of the other like nano-sized blocks of Lego to form the
long ribbons of the double helix.
Oncogene:
A gene that has the potential to cause cancer. Very often these are genes that have a normal role to play in the growth of cells, but that have
sustained a
mutation
and lost the ability to respond to control signals.
Oncogenic:
Causing development of a tumour or tumours.
Oncology:
The study of cancer (hence
oncologist
, a doctor or scientist specialising in cancer).
‘Postdoc’:
A postdoctoral scholar; an individual with a doctoral degree who is engaged in a temporary period of mentored research and/or scholarly
training in order to acquire the professional skills needed for his or her future career.
Recombinant DNA:
DNA that has been formed artificially by combining genetic material from different organisms.
Sarcoma:
A type of cancer that forms in the connective or supportive tissues of the body such as muscle, bone and fatty tissue. Sarcomas account for less than
1 per cent of cancers.
Senescence:
In this book the term is used to describe a state in which cell is no longer able to divide but remains alive and functioning.
Somatic mutation:
A
mutation
in a mature cell that has occurred spontaneously during the course of life, as opposed to one that is inherited
and will be present in all the cells, both normal and cancerous.
Tissue culture:
The growth of tissues or cells removed from an organism. The living material is placed in a lab dish such as a test tube or Petri dish with a
growth medium, typically a broth or agar gel, that contains special nutrients.
Transcription factor:
A protein that binds to
DNA
at a specific site and controls the expression of a gene or genes in the vicinity, switching
them on and off as appropriate.
Transformation:
In this book, this term is used to describe the process by which a cell acquires the properties of cancer (commonly described also as
‘malignant transformation’).
Tumour suppressor:
A gene whose function is to prevent cells from becoming malignant.
Wild type:
Used in reference to a gene, this means the ‘normal’ gene that functions as nature intended, as opposed to the
‘
mutant
’ gene whose behaviour is aberrant.