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Illumina, Inc. (NASDAQ:ILMN) announced that it has delivered Hermann Hauser’s genome sequence. Dr. Hauser, Partner, Amadeus Capital Partners Ltd, is the first consumer to purchase Illumina’s individual genome sequencing service working with his physician, Michael Nova, MD, of Pathway Genomics. The genome was completed in Illumina’s CLIA-certified and College of American Pathologists (CAP) accredited laboratory using the Genome Analyzer technology. Over 110 billion base calls were generated, delivering over 30X coverage of the genome. Data analysis showed 300K novel SNPs in the genome that have not been documented elsewhere. This discovery demonstrates the power of whole genome sequencing as an exploratory tool, as these SNPs were novel but not necessarily unique.

“We are very excited to be delivering our first individual genome sequence to Hermann Hauser,” said Jay Flatley, President and CEO of Illumina. This is a landmark since just two months ago we launched the availability of this service from Illumina. The experience we created for Hermann was not only one of personal genetic exploration, but one that points to a future where genome sequencing will become a routine practice and the information generated will enable physicians to make better healthcare decisions for the individual. This information has long term value for Hermann as he can continue to access it and gain personal genomic insights as new discoveries are made.

Dr. Hauser’s genome was delivered by a team consisting of his physician, Dr. Michael Nova, a bioinformatics specialist and geneticist at Illumina’s San Diego headquarters on Thursday, August 20, 2009. The visit included a consultation, facility tour and ceremony during which Dr. Hauser’s genome was delivered on an iMac® computer using GenomeStudio® software as a genome browsing interface.

Hermann Hauser is one of the first of a small, select group of individuals who have had their genome sequenced. “Going through Illumina’s process was very exciting for me personally. I am looking forward to the information on gene variants that will give my doctors guidance on effective treatments and drug dosage based on pharmacogenetic information, for any future medical condition I may develop. This is the beginning of personalized medicine and I am delighted to be there at the start of it. As an early investor in the gene sequencing technology used in this work, I am proud that Illumina has introduced this service to consumers. It fulfills an early dream to substantially reduce the cost of whole genome sequencing,” said Hauser.

Dr. Hauser is a pioneer member of a growing community that is driving education and exchange of information for those who have had their genomes sequenced. As more information becomes available, participants will be in a position to mine their personal genome sequence data to understand their identity in ways which have never been possible before. For more information about Illumina’s individual genome sequencing service, please visit everygenome.

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Illumina Continue reading →

It is an accepted fact that genetics play a key role in a person’s susceptibility to cancer, and that throughout life, mutations can cause damage to tumor suppressor genes (TSGs) further increasing the chances of developing cancerous tumors.

Now a new study led by scientists at Beth Israel Deaconess Medical Center (BIDMC) demonstrates that even subtle changes in expression of the PTEN tumor suppressor gene can significantly increase cancer susceptibility in specific tissues, suggesting that environmental factors, such as diet or exposure to carcinogens, may have a more dramatic influence on tumor development than previously recognized. Appearing in this week’s Advance On-line issue of Nature Genetics, the findings propose a new model for the role of tumor suppressor genes in the onset of cancer and could prove valuable in the development of diagnostic tests targeted to these gene alterations.

“More than 30 years ago, it was proposed that a person’s susceptibility to cancer was dependent on a ‘two-hit’ model,” explains Pier Paolo Pandolfi, MD, PhD, Director of the Cancer Genetics Program at BIDMC and George C. Reisman Professor of Medicine at Harvard Medical School. This meant that there had to be two genetic alterations of a single tumor suppressor gene (TSG) to activate tumor development – one gene would be missing from birth, while the second would be lost to other factors during one’s lifetime.

“Our study adds another dimension to this Knudsonian model [so-named for its creator, cancer geneticist Alfred Knudson] demonstrating that cancer susceptibility can be driven in specific tissues by a progressive – but slight – continuum reduction in tumor suppressor levels,” explains Pandolfi. “Consequently, subtle modulation of TSG levels can result in increased cancer susceptibility. This implies that any factor that affects PTEN levels – chemicals, diet, other carcinogens – could increase tumor susceptibility, even in the absence of a full blown genetic mutation.”

Tumor suppressor genes function to slow down cell division, repair DNA and help alert damaged cells when it is time to die, and PTEN is one such example. (In addition to preventing uncontrolled cell growth, PTEN is also responsible for controlling cell movement or migration, controlling the adhesion of cells to surrounding tissues and helping to control the formation of new blood cells.) But, when TSGs are absent or malfunctioning – as is the case of a genetic mutation – cells can multiply too quickly, growing out of control and leading to the development of cancerous tumors.

In recent years, with the advent of functional genomics, the idea that subtle changes in TSG levels could influence tumor development had been proposed but not formally investigated. To test this hypothesis, the Pandolfi team created a mouse model of PTEN that expressed the gene at approximately 80 percent of total levels. Next, they used a gene targeting approach which drives a transcriptional interference of the PTEN gene, resulting in inefficient protein production. The authors report that the presence of one targeted allele resulted in approximately 80 percent of PTEN expression relative to the normal level of PTEN expressed in specific tissues – in this case, mammary gland tissue. And, as predicted, the scientists subsequently identified an increased incidence of mammary tumors in these mice, and through a careful histopathological and molecular analysis were able to demonstrate that mammary tumors maintained both the targeted and wild-type PTEN alleles intact.

“These mice showed mammary cancer at a high incidence and in the absence of further alterations to the PTEN gene,” explains Pandolfi. “This confirms that the PTEN gene is a ‘quasi-insufficient’ tumor suppressor, such that even a subtle 20 percent decrease in gene expression is sufficient to impair its full tumor-suppressive activity.”

This discovery, say the authors, is tremendously relevant for how genetic alterations in cancer are detected, studied, evaluated and treated. “From a diagnostic perspective, our findings encourage the implementation of quantitative methods to evaluate cancer gene expression levels, and the design of therapies oriented to target these alterations,” they write. Adds Pandolfi, “Our immediate aim is to develop a genetic test to be used for the screening of patients at risk of developing breast cancer. Such a test might also be useful in predicting the outcome of certain treatments [i.e. Trastuzumab] for breast cancer patients.”

Coauthors include BIDMC investigators Andrea Alimonti, Arkaitz Carracedo and John Clohessy, Caterina Nardella, Ainara Egia, Leonardo Salmena, Katia Sampieri and William J. Haveman; Edi Brogi of Memorial Sloan-Kettering Cancer Center; Andrea Richardson of Brigham and Women’s Hospital; Jiangwen Zhang of Harvard University; and Lloyd Trotman of Cold Spring Harbor Laboratory.

This study was supported, in part, by grants from the National Cancer Institute and support from the European Molecular Biology Organization.

Source:
Bonnie Prescott
Beth Israel Deaconess Medical Center Continue reading →

Use of an experimental targeted drug to treat metastatic melanoma tumors with a specific genetic signature was successful in more than 80 percent of patients in a phase 1 clinical trial. Results of the trial of PLX4032, an inhibitor of a protein called BRAF that is overactive in more than half of all melanomas, appear in the New England Journal of Medicine.

“Metastatic melanoma has a devastating prognosis and is one of the top causes of cancer death in young patients,” says Keith Flaherty, MD, director of Developmental Therapeutics at the Massachusetts General Hospital (MGH) Cancer Center, lead and corresponding author of the NEJM article. “Until now, available therapies were few and unreliable, so these findings can really change the outlook for patients whose tumors are fueled by this mutation.”

Although surgical removal is usually successful in treating early-stage melanoma, once the skin tumor has spread to other sites in the body, the outlook has been grim. The two FDA-approved drugs – interleukin-2 and dacarbazine – produce a response in only 10 to 20 percent of patients. The current prognosis for survival in metastatic melanoma is 9 months or less, with 9,000 people dying in the U.S. each year.

The role in melanoma of the BRAF mutation – which keeps the protein constantly activated and driving cell growth – was discovered in 2002 by researchers at the Sanger Institute in Britain. Flaherty – who was then at the University of Pennsylvania Abramson Cancer Center – began to explore whether drugs targeting the mutation might interfere with tumor growth. After one potential drug was not effective, he began working in collaboration with Paul Chapman, MD, of Memorial Sloan-Kettering Cancer Center in New York to study PLX4032, an agent developed by Plexxikon and licensed to Roche Pharmaceuticals. Initial trial results were disappointing, but a new formulation that increased the bioavailability of PLX4032 proved to have rapid results that are being reported in the NEJM paper.

The initial stage of the study – led by Flaherty, Chapman and colleagues at six sites in the U.S. and Australia – was designed to establish the effective dose. It enrolled 55 cancer patients, most with metastatic melanoma, who received escalating doses of PLX4032 until unacceptable side effects occurred. BRAF mutations were present in the melanomas of 16 participants in the latter part of this stage, and in 11 of those patients, tumors quickly shrank or, in one instance, disappeared. Three participants with BRAF-mutated thyroid cancers also had their tumors shrink or stabilize in response to PLX4032 treatment.

The second stage enrolled 32 patients with BRAF-mutated melanoma who received the PLX4032 dosage established in the first phase: 960 mg twice a day. In 26 of those participants, tumors shrank more than 30 percent, meeting the criteria for clinical response, and completely disappeared in two. Since another two participants had some reduction in the size of their tumors, Flaherty projects that PLX4032 appears to shrink tumors in approximately 90 percent of patients with BRAF-mutated melanomas.

“One of the things that make these results truly remarkable is that this drug works so reliably,” he explains. “And patients who have been experiencing symptoms like pain and fatigue begin to feel better within a week of starting treatment, giving them a much better quality of life.

As seen in trials of other targeted cancer treatments, resistance to PLX4032 developed in the tumors of many participants, leading to resumed tumor growth. Currently tumor suppression has been maintained from about three months to longer than two years, with an average progression-free survival of eight months, and follow-up studies are exploring how resistance occurs and potential strategies to get around it. Two additional MGH-based clinical trials are now underway – a phase 2 study in patients unsuccessfully treated with the FDA-approved drugs, enrollment for which is complete, and a larger phase 3 study that compares PLX4032 with dacarbazine in newly diagnosed patients.

“Until now, we’ve never had a credible first treatment option for metastatic melanoma, so this has completely transformed how we approach treatment for patients with the BRAF mutation,” says Flaherty, who is a member of the Harvard Medical School faculty. “Although we don’t know how long response may last, the ability to beat this disease down in the short term will buy us time to strategize second-line therapies and design the next generation of trials.”

Notes:

Along with senior author Paul Chapman, MD, Memorial Sloan-Kettering Cancer Center, co-authors of the NEJM article are Igor Puzanov, MD, and Jeffrey Sosman, PhD, Vanderbilt University; Kevin Kim, MD, M.D. Anderson Cancer Center; Antoni Ribas, MD, University of California at Los Angeles; Grant McArthur, MB, BS, PhD, Peter MacCallum Cancer Centre, East Melbourne, Australia; Peter O’Dwyer, MD, University of Pennsylvania Abramson Cancer Center; Richard Lee, MD, PhD, and Joseph Grippo, Roche Pharmaceuticals, and Keith Nolop, MD, Plexxikon. The study was funded by Plexxikon and Roche.

Source:
Katie Marquedant
Massachusetts General Hospital Continue reading →

Scientists have identified genes related to reaching age 90 with preserved cognition, according to a study published in the September issue of the American Journal of Geriatric Psychiatry. The study, which was conducted at the University of Pittsburgh is among the first to identify genetic links to cognitive longevity.

“Successful aging has been defined in many ways, however, we focused on individuals who had reached at least 90 without significant decline in mental capacity,” said lead researcher George S. Zubenko, M.D., Ph.D., professor of psychiatry and biological sciences at the University of Pittsburgh. “While this is a goal that many of us share, such a definition of ‘successful aging’ can be determined objectively and consistently across subjects–an important requirement of scientific studies.”

While previous research has revealed that genes make important contributions to exceptional longevity, the goal of this study was to identify regions of the human genome that contributed, along with lifestyle factors, to reaching age 90 with preserved cognition.

The study involved 100 people age 90 and older who had preserved cognition as measured by clinical and psychometric assessments. Half of the subjects were male, half were female. Using a novel genome survey method, scientists compared the DNA of the study sample with that of 100 young adults, aged 18-25, who were matched for sex, race, ethnicity and geographic location. Particularly, Dr. Zubenko and his research team attempted to identify specific genetic sequences present in older individuals that may be linked to reaching older ages with preserved cognitive abilities, or conversely, specific genetic sequences present in younger individuals (and not present in those over age 90) that may impede successful aging. The study also looked at a variety of lifestyle factors, such as smoking and alcohol consumption, with the goal of eventually exploring the interactive effects of genes and lifestyle on successful aging.

The study identified nine genetic regions that were associated with successful aging, some of which affected men or women, but not both. “Historically women have lived longer than men on average, the prevalence of numerous serious diseases differs in men and women, and there are important differences in age-related physiological changes that occur between the sexes over the life span,” said Dr. Zubenko. “It would not be surprising if the collection of genes that influences the capacity to reach old age with normal mental capacity differs somewhat for men and women.” The majority of the successful aging or “SAG” regions overlapped with gene locations previously reported to show linkage to susceptibility genes for cardiovascular disorders, psychiatric disorders and the accumulation of tissue damage due to oxidative stress. The results of the study also highlighted the detrimental effects of cigarette smoking, excessive drinking and serious mental disorders on successful aging in both sexes.

“The finding that genetics, lifestyle decision making, and their interactions, may influence the ability to reach old age with preserved cognition is exciting,” stated Dr. Zubenko. “Identifying such genetic and behavioral factors may hold promise for better understanding the aging process and perhaps one day enriching or extending the lives of other individuals.”

The study was published online ahead of print at ajgponline/ in August. The American Journal of Geriatric Psychiatry, published monthly, is the official journal of the American Association for Geriatric Psychiatry.

Co-authors of the paper include Hugh B. Hughes, III, M.D., and Wendy N. Zubenko, Ed.D., A.P.R.N., both of the department of psychiatry, University of Pittsburgh School of Medicine; and Brion S. Maher, Ph.D., of the Center for Craniofacial and Dental Genetics at the University of Pittsburgh School of Dental Medicine.

The study was funded by the National Institute of Mental Health, one of the National Institutes of Health.

Contact: Jocelyn Uhl Duffy
University of Pittsburgh Medical Center Continue reading →

Certain cancer risks can be passed down through families, the result of tiny changes in a family’s genetic code. But not all genetic changes are deadly. To help medical counselors and physicians identify the mutations that pose the greatest health risks, researchers at four institutions, including Johns Hopkins, have developed and validated a new computer tool.

The system, described in the Public Library of Science Computational Biology, evaluates 16 “predictive features” to help answer a critical question: Is a particular mutation a harmless variation or a genetic glitch that could set the stage for cancer? In blind biochemical tests involving 36 samples containing genetic mutations whose association with breast and ovarian cancer was unknown, the computer tool demonstrated an accuracy rate exceeding 94 percent in identifying protein functions that are believed to be linked to a higher risk of cancer.

The researchers cautioned that the computer tool by itself cannot yet predