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Cancer 2&3Comments>>

发表于 2008-01-14 19:54 | Tags 标签:, ,

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Patients doing it for themselves

Doctors and scientists are no longer the only ones steering cancer research, says Jim Giles

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EXPERT TIP Keep your weight down

“I have never smoked, I’m not overweight, I avoid getting sunburnt and I don’t drink much alcohol. I also cycle or walk most days. I have been a vegan for over 30 years because I don’t like slaughterhouses. But whether this has any effect on cancer risk remains to be seen”

Tim Key of Cancer Research UK’s Cancer Epidemiology Unit, University of Oxford

KATHRYN GIUSTI was driving home when her doctor called. She and her husband had been having trouble conceiving, and she was feeling constantly tired. Her doctor had the answer, but it was one that no one would want to hear. Giusti had multiple myeloma, a cancer that forms in the bone marrow and kills two-thirds of patients within five years.

I was devastated, she says. I was 37 years old, at the top of my career and the mother of a 1-year-old girl. Then I was told I had three years to live.

That was in January 1996. Giusti is now in remission after a bone marrow transplant and drug treatment. But she has done more than beat the odds on her survival. In 1997 she and her sister founded the Multiple Myeloma Research Foundation (MMRF), a patient advocacy group and funding body that has changed the face of multiple myeloma research. Over the past decade, the MMRF has raised tens of millions of dollars to fund clinical trials, and helped to bring several potentially life-saving treatments to market in a fraction of the usual time.

In recent years, patient groups like the MMRF have become a powerful force in cancer research. No longer simply trusting the words of doctors and researchers, patients increasingly come armed with knowledge about the latest scientific developments and experimental treatments. Advocates have gained acceptance and respect from scientists and drug companies, and are invited to help set research priorities and comment on research proposals. What’s more, they ask difficult questions about why promising treatments take so long to reach patients.

At the time of her diagnosis, Giusti was a marketing executive with the pharmaceutical company Searle. She used this experience, combined with what she had previously learned at Harvard Business School, to launch the MMRF a year later. Using money raised from corporate sponsorship and events, the charity now spends $30 million a year on researching the condition – the same amount as the US National Cancer Institute (NCI). The biggest myeloma research centres in North America now work with the foundation. Drug companies approach Giusti when they want to test their products and patients ask the MMRF about joining these tests. The result is a pipeline of potential treatments that is flowing fast enough for Giusti herself to have benefited.

She has done an amazing job, says Beverly Laird, a breast-cancer survivor who advises the NCI and other cancer funding bodies. Giusti has moved along science that would have taken years to complete.

Achieving this level of influence took more than a flair for fund-raising. I spent hours at the library poring over scientific journals, abstracts and anything else I could get my hands on, says Giusti. Then I reached out directly to researchers, clinicians and a handful of companies focusing on myeloma.

That research convinced Giusti that she needed to change the way science is carried out. For researchers outside the pharmaceutical industry, papers and grants, not treatments, are the measure of success and results are kept secret until publication. Giusti, however, wants treatments to emerge as quickly as possible, so one condition of receiving funding from the MMRF is that results must be shared. The foundation also holds researchers accountable when progress slows. We approach the drug development process with a sense of urgency, she says.

The process begins when a promising drug emerges from the lab. Researchers at 15 partner centres test the compound on the foundations blood and bone-marrow samples, and the results are posted on a shared database. If a treatment looks promising, the foundation will consider funding a clinical trial. Here, its link with patients comes into its own. The MMRF has a database of over 50,000 patients who can be alerted to new clinical trials that they may be eligible for. This can help speed up the time-consuming task of finding suitable subjects.

The process seems to be working. The foundation has run 16 clinical trials in just three years, many more than would usually be possible in that time. It also helped to find thousands of patients for a trial of lenalidomide, a drug which slows the division of cancer cells. Marketed as Revlimid, the drug was approved in 2006 and helped Giusti achieve remission.

While not all patient groups can boast this kind of success, smaller organisations can have a significant impact too. When Ginny Mason joined the Inflammatory Breast Cancer Research Foundation in 2003, there was a shortage of tissue samples from patients with this condition, which accounts for no more than 5 per cent of all breast cancers. So Mason established a tissue bank which now contains over a hundred samples. Were not just about raising money,” says Mason. We want to be involved in the whole research process. Another bank of hard-to-obtain samples – breast tissue from normal women – has been set up at the Indiana University Simon Cancer Center, Indianapolis, by advocates.

Advocates can also provide unique input into treatments. When a group of oncologists designed a study to test the combination of lenalidomide and the steroid dexamethasone, patient advocates objected to the proposed steroid dose as it can make users unpleasantly hyperactive. Its a drug that has you vacuuming at 3 am and snapping at your wife, says Michael Katz, a myeloma patient who examined the proposals. Reluctantly, the oncologists agreed to also trial a lower dose of the steroid – a decision that was vindicated when survival rates in the low-dose group proved to be significantly higher. What was really fabulous was that this immediately changed the standard of care, says Katz.

Not everyone is in favour of this change in the balance of power, however. One charge against advocacy groups is that they focus on new therapies at the expense of improving existing ones. Another is that they take too much credit for advances that also required government funding and basic research into the disease. Despite these quibbles, cancer researchers who spoke to New Scientist credit advocates with bringing new money and focus to their field. In fact, most of complaints tend to come from those working in fields without strong advocate communities.

Bladder cancer is one such example. It is the sixth most common form of cancer in the US, killing around 14,000 people a year, yet there are only a handful of small advocacy groups that focus on the condition. This could help to explain why it attracts less than half the funding of multiple myeloma, which claims almost 4000 fewer lives per year but has a strong advocate community.

Lack of advocacy also means a lack of awareness, adds Mark Soloway, who treats bladder cancer at the University of Miami in Florida. Smokers are at a higher risk of the condition, so any smoker who develops symptoms such as blood in their urine should immediately be tested for it. Few smokers are aware of this, though, so they may delay before talking to their doctor. Since the window for life-saving treatment can be as short as three weeks, ignorance can be fatal. Some attention from well-informed advocates could be just what the field, and patients, need to help them beat the disease.

EXPERT TIP Eat a balanced diet

“There are many nutrients that are thought to be potentially protective for cancer, including vitamin D, selenium, carotenoids, other antioxidants, and specific fatty acids. However, I don’t take any dietary supplements because I do not think there is strong evidence that supplements have benefits for cancer beyond the nutrients that would be in a varied and balanced diet”

Kay-Tee Khaw, clinical gerontologist, University of Cambridge

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Patient advocates like Kathryn Giusti have a major say in clinical trials

cancer 2 ends

cancer 3

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Tumours under lock and key

Can the immune system be harnessed to control cancer, asks Linda Geddes. Maybe so, if we can mimic natural cases of dormancy .

THEY were supposed to be lifesavers.

In May 1998, a British man and woman in dire need of a transplant each received a new kidney from a donor who had died from a brain haemorrhage. Just 18 months later, the woman discovered a tumour in her breast, and died within four months. Then, in May 2000, the man developed a lump on his kidney, and a biopsy confirmed that he, too, had cancer.

While the organ donor had been treated for melanoma 15 years earlier, she had been carefully monitored, and there had been no hint that the cancer had returned. These cancer cells apparently lay in a dormant state for over 15 years, says Rona Mackie

of Glasgow University, UK, who treated the two recipients. Yet when the melanoma cells were transplanted along with the donor kidneys, they reawakened with awful consequences.

The man fought off the cancer and survived after being taken off the drugs that had damped down his immune system so that his body would not reject the kidney. As a result, he lost the organ and is now on dialysis.

What happened when his immune system was restored to full capacity holds the key to the entire mystery, Mackie believes. The donors immune system had presumably kept the melanoma cells in check – only for them to bounce back with a vengeance in the immunosuppressed recipients of the kidneys. Once the mans immune system came back online, he quashed the cancer.

The idea of cancer lying dormant in the body is not new, but only recently has the immune system been implicated in keeping some forms of cancer at bay. If immunologists can learn to mimic this process, people may be able to hold their tumours in check indefinitely.

Fortunately, cases of cancer from a transplanted organ are rare. But there are intriguing hints that many more people may be living with dormant tumours. For example, a team led by Jonathan Uhr of the University of Texas Southwestern Medical Center in Dallas have shown that around one-third of breast cancer survivors have tumour cells circulating in their blood – some up to 22 years after they were successfully treated (Cell Cycle, vol 5, p 1772). Because cancer cells can only survive in the circulation for a few hours, somewhere in the body a microtumour must be constantly shedding cells, says Uhr.

