Chemotalk Newsletter

Chemotalk Newsletter, Vol. 77: September 1, 2014

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When I was diagnosed with breast cancer, my oncologist thought I was high risk for either BRCA1 or BRCA2 genes, so she had me tested.  I had neither. I asked her why so many women on my mother's side of the family had some form of reproductive cancer.  There had to be some genetic component.  She said that there probably was, they just hadn't discovered that particular gene yet.  I don't know if I have the PALB2 gene, but clearly finding it will help many women get the most effective treatment.


By Marilynn Marchinoe

It has long been known that faulty BRCA genes greatly raise the risk for breast cancer. Now scientists say that a more recently identified, less common gene can do the same.

Mutations in the gene can make breast cancer up to nine times more likely to develop, an international team of researchers reports in New England Journal of Medicine.

About 5 to 10 percent of breast cancers are thought to be caused by mutated BRCA1 or BRCA2 genes. Beyond those, many other genes are thought to play a role, but how much each one raises risk has not been known, said Jeffrey Weitzel, a genetics expert at City of Hope Cancer Center in Duarte, Calif.

The new study on the gene ‹ called PALB2 ‹ shows that ³this one is serious,² and probably is the most dangerous in terms of breast cancer after the BRCA genes, said Weitzel, one of leaders of the study.

It involved 362 members of 154 families with PALB2 mutations ‹ the largest study of its kind. The faulty gene seems to give a woman a 48 percent chance of developing breast cancer by age 70 and an even greater risk if she has two or more close relatives with the disease.

That¹s nearly as high as the risk from a faulty BRCA2 gene, Michele Evans of the National Institute on Aging and Dan Longo of the medical journal staff write in a commentary in the journal.

The PALB2 gene works with BRCA2 as a tumor suppressor, so when it is mutated, cancer can flourish.

How common the mutations are isn¹t well known, but it's "probably more than we thought because people just weren¹t testing for it," Weitzel said. He found three cases among his own breast cancer patients in the past month alone.

Among breast cancer patients, BRCA mutations are carried by 5 percent of whites and 12 percent of Eastern European (Ashkenazi) Jews. PALB2 mutations have been seen in up to 4 percent of families with a history of breast cancer.

Men with a faulty PALB2 gene also have a risk for breast cancer that is eight times greater than men in the general population.

Testing for PALB2 often is included in more comprehensive genetic testing, and the new study should give people with the mutation better information on their risk, Weitzel said. Doctors say that people with faulty cancer genes should be offered genetic counseling and may want to consider more frequent screening and prevention options, which can range from hormone-blocking pills to breast removal.

The study was funded by many government and cancer groups around the world and was led by Marc Tischkowitz of the University of Cambridge in England. The authors include Mary-Clare King, the University of Washington scientist who discovered the first breast cancer predisposition gene, BRCA1.

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Following is an interesting argument:


Professor Mel Greaves claims that most cancers cannot be cured and experts should look at ways of preventing and managing the disease instead

Cancer will evolve to get past any treatment to kill it and so scientists should develop ways to manage it.  Most cancers cannot be cured and scientists should give up trying and, instead, look for ways to manage the disease, the director of the Centre for Evolution and Cancer at The Institute of Cancer Research, has claimed.

Professor Mel Greaves, an expert in childhood leukemia, said developing more advanced cures would only lead to cancer cells becoming more resistant to treatment.  He believes that scientists should focus on prevention, such as giving aspirin to all over 50s to stop the onset of stomach cancer, and stalling the disease once it has emerged.

"With a lot of respect to oncologists we need to get smarter," he told journalists at a press briefing in London.  "Very intelligent people who aren't scientifically minded think there must be a cause, there must be a cure and it's just not right. It¹s fundamentally wrong.  Talking about a cure in terms of elimination is just not very realistic. There are some examples of it. Childhood leukemia had a cure rate now of 90 per cent but that is an exception.

"There are a few cancers that are curable but most are probably not including the common carcinomas in adults.  We should be a bit more subtle. We should not try to eliminate the cancer, we should try to hold it in check."

Many institutions are attempting to find cures for individual cancers using increasingly advanced methods.  They include ramping up the body¹s own immune system to fight the disease; personalized treatments based on the DNA of the tumors and gene therapies.  But Prof Greaves believes no therapy will work in the long term because tumors continue to evolve like all life-forms. He is a leading figure in the study of cancer evolution ­ the Darwinian process by which cancer cells mutate and diversify by natural selection within our tissue ecosystems.

"You must have noticed that when you read reports about new target therapies, isn¹t it odd that they work dramatically, but three months later (cancer) is back with a bang. It¹s almost always the story," says Greaves. "I would argue that if you look at the age distribution of cancers, most people are in the 60s, 70s and 80s. If you could slow everything down for 10 to 15 years, maybe 20, then that would be a huge advance.  It is wrong to think we need some fancy therapy that kills it. I think slowing it down is a much more interesting proposition."

However, leading cancer expert Professor Karol Sikora, Dean of Medicine at the University of Buckingham, said he was confident cures could still be found.  ³I think this is a pessimistic view, and strange given that Professor Greaves has done so much to help find a cure for leukemia.  I absolutely think we will find new cures in the future and the closer we get to understanding the mechanism of the disease, the quicker this will happen.²

There are more than 200 types of cancer and more than 330,000 people are diagnosed each year. More than one in three people will develop some form of cancer in their lifetime.  Breast, lung, prostate and bowl account for more than half of all new cancers each year and more than a third of cancers are diagnosed in people over the age of 75.  Half of people now survive cancer for at least 10 years and survival rates have doubled in the UK in the last 40 years. But it still causes more than one in four of all deaths.

Prof Greaves said that preventing cancer should be of primary importance, using drugs which tackle the Œecosystem¹ of the disease ­ by changing the chemical make-up of the body.  "I think one of the best drugs that exists is aspirin. It¹s fantastic what it does. There is a big debate about whether we should all take aspirin over a certain age. I think over 50 we probably should, because it has a huge impact on gastro-intestinal cancers.  Here is another drug that doesn¹t attempt to kill the cancer; it simply tries to restrain it."

However Professor Peter Johnson, chief clinician at Cancer Research UK said many people had already seen their cancers cured.  ³We already have cures for many types of cancer. For example, millions of people who have had breast cancer, prostate cancer or bowel cancer are alive years after their surgery to remove the tumor, if it was caught early enough," he said.

"However, when people talk about a cure for cancer they usually mean drugs, and here things are more complicated. Cancer isn¹t just one disease ­ there are hundreds of types, and as we understand the genetic signatures of individual tumors it¹s becoming clear that each person¹s cancer is as unique as they are ­ so it¹s simplistic to talk about a single cure."

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A research study led by cancer specialists at MedStar Washington Hospital Center found that African-American women frequently present with biologically less favorable subtypes of breast cancer.

Researchers at the Hospital Center¹s Washington Cancer Institute analyzed the biology of breast cancer in 100 African-American women, using a method of genomic profiling. These genomic tests look at the expression of genes associated with the risk of recurrence in the population and further characterizes the biology of the tumor. The 70-gene MammaPrint test was used to determine the likelihood of a cancer recurrence. Out of the 100 patients, 66 women in the study were found to be high risk, meaning that their tumors had a higher risk of recurrence.

A companion BluePrint test was used to define the specific molecular subtype of each cancer. When classified by both genomic tests, African- American women with stage I to III breast cancer often presented with gene expression subtypes that were less favorable. The co-author of the research, Raquel Nunes, MD, a medical oncologist at the Washington Cancer Institute, presented the data as a scientific poster at the recent American Society of Clinical Oncology annual meeting.

"It's important that research continues to address these issues comprehensively, from the biology of the disease to the development of optimal treatment and access to healthcare." said Dr. Nunes. ³This work is particularly meaningful for us because it complements our interest in health disparities and highlights the enthusiastic participation of African-Americans in breast cancer research."

Unlike genetic tests such as those for BRCA genes (which are inherited and look at overall susceptibility for developing breast cancer), genomic tests look at the genes inside a breast cancer cell and how strongly they are expressed. The findings support prior research that has looked at the biologic characteristics of breast cancer in African-American women, but this specific methodology reported here was used for the first time in this population.

Cancer specialists will continue to follow the patients in the research study over the next five years to evaluate their survival with treatment, according to their gene profile.

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By Adam Hochron European researchers may have found a key to unlocking a cure for rheumatoid arthritis.

