The Harvard report

News from the Harvard Medical School research community.
The Harvard report
By Partners Harvard Medical International
Sat 20 Dec 2008 04:00 AM

News from the Harvard Medical School research community.

Lung cancer:Landmark genomic lung cancer study published

Scientists have announced the results of the largest genomic study to date of lung adenocarcinoma, the most common form of lung cancer.

Led by researchers from Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, and other research institutions nationwide, the collaborative study unearthed a variety of genetic alterations in patient tumours and pinpointed 26 frequently altered genes - more than doubling the number already linked to the disease.

The work, which appears in the the journal Nature, draws upon multiple large-scale approaches to highlight key molecular defects in lung tumours that are often found in other forms of cancer, a convergence that could open important avenues for treatment.

"In recent years, there have been some important successes for targeted therapies for some types of lung cancer," said co-senior author, Dr Matthew Meyerson, an associate professor at Dana-Farber Cancer Institute and Harvard Medical School and a senior associate member of the Broad Institute of MIT and Harvard. "This work helps identify new targets that might show promise for treating broader groups of lung cancer patients."

Lung cancer exacts an overwhelming human toll. With over a million deaths worldwide each year, it ranks as the primary cause of cancer-related mortalities.

As in the majority of cancers, lung adenocarcinoma stems from abnormalities that accumulate in cells' DNA over a person's lifetime, causing uncontrolled cell growth. But the nature and precise genomic locations of those changes, and how they work to promote cancer, are largely unknown.

Harnessing the latest tools and technologies, a consortium of researchers came together to characterise the complete sets of DNA, or genomes, derived from tumours of nearly 200 patients with lung adenocarcinoma.

The effort, called the Tumor Sequencing Project (TSP), involved decoding or sequencing the DNA of several hundred genes with known or suspected ties to cancer.

In addition, the scientists scanned tumour genomes to reveal chunks of DNA that are either missing or present in excess copies. Scanning the tumour genomes also allowed them to identify abnormally active as well as silent genes. These techniques, known as DNA copy number analysis and gene expression analysis, together with advanced computational methods, helped provide a detailed view of the genomic landscape of lung cancer.

"Integrative approaches like these allow us to more clearly pinpoint important genes than a single method alone would," said Dr Meyerson.

As a result of this work, the researchers identified more than 1,000 genetic alterations, the majority of which had not been previously described. While some of these mutations reflect genes already linked to lung adenocarcinoma, a substantial number signify new discoveries.

For example, the NF1, ATM, RB1 and APC genes, which have not before been associated with lung cancer, were mutated in a significant portion of the lung tumours analysed. Interestingly, these genes have been implicated in other tumour types, suggesting roles in multiple forms of cancer.

The consortium also unearthed genetic ties to a critical class of genes known as tyrosine kinases. Kinases act as molecular switches - when flipped on, they can promote cell growth - and are considered important candidates in the search for new cancer drugs.

In lung tumours, the researchers uncovered mutations that cluster in several groups of related tyrosine kinase genes, including the EGF, EPH, FGF, NTRK, and VEGF receptor gene families.

Beyond revealing abnormalities within individual genes, the researchers uncovered extraordinary connections among them. By integrating DNA sequencing, gene expression, and DNA copy number data, they discovered that genetic aberrations are often localised to groups of genes that function together, relaying information from one part of the cell to another.All told, there are about 200 of these molecular circuits or "signalling pathways" that operate in human cells - far fewer than the roughly 20,000 genes.

"One of the key findings from our study is that some of the newly discovered genes and pathways that are mutated in lung cancer are also known to be defective in other cancers," said Dr Meyerson. "That gives us hope that targeted therapies could be used across multiple cancer types."

Among the broken pathways identified are the MAPK, Wnt, p53, and mTOR pathways. Strikingly, the MAPK pathway was altered in roughly 70% of the tumours analysed, suggesting a broad role in the disease. In addition, the p53 and mTOR pathways were affected in roughly one-half and one third of the tumours, respectively.

The TSP was first launched as a pilot project to investigate how various genomic technologies could be effectively applied and integrated to reveal the molecular underpinnings of lung adenocarcinoma.

Together with related efforts, including The Cancer Genome Atlas (TCGA), the results of the Nature paper provide a critical foundation to enhance future genomic work in lung adenocarcinoma and initiate comprehensive genomic mapping for other common cancers.

Gene theraphy for the brain:New approach to gene therapy may shrink brain tumours, prevent their spread

Massachusetts General Hospital (MGH) researchers are investigating a new approach to gene therapy for brain tumours - delivering a cancer-fighting gene to normal brain tissue around the tumour to keep it from spreading.

An animal study published in the journal Molecular Therapy, the first to test the feasibility of such an approach, found that inducing mouse brain cells to secrete human interferon-beta suppressed and eliminated growth of human glioblastoma cells implanted nearby.

"We had hypothesised that genetically engineering normal tissue surrounding a tumour could create a zone of resistance - a microenvironment that prevents the growth or spread of the tumour," says Miguel Sena-Esteves, PhD, of the MGH Neuroscience Center, the study's senior author.

"This proof of principle study shows that this could be a highly effective approach, although there are many additional questions that need to be investigated."

Glioblastoma is the most common and deadly form of brain tumour. Human clinical trials of other gene therapies have not significantly reduced tumour progression.

One problem has been that patients' immune systems target the viral vectors used to deliver cancer-eliminating genes. Another issue has been inefficient gene delivery, due in part to the inherent cellular diversity found within an individual patient's tumour as well as among tumours from different patients.

In addition, if tumour cells are successfully induced to express an anticancer protein, production of that protein will drop as the tumour dies, allowing any cells that did not receive the gene to resume growing.

In the current study the MGH team examined whether expression of a therapeutic gene in normal brain cells could form a stable and effective anti-tumour reservoir.

The researchers first pretreated immune-deficient mice by delivering a gene for human interferon-beta - a protein being tested against several types of cancer - into the animals' brains, using adeno-associated virus vectors known to deliver genes to neurons in the brain without the immune reaction produced by other vectors.

Two weeks later, human glioblastoma cells were injected into the same or adjacent areas of the mice brains. After only 4 days, mice expressing interferon-beta had far smaller tumours than a control group pretreated with gene-free vector. Two weeks after the glioblastoma cells were introduced, the tumours had completely disappeared from the brains of the gene-therapy-treated mice.Several additional experiments verified that the anti-tumour effect was produced by expression of interferon-beta in normal tissue. The same tumour growth suppression was seen when the genes were delivered to one side of the brain and tumour cells were injected into the other.

Using a specialised vector that allows genes to be expressed only in neuronal cells (and not the glial cells from which glioblastomas originate) also produced similar results.

While other gene therapy studies that have induced tumour regression in mouse models required several vector injections, these experiments were able to suppress growth and eliminate the implanted tumour with a single injection of the interferon-beta- encoding vector, underscoring the approach's effectiveness.

"These results are particularly important as we build on our understanding of the microenvironments that allow tumours to grow and spread," explains Sena-Esteves, assistant professor of Neurology at Harvard Medical School.

The therapeutic principle of genetically engineering normal brain tissue could be used to manipulate proteins required for that microenvironment, preventing tumours from migrating within the patients brain and escaping other therapies."

The same zone-of-resistance approach could also be applied to the treatment of other solid tumours, he notes.

Since interferon-beta treatment is known to have side effects, it will be important to identify any toxicity caused by long-term secretion of the protein in the brain and develop preventive strategies, such as turning off the introduced genes.

Next the MGH team is planning to test this strategy on glioblastomas that occur naturally in dogs, which could not only generate additional data supporting human trials but also develop veterinary treatments for canine patients.

Breast cancer:No link between caffeine consumption and overall breast cancer risk

Researchers at Brigham and Women's Hospital (BWH) have dispelled a past belief that caffeine consumption may increase breast cancer risk. Their findings, published in the October 13 issue of Archives of Internal Medicine, show that caffeine consumption does not appear to be linked with overall breast cancer risk.

Caffeine, one of the most commonly consumed drugs worldwide, was previously thought to increase the risk of breast cancer after a study showed that women with non-cancerous breast disease experienced symptom relief after removing caffeine from their diet.

In this study, Dr Ken Ishitani and colleagues from BWH studied 38,432 women 45 years or older who provided dietary information in 1992-1995. Over an average of 10 years of follow-up, 1,188 of the women developed invasive breast cancer.

Although caffeine was not statistically significantly associated with overall risk of breast cancer, researchers note that there is a possibility of increased risk for women with benign breast disease or for tumours that are hormone-receptor negative or larger than 2cm. This potential risk was observed in women with the highest consumption; four or more cups of coffee daily.

Researchers also note that consuming caffeine was associated with a 68% increased risk of estrogen receptor-negative and progesterone receptor-negative breast cancer, or tumours to which the hormones oestrogen and progesterone do not bind, and a 79% higher risk for breast tumours larger than 2cm.

"The mechanisms by which caffeine may affect the development of breast cancer are complex and remain unclear. Our findings indicate that caffeine consumption may affect breast cancer progression, and such an effect may be independent of the oestrogen pathway," said Dr Shumin Zhang. "Further study is required to better understand caffeine's role."

Research Matters brings together selected research being conducted at Harvard Medical School and its affiliated teaching hospitals and research institutes. For more information, visit the Harvard Medical School website at www.hms.harvard.edu.

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