EXPERT TIP Choose your parents carefully

“I don’t smoke, and that’s the very best thing anyone can do to avoid cancer. I’m a pale-skinned Scotsman, so I avoid the sun where possible and wear sunblock to avoid melanoma. Another tip would be to choose your parents carefully, to check for inheritable cancers, but that’s a bit tricky”

Iain McNeish, medical oncologist, Barts and the London School of Medicine

While some studies of the immune system’s role in cancer have focused on its role in eliminating individual cancer cells when they first arise (see Youre surrounded, right), these mechanisms are thought to be different from those that might keep an established tumour in check.

Now researchers are starting to understand how the immune system controls tumour growth. Variations in an individuals immune response seem to make a difference to how cancer progresses. A team led by Jérôme Galon of the medical research agency INSERM in Paris, France, has shown that for colorectal cancer, the type, density, and location of immune cells within a tumour predicts how likely a patient is to survive; it is even more predictive than standard measures such as the size and invasiveness of the tumour (Cancer Research, vol 67, p 1883). Even patients with a very small tumour could have a very bad prognosis if they have a weak immune response, says Galon.

While he tries to develop better prognostic tests, what cancer immunologists really want to do is to harness the immune system to halt or reverse cancer growth – making a vaccine that would train the immune system to fight cancer. Despite some promising results in animals, however, progress in people has been slow. It is a difficult thing to do because a lot of people with cancer have developed tolerance to their tumour, says Peter Johnson, chief clinician with Cancer Research UK. This tolerance may be what enabled the tumour to escape immune control and grow in the first place.

Still, a better understanding of how the immune system responds in people who survive cancer is throwing up new strategies for fighting the disease. From Galons work, we know that less aggressive tumours contain large numbers of killer T-cells and memory T-cells, which are both powerful weapons of the immune system, suggesting that it is mounting an effective response.

Other research has shown that tumours actively recruit regulatory T-cells, which help dampen down our immune responses.

People with larger tumours have more of these T-regs in their blood and lymph nodes, and when there are many T-regs in a tumour the prognosis is worse. So by manipulating the balance of T-regs and cancer-fighting T-cells, it may be possible to throw cancer into reverse.

Some of the most impressive results have come from clinical trials using cancer-fighting T-cells from people with melanoma that has spread from the skin to other organs. Tumours shrank in about half of patients after their T-cells were removed, multiplied in the lab and injected back into them.

Preliminary studies also suggest that tumours that have spread to the bone, lymph nodes and elsewhere can be nudged into regression following treatment with a drug called denileukin diftitox, which reduces the number of T-regs. Other researchers are using antibodies to try to block the interactions through which T-regs diminish the other T-cells effectiveness, in the hope that this will reawaken the cancer-fighting T-cells.

EXPERT TIP Think positive

“My advice? Well, don’t smoke, eat good green stuff, make very good friends with doctors so that they can snip off the odd mole and do the odd colonoscopy. Also, climb mountains and be very happy and positive the whole time”

David Lane, University of Dundee, UK, who showed that defects in the p53 gene cause a range of cancers

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You’re surrounded

The immune system is always on the watch for anything unusual – and that includes an aberrant, potentially cancerous cell.

Studies in mice and people suggest that immune surveillance is top-notch in some individuals. In 2003, for instance, Zheng Cui and his colleagues at Wake Forest University in Winston-Salem, North Carolina, announced that they had bred mice whose immune systems would rapidly destroy any cancer cells injected into their bodies.

When tumour cells are injected into these mice, they are rapidly surrounded and destroyed by white blood cells called granulocytes. Since then Cui has been studying human granulocytes, which seem to vary greatly in their ability to fight cancer. “At one end people respond very nicely and at the other end they don’t respond at all,” he says. “Most people are in between.”

Armed with this knowledge, Cui is planning a trial in which granulocytes with high cancer-fighting potential are injected into people with cancer – a strategy that already works for mice.

Although some people generate immune cells against their tumour, the numbers are too few to slow the disease. So researchers led by Steven Rosenberg of the National Cancer Institute in Bethesda, Maryland, genetically modify normal T-cells with the help of viruses, getting them to produce receptors specific to the cancer. Then they grow the modified T-cells outside the body before injecting them back in again. When 15 people with melanoma were given this treatment, two responded well (Science, vol 314, p 126) and are still free of cancer two years later.

Rosenbergs team is now running trials in people with other common cancers – including those where there is no evidence that the immune system keeps the tumours dormant naturally.

Mimicking dormancy, rather than eliminating cancer, has become the prime goal – at least in the short term, says Robert Schreiber, an immunologist at Washington University in St Louis, Missouri. If immunotherapy can’t yet be used to cure cancer, maybe it can be used to make cancer a controllable disease instead. ~

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