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Friday, October 24, 2008

Genome Study Finds 26 Lung Cancer Genes

US scientists working on the largest study ever to map the genetic changes involved in lung adenocarcinoma have identified 26 genes that are frequently mutated in this most common form of lung cancer, further increasing opportunities for individualized diagnosis and treatment of the country's leading cause of cancer deaths.

The Tumor Sequencing Project (TSP) consortium study was funded by the National Human Genome Research Institute (NHGRI) of the National Institutes of Health (NIH) and was the work of investigators from many research centers throughout the US and two in Germany. It is published in the 23 October print issue of the journal Nature.

Acting Director of the NHGRI, Dr. Alan E. Guttmacher said:

"By harnessing the power of genomic research, this pioneering work has painted the clearest and most complete portrait yet of lung cancer's molecular complexities."

"This big picture perspective will help to focus our research vision and speed our efforts to develop new strategies for disarming this common and devastating disease," he added.

The TSP consortium's achievement more than doubles the number of genes that were already known to be linked to lung adenocarcinoma, a deadly form of lung cancer.

However, the study did more than identify gene mutations, it also discovered detailed gene signaling pathways involved in the development of lung adenocarcinoma, and mapped the genetic differences among subgroups of lung cancer patients, such as between smokers and never- smokers.

Most cancers, including lung adenocarcinoma happen because DNA changes accumulate as people age, but not much is known about the biology of how the DNA changes lead to uncontrolled cell growth.

The TSP consortium is one of many multi-institution groups seeking to chart the complete DNA or genome map of many types of cancer.

A senior author of this paper, Dr. Matthew Meyerson, who is a senior associate member of the Broad Institute of MIT and Harvard and an associate professor at the Dana-Farber Cancer Institute and Harvard Medical School, said:

"We found lung adenocarcinoma to be very diverse from a genetic standpoint."

Meyerson explained that the study uncovered many new targets for therapy: both in terms of oncogenes (genes that drive cancer growth) and tumor suppressor genes (genes that prevent cancer growth).

For the study, the TSP investigators took DNA from tumor tissue donated by 188 patients with lung adenocarcinoma and matched it with DNA from non-cancerous tissue. They purified the DNA and then sequenced it to look for mutations in 623 genes that were already suspected of being linked to cancer.

They found 26 genes that were mutated in a significant number of the samples. Before this, scientists only knew fewer than a dozen genes to be involved in lung adenocarcinoma.

Some of the new lung adenocarcinoma genes they found included:

* Neurofibromatosis 1 (NF1). Mutations of this gene are already known to cause neurofibromatosis 1, a rare inherited disorder that involves uncontrolled growth of nervous system tissue.

* Ataxia Telengiectasia Mutated (ATM). This gene is involved in various types of leukemia and lymphoma, and in ataxia telangiectasia, a rare inherited childhood neurological disorder.

* Retinoblastoma 1 (RB1). This gene plays a role in retinoblastoma, a relatively uncommon type of childhood cancer that starts in the retina of the eye.

* Adenomatosis polyposis coli (APC). Mutations of this gene are linked to colon cancer.

* Ephrin receptors A3 and A5 (EPHA3 and EPHA5), neurotrophin receptors (NTRK1 and NTRK3) and other tyrosine kinases tied to receptors (ERBB4, KDR and FGFR4). These genes control the action of cell receptors used by a family of enzymes known as the tyrosine kinases that play a key role in cell growth, differentiation and death, and are prime targets for new cancer treatments.

Having found the genetic mutations the TSP investigators then looked for the biological pathways they used that could be important to the development of lung adenocarcinoma. This work is valuable for improving cancer treatment.

One example of this valuable work lies in the TSP team's discovery that more than two thirds of the 188 tumors they investigated had at least one mutated form of a gene that affects the mitogen-activated protein kinase (MAPK) pathway, showing it is probably an important player in the development of lung cancer.

Such a discovery will open the way for new treatments using drugs that target the MAPK pathway. One group of similar drugs called MEK inhibitors has already shown promising results in the treatment of colon cancer in mice.

The TSP team also found that more than 30 per cent of tumors had gene mutations that affected the mammalian target of rapamycin (mTOR) pathway. The team believes this means that the drug rapamycin, which is used to treat organ transplant and renal cancer patients, may have a potential use in the treatment of lung cancer.

Among other numerous discoveries made in this study is the possibility that chemotherapy drugs currently used to treat other cancers may be effective in the treatment of certain types of lung cancer. This is because some of the genes activated in lung cancer are the same in other cancers.

The TSP team also analyzed differences in genetic patterns among subgroups of lung adenocarcinoma patients. One such analysis was the difference between smokers and never-smokers.

About 10 per cent of lung cancer patients say they have never used tobacco. In this study, the TSP investigators found that DNA samples from smokers had significantly more gene mutations than samples from never-smokers. Some of the tumors of the smokers had as many as 49 mutations, whereas none of the never-smokers' tumors had more than 5 mutations.

This discovery suggests more research is needed to find out what this means for the management of lung cancer. Information from other cancer studies suggests that the more mutations present, the faster the cancer develops and the harder it is to treat.