Researchers at ETH Zurich who were studying mice with rheumatoid arthritis found a product that cured the animals of the condition as a precursor to what could be a much larger and beneficial discovery for humans. A statement from the company said the therapy is an 'active substance consisting of two fused components.'

One key part in the equation is the patient¹s own immune messenger interleukin 4 (IL-4), which has already been proven in previous studies to play a role in preventing cartilage and bone damage. The second part of the therapy was described in the statement as being an antibody to the IL-4 which 'binds to a form of a protein that is found only in inflamed tissue in certain diseases (and in tumor tissue.)'

Pharmacist Teresa Hemmerle said the IL-4 is then able to "reach the site of the disease when the fusion molecule is injected into the body." She added, "It allows us to concentrate the active substance at the site of the disease. The concentration in the rest of the body is minimal, which reduces side-effects."

The study was conducted with a CTI project with Philochem, an ETCH spin-off, according to the statement. The mice, with "inflamed toes and paws," were treated with the fusion combination and dexamethasone, which is an anti-inflammatory already on the market.

Results showed that separately the two treatments slowed, but did not stop, the progress of the condition. When used in tandem 'the typical signs of arthritis, such as swollen toes and paws, disappeared within a few days when both medications were administered at the same time.' As the pain subsided the researchers also noted a return to normalcy in several of the animal¹s blood levels.

Looking at the data, Hemmerle concluded that 'this combined treatment creates a long-term cure.'  Since the study concluded Hemmerle reported starting to work for Philochem as a continuation of the project. As a result of the early success, the company announced it is preparing for human trials of the drug, which should begin in 2015.

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Copaxone is indicated for the treatment of patients with relapsing forms of multiple sclerosis (MS). It had US sales of approximately $ 411.5 million for the 12 months ending June 30, 2014, according to IMS Health.

Natco in a statement said that Mylan expects to be eligible for 180 days of marketing exclusivity in the US upon final FDA approval for the drug.

Copaxone is marketed by Teva Neuroscience Inc, which is a subsidiary of Teva, in the US.

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Researchers find method to expand blood stem cells

A team of scientists from the University of Colorado School of Medicine has reported the breakthrough discovery of a process to expand production of stem cells used to treat cancer patients. These findings could have implications that extend beyond cancer, including treatments for inborn immunodeficiency and metabolic conditions and autoimmune diseases.

In an article published in PLOS ONE, researchers from the Charles C. Gates Center for Regenerative Medicine and Stem Cell Biology and Taiga Biotechnologies, Inc. said they have uncovered the keys to the molecular code that appear to regulate the ability of blood stem cells to reproduce and retain their stem-like characteristics.

The team developed protein products that can be directly administered to blood stem cells to encourage them to multiply without permanent genetic modifications.

"Use of stem cells to treat cancer patients who face bone marrow transplants has been a common practice for four decades," said Yosef Refaeli, Ph.D., an associate dermatology professor and one of the study's lead scientists. "The biggest challenge, however, has been finding adequate supplies of stem cells that help patients fight infection after the procedure."

Gates Stem Cell Center Director Dennis Roop, Ph.D., recognized the magnitude of the team's work.  "Researchers have long attempted to increase the number of blood stem cells in a lab," Roop said. "Most of those approaches have been limited by the nature of the resulting cells or the inadequate number of cells produced."

The technology described in the PLOS ONE article has worked with blood stem cells obtained from cord blood, adult bone marrow or peripheral blood from adults.  "The ability to multiply blood stem cells from any source in a dish will be critical for adoption of this new technology in clinics," said Brian Turner, Ph.D., MHS, Taiga Biotechnologies' chief scientific officer. Dr. Turner is also one of the paper's lead authors.

The goal now is to move the technology from the lab into clinical trials. Taiga Biotechnologies is in the process of setting up first-in-human clinical trials with the blood stem cell expansion approaches described in the article. The clinical applications for expanded human blood stem cells vary from inborn immunodeficiency conditions, like SCID and sickle cell anemia, to metabolic conditions, like Hurler's disease or Gaucher syndrome. Autoimmune diseases that could be affected include severe multiple sclerosis and lupus. And the types of cancer that could be treated as a result of this research include leukemia, lymphoma, myeloma and other types of solid tumors.

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I can relate.  See you next month.

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And if you have any thoughts of how this newsletter could be improved, please email me directly, at

Elaine Jesmer

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