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PERSONALIZED ANTI-CANCER COCKTAILS @$5,000 A POP

PERSONALIZING CANCER DRUGS:“Starting this spring, for about $5,000, any oncologist will be able to ship a sliver of tumor in a bar-coded package to Foundation’s lab. Foundation will extract the DNA, sequence scores of cancer genes, and prepare a report to steer doctors and patients toward drugs, most still in early testing, that are known to target the cellular defects caused by the DNA errors the analysis turns up. Pellini says that about 70 percent of cases studied to date have yielded information that a doctor could act on—whether by prescribing a particular drug, stopping treatment with another, or enrolling the patient in a clinical trial.”

 

CHANGED METABOLISM CAUSES CANCER?

Cancer-causing mutations yield their secrets

Changes to metabolism disrupt cells' ability to differentiate.

•                     Heidi Ledford

15 February 2012 – NATURE MAGAZINE

The mystery of how mutations in a gene called isocitrate dehydrogenase 1 (IDH1) cause brain cancer and leukaemia is beginning to be unravelled. Researchers have discovered that the mutations cause the production of an enzyme that can reconfigure on–off switches across the genome and stop cells from differentiating.

The findings, published in three papers today in Nature1–3, could be used in the development of drugs for cancers with these mutations — a search that is already under way in many pharmaceutical companies.

Some cancer patients could benefit from new treatments that target mutations in the isocitrate dehydrogenase 1 gene.

SIMON JARRATT/CORBIS

IDH1 acts in an energy-generating pathway known as the citric-acid cycle, and the IDH1 mutations associated with cancer cause a metabolite called 2-hydroxyglutarate to accumulate. The mutations were identified through several cancer genome projects as part as a surge of interest in understanding and harnessing the unusual metabolism of cancer cells.

The field has grown so hot that a company focused on targeting cancer metabolism, Agios Pharmaceuticals in Cambridge, Massachusetts, raised more than US$260 million from investors before any of its compounds reached clinical trials. Late last year, the company, one of those racing to find drugs that target mutant IDH1, became the subject of a high-profile lawsuit when the Abramson Family Cancer Research Institute in Philadelphia accused former employee Craig Thompson of founding the company to pursue findings he made at the institute without notifying institute officials. Thompson, now president of the Memorial Sloan-Kettering Cancer Center in New York, is a coauthor on two of the three Nature papers published today2^, 3, but was not available for comment.

But despite this attention, the relevance of cancer’s unorthodox metabolism long remained unclear. “There has been a debate for nearly a century,” says William Kaelin, an oncologist at the Dana-Farber Cancer Institute in Boston, Massachusetts, and an author on one of the papers1. “Is altered metabolism a cause or a consequence of cancer?”

And although IDH1 mutations are found in multiple cancers, including more than 70% of a type of brain tumour called low-grade glioma — researchers are struggling to work out how the changes contribute to cancer. “For years people have tried,” says Timothy Chan, a radiation oncologist at the Memorial Sloan-Kettering Cancer Center, and an author of the same two papers as Thompson2^, 3. “We were really perplexed as to what mutant IDH1 was really doing, and how it leads to cancer.”

Researchers have now identified several ways in which IDH1 mutations contribute to disease. Kaelin and his colleagues found1 that the form of 2-hydroxyglutarate that accumulates in IDH1-mutant cancer cells promotes cell growth by inhibiting the activity of a protein called hypoxia inducible factor (HIF), which can sometimes suppress tumours.

Chan and his coworkers showed2 that IDH1 mutations unleash what Chan calls “epigenetic chaos” by interfering with an enzyme that regulates the deposition of methyl groups on DNA. This ‘methylation’ can switch gene expression on and off. “It’s one mutation but it can reconfigure the on–off switches across the whole genome,” says Chan.

And Thompson, Chan and their colleagues showed3 that changing the methylation state of crucial DNA–protein complexes called histones prevents cells from differentiating. A lack of differentiation is a hallmark of cancer cells.

Altogether, the findings are “fascinating”, says Martin van den Bent, a neuro-oncologist at the Daniel den Hoed Cancer Center in Rotterdam, the Netherlands. The methylation results, in particular, add to previous clinical studies showing that IDH1-mutant brain tumours have altered DNA methylation patterns.

“This work shows that indeed there is a causal relationship between the mutation and those methylation changes,” says van den Bent. “One gets the feeling that we are getting closer to the dream of developing a treatment for IDH1-mutant cancers.”

Nature doi:10.1038/nature.2012.10029

References 

1. Koivunen, P. et al. Nature advance online publication http://dx.doi.org/10.1038/nature10898 (2012).
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2. Turcan, S. et al. Nature advance online publication http://dx.doi.org/10.1038/nature10866 (2012).
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Lu, C. et al. Nature advance online publication http://dx.doi.org/10.1038/nature10860 (2012).
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SHORT FASTING CAN HELP KILL CANCER?

Short fasting cycles work as well as chemotherapy in mice

February 8th, 2012 in Cancer 

 

Man may not live by bread alone, but cancer in animals appears less resilient, judging by a study that found chemotherapy drugs work better when combined with cycles of short, severe fasting.

Even fasting on its own effectively treated a majority of cancers tested in animals, including cancers from human cells.

The study in Science Translational Medicine, part of the Science family of journals, found that five out of eight cancer types in mice responded to fasting alone: Just as withchemotherapy, fasting slowed the growth and spread of tumors.

And without exception, "the combination of fasting cycles plus chemotherapy was either more or much more effective than chemo alone," said senior author Valter Longo, professor of gerontology and biological sciences at the University of Southern California.

For example, multiple cycles of fasting combined with chemotherapy cured 20 percent of mice with a highly aggressive type of children's cancer that had spread throughout the organism and 40 percent of mice with a more limited spread of the same cancer.

No mice survived in either case if treated only with chemotherapy.

Only a clinical trial lasting several years can demonstrate whether humans would benefit from the same treatment, Longo cautioned.

Results from the first phase of a clinical trial with breast, urinary tract and ovarian cancer patients, conducted at the USC Norris Comprehensive Cancer Center and led by oncologists Tanya Dorff and David Quinn, in collaboration with Longo, have been submitted for presentation at the annual meeting of the American Society of Cancer Oncologists.

The first phase tests only the safety of a therapy, in this case whether patients can tolerate short-term fasts of two days before and one day after chemotherapy.

"We don't know whether in humans it's effective," Longo said of fasting as a cancer therapy. "It should be off limits to patients, but a patient should be able to go to their oncologistand say, 'What about fasting with chemotherapy or without if chemotherapy was not recommended or considered?"

In a case report study with self-reported data published in the journal Aging in 2010, 10 cancer patients who tried fasting cycles perceived fewer side effects from chemotherapy.

Longo stressed that fasting may not be safe for everyone. The clinical trial did not enroll patients who already had lost more than 10 percent of their normal weight or who had other risk factors, such as diabetes. Fasting also can cause a drop in blood pressure and headaches, which could make driving and other activities dangerous for some patients.

In mice, the study found that fasting cycles without chemotherapy could slow the growth of breast cancer, melanoma, glioma and human neuroblastoma. In several cases, the fasting cycles were as effective as chemotherapy.

Fasting also extended survival in mice bearing a human ovarian cancer. In the case of melanoma, the cancer cells became resistant to fasting alone after a single round, but the single cycle of fasting was as effective as chemotherapy in reducing the spread of cancer to other organs.

For all cancers tested, fasting combined with chemotherapy improved survival, slowed tumor growth and/or limited the spread of tumors.

As with any potential cancer treatment, fasting has its limits. The growth of large tumor masses was reduced by multiple fasting and chemotherapy cycles, but cancer-free survival could not be achieved. Longo speculated that cells inside a large tumor may be protected in some way or that the variety of mutations in a large mass may make it more adaptable.

But he noted that in most patients, oncologists have at least one chance to attack the cancer before it grows too large.

Longo and collaborators at the National Institute on Aging studied one type of breast cancer in detail to try to understand the effects of fasting.

While normal cells deprived of nutrients enter a dormant state similar to hibernation, the researchers saw that the cancer cells tried to make new proteins and took other steps to keep growing and dividing.

The result, Longo said, was a "cascade of events" that led to the creation of damaging free radical molecules, which broke down the cancer cells' own DNA and caused their destruction.

"The cell is, in fact, committing cellular suicide. What we're seeing is that the cancer cell tries to compensate for the lack of all these things missing in the blood after fasting. It may be trying to replace them, but it can't," Longo said.

The new study bookends research published in Proceedings of the National Academy of Sciences in 2008.

In that study, Longo's team showed that fasting protected normal cells against chemotherapy, but did not address the effect on cancer cells. The study also focused only on a single cancer and chemotherapy drug.

The new study on a range of cancers and common chemotherapy drugs extends the 2008 results by showing that fasting not only fails to protect cancer cells, but makes them more vulnerable.

Longo called the effect "Differential Stress Sensitization" to reflect the change in vulnerability between normal and cancerous cells.

Longo's interest in fasting and cancer grew from years of studies on the beneficial effects of fasting in yeast and other organisms. He showed 15 years ago that starved yeast cells enter a stress-resistant mode as they wait for better times.

By contrast, he said, the mutations in cancer cells come at a cost, such as a loss in adaptability to diverse environments. For example, Longo found that yeast genetically modified to resemble cancer cells become much more sensitive to several toxins.

"A way to beat cancer cells may not be to try to find drugs that kill them specifically but to confuse them by generating extreme environments, such as fasting that only normal cells can quickly respond to," Longo said.

Provided by University of Southern California

 

 

PROMISING T-CELL IMMUNE SYSTEM CANCER FIGHTING THERAPY

Using Immune Cells from Healthy People to Fight Cancer

Professor Johanna Olweus has found a completely new method of using the immune system to attack cancer. (Credit: Yngve Vogt)

Journal Reference:

I W Abrahamsen, E Stronen, S Wälchli, J N Johansen, S Kjellevoll, S Kumari, M Komada, G Gaudernack, G Tjonnfjord, M Toebes, T N Schumacher, F Lund-Johansen, J Olweus. Targeting B cell leukemia with highly specific allogeneic T cells with a public recognition motif. Leukemia, 2010; 24 (11): 1901 DOI: 10.1038/leu.2010.186  

 

ScienceDaily (Feb. 3, 2012) — Immune cells from healthy individuals can be the new immune cure for cancer. This treatment can kill cancer cells without destroying neighbouring cells. The hope is to eradicate cancer for ever. Today's cancer vaccines are unfortunately not a cure.

 

"The vaccines are based on stimulating the patient's own defence system to attack the tumour. In spite of the tremendous research efforts over the last decades by researchers all around the world, the results have been limited," comments Professor Johanna Olweus at the Immunology Institute at the University of Oslo. Together with her research team, she has found a completely new way to use the immune system to attack cancer.

"We have found a niche that few other people are aware of. In order to achieve effective treatment the immune system must react strongly. This is difficult with the patient's own immune system."

Instead of making a vaccine that builds up the patient's own immune system, the vaccine utilises a strong immune response from healthy individuals.

"Our studies show that the healthy immune cells attack and kill the cancer cells very effectively."

Own immune cells offer poor resistance to cancer

In order to understand the innovation, it is first necessary to understand why it has been so difficult to produce a vaccine against cancer.

Vaccination against infectious diseases is one of the greatest advances in the history of medicine. The immune system recognises a virus or bacteria as dangerous and foreign. When we vaccinate against a virus for example, a message is sent to the foot soldiers, the T cells, so that they are prepared. Then, any later viral infection can be knocked out by the immune system so quickly that we do not notice.

"However, we have not been able to successfully transfer this technique to cancer," states Olweus in the research magazine Apollon.

Once the cancer has gained a foothold, it lives a relatively peaceful co-existence with the immune system, even though it would desirable for the immune system to react aggressively.

Olweus believes this peaceful co-existence can be explained from an evolutionary perspective.

"The existence of the human race has always been dependent on an immune system that defeats infections. But in contrast to infections, cancer generally affects people after they have had children when survival of the human race is no longer dependent on cancer being defeated by the immune system.

Immune cells commit suicide

Neither is it enough that immune cells identify cancer cells as foreign. Cancer cells must also be recognised as being dangerous. Unfortunately, cancer cells do not give enough danger signals because they only cause slight inflammation. Inflammation is important if the immune system is to react.

"A cancer cell must be both foreign and somewhat dangerous if the T cells are to react. When the T cells do not recognise the cancer cells as dangerous, the T-cells kill themselves. This happens primarily with the T cells which could have given the most effective response."

The explanation is that our immune system tries to protect us against over-reaction to our own tissues. Over-reaction can cause autoimmune diseases such as arthritis and multiple sclerosis.

And as if this wasn't enough, the cancer cells have the abominable property of excreting substances that inhibit the T cells that have survived.

Moreover, most of today's vaccines aim at triggering an immune response against proteins that are present in higher numbers in cancer cells than in normal cells.

The problem is: these are normal proteins that are not normally recognised as foreign, even though there may be a particularly large number of them present in cancer cells.

Difficult mutations

A cancer cell can have hundreds of mutations. A mutation is a change in the DNA strand. These mutations can be recognised as foreign by the T cells.

The problem is that it is very difficult to find the mutations that are common to all patients with one particular type of cancer.

Mutations in cancer cells are generally specific for the individual patient. Thus it becomes difficult to know what to "target."

"However, if it is possible to direct many "weak" T cell responses to a large number of mutations, this could possibly have an effect. This may be the explanation why, in trials on treatment of melanomas, antibodies that remove the "brake" for all types of T cells appear to have a promising effect. But this form of treatment is highly risky because the immune system can run "out of control."

Immune response from healthy people

Today, two types of immunotherapy are used as part of the standard treatment for cancer. These are based on immune responses that are produced outside the patient. When you transfer an immune response to a patient, it's able to function independently of the patient's own weakened immune system.

This has resulted in a number of success stories.

The first type of treatment uses therapeutic antibodies that are made by vaccinating animals with human cells. The antibodies recognise the proteins that are only found on a certain cell type. This treatment is particularly effective in lymphatic cancer, even though the antibodies also kill a certain type of healthy immune cells called B cells. These B cells are an important part of the immune system.

The second type of treatment is a bone marrow transplant from healthy individuals to patients with leukemia or lymphatic cancer. This treatment is highly challenging and can be the patient's only chance of survival.

The transplanted bone marrow contains both blood stem cells and healthy T cells from the donor. These T cells can attack the cancer cells and in the best case cure the patient.

In contrast to the patient's own T cells which have been significantly weakened by the disease, the new and healthy T cells from the donor have not been exposed to "tolerance" over a long period of time. Therefore the T cells do not commit suicide. They react instantly to the foreign immune cells. The explanation is that the chemotherapy and radiotherapy have triggered the inflammation and the danger signals.

"The T cells will be able to recognise the cancer cells as both foreign and dangerous and attack them.

The treatment is effective, but is also so dangerous that it is normally only given to patients younger than 60 who are in good health.

The side effects are large. In three of four cases, the added T cells also attack normal cells in the skin, liver and intestines. In the worst case, the patient can die from the treatment."

Can remove undesired effects

The research group led by Olweus has managed to produce a method that distinguishes between desired and undesired effects.

The results have been published in a number of journals including Leukemia.

"Our method is now being used to produce T cells that kill certain types of cancer cells," researchers say.

In order to produce the desired T cells, they use cells from healthy volunteers. The T cells target a certain protein.

"Then we can use the same principle as that used so successfully in antibody therapy. We target the attack at a given cell type by making these T cells recognise parts of a protein that is only found in this cell type.

The T cells can then kill all cells that contain this protein, both healthy and sick. Normally, T cells do not react to these normal proteins.

"The reason that we can get T cells to recognise such proteins as foreign is our innovative trick: We combine the T cells with foreign tissue type molecules.

Tissue type molecules are found in nearly all cells. They are located on the surface and tell the immune system what is happening in the cell. Thus immune cells, just like the T cells, can receive a message that there is something foreign in the cell that must be killed.

If a patient has a type of lymphatic cancer called B cell cancer, prostate cancer or ovarian cancer, the patient can tolerate that the treatment also kills the healthy cells.

It is fully possible to continue living without B cells, a prostate or ovaries.

Prize-winning target-seeking missile

However, Olweus wants to take it a step further.

"T cells kill in a different way to antibodies or chemotherapy. T cells can thus be highly effective when antibody treatment or chemotherapy does not work. But all treatments involving cells have a high resource consumption. Another goal for our immunotherapy is therefore to use the T cell receptors that work as "Target-seeking missiles."

The research group led by Olweus has found a method to isolate the DNA code for the "target-seeking missiles" and produce them as soluble molecules. This means the treatment can be administered intravenously. A patent has been applied for, and last year the method was awarded the annual innovation prize from the Innovation company Invent2 from the UiO and South-Eastern Norway Regional Health Authority.

T cells have the potential to be a far better attack weapon than antibodies. Treatment with antibodies primarily prolongs life expectancy. Few of them cure.

"Antibodies have a substantial limitation. They only recognise proteins on the cell surface. In contrast, T cells also recognise proteins inside the cells. The vast majority of proteins are found only inside the cells. The new therapy can be directed at the proteins inside the cells that are important for the survival of the cancer cells. This can be an important innovation in the battle against cancer.

Combined treatment

Johanna Olweus anticipates that this treatment can be given in combination with antibodies, chemotherapy and radiotherapy.

In order to determine which proteins the treatment has to attack, the research team has mined databases which compare protein collections in cancer cells and organs from thousands of patients.

"If there is a high concentration of one protein in the organ in which the cancer originates and the protein is practically absent from the other normal organs, we can use this protein as a target for the T cells.

Hope to eradicate cancer

The treatment could solve one of today's greatest problems in cancer therapies. After chemotherapy and radiotherapy, loose cancer cells continue to circulate around the body.

"This immune therapy offers the possibility to also destroy these cancer cells, without harming neighbouring cells. This is important. Our hope for the future is that cancer can be eradicated for good, but we must take this step by step. We anticipate that this treatment can be tailored for all types of cancers in organs that are not essential for us to live such as the prostate, ovaries and breasts. We also anticipate that the treatment can also work against cancer in those organs which today can be transplanted such as blood, kidneys and liver. The hope is that our new treatment can be trialled on patients within a few years," states Johanna Olweus.