A senior author of the paper, Dr. Richard K. Wilson, who is director of the Genome Sequencing Center at Washington University School of Medicine, St. Louis, said:

"Our findings underscore the value of systematic, large-scale studies for exploring cancer."

"We now must move forward to apply this approach to even larger groups of samples and a wider range of cancers," he added.

His colleague and co-author Dr. Richard Gibbs, who is director of the Human Genome Sequencing Center at Baylor College of Medicine, agreed, adding that:

"Clearly, much still remains to be discovered. We have just begun to realize the tremendous potential of large-scale, genomic studies to unravel the many mysteries of cancer."

Over 1 million lives, including 150,000 in the US, are lost every year throughout the world because of lung cancer, the most commonly diagnosed form being lung adenocarcinoma. On average, only about 15 per cent of patients survive more than 5 years after diagnosis, with those who are diagnosed early surviving the longest.

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MS Damage May Be Reversed By Leukemia Drug

Researchers in the UK found that alemtuzumab, a drug initially developed to treat leukemia, stopped the advance of multiple sclerosis (MS) in patients with early stage active relapsing-remitting multiple sclerosis (RRMS) and may even have reversed some of the damage caused by this debilitating neurological disease.

The study was the work of scientists at the University of Cambridge and was published online on 23rd October in the New England Journal of Medicine (NEJM).

The Cambridge group has a long connection with alemtuzumab, a monoclonal antibody that started out as Campath-1H and is now licensed for the treatment of chronic lymphocytic leukaemia. The drug has also been tested for use in other diseases like MS that are caused by an overactive immune system.

MS is a disease where the immune system attacks nerve fibers and the protective myelin sheath that surrounds them. The damage means that electrical signals can't travel so well in the nerve fibers and leak through the damaged sheath, leading to loss of physical skills, sensation, vision, bladder control, and intellectual ability.

Alemtuzumab is a humanized monoclonal antibody that targets the immune system cells that attack the nerve fibers and the myelin sheath.

The study was a phase 2, randomized, blinded trial involving 334 participants who had not been treated for early, relapsing-remitting multiple sclerosis (RRMS). They had all scored 3.0 or less on the Expanded Disability Status Scale and had the disease for three years or less.

Relapsing-remitting multiple sclerosis (RRMS) is the most common form of the disease and is often followed by the more disabling form which is called secondary-progressive MS (SPMS).

The participants were randomized to one of two groups. One group received alemtuzumab intravenously (at a dose of either 12 or 24 mg a day) for five days and then again for three days one year later. The other group received 44 microgram injections of interferon beta-1a three times a week.

The participants were followed for 36 months to find out how effective the treatments were and how their disabilities changed.

The alemtuzumab therapy was stopped after one annual cycle because three patients died after developing immune thrombocytopenic purpura (low platelet count). The interferon beta-1a group continued with treatment for the rest of the study period.

The results showed that:

* Compared with interferon beta-1a, alemtuzumab significantly reduced the rate of sustained accumulation of disability (26.2 versus 9.2 per cent respectively).

* The annual rate of relapse in the interferon beta-1a group was significantly higher than the alemtuzumab group (0.36 versus 0.10).

* On a 10-point scale of disability, the mean score significantly improved by 0.39 point in the alemtuzumab group and worsened by 0.38 point in the interferon beta-1a group.

* The lesion burden (a way of assessing the neurological damage of the disease using a method called T2-weighted magnetic resonance imaging or MRI) in the alemtuzumab group was lower than that of the interferon beta-1a group.

* From month 12 to month 36 of the study, brain volume (measured by viewing T1-MRI scans) increased in the alemtuzumab group but decreased in the interferon beta-1a group.

* There were some serious increases in adverse events in the alemtuzumab group compared to the interferon beta-1a group. These were: two types of autoimmunity event (thyroid disorders [23 versus 3 per cent respectively] and immune thrombocytopenic purpura [3 versus 1 per cent]) and infections (66 versus 47 per cent respectively).

* There were no signficant differences between the two doses of alemtuzumab (12 mg and 24 mg).

The researchers concluded that:

"In patients with early, relapsing-remitting multiple sclerosis, alemtuzumab was more effective than interferon beta-1a but was associated with autoimmunity, most seriously manifesting as immune thrombocytopenic purpura. The study was not powered to identify uncommon adverse events."

The next stage will be a phase 3 trial, which principal investigator Alastair Compston, Professor of Neurology and the Head of the Department of Clinical Neurosciences at the University of Cambridge hopes will confirm that alemtuzumab "can both stabilize and allow some recovery of what had previously been assumed to be irreversible disabilities".

Head of research at the MS Society in the UK, Lee Dunster, welcome the study. He said in a press statement that:

"The MS Society has been following this trial closely and we are delighted that it has reported such positive results."

"This is the first drug that has shown the potential to halt and even reverse the debilitating effects of MS and this news will rightly bring hope to people living with the condition day in, day out," said Dunster, and although more research is needed to prove the drug's long term effectiveness, the society is:

"Very much looking forward to the results of the next stage of this important research, which is already underway."

There are nearly 100,000 people living with MS in the UK, about 400,000 in the US and several million worldwide.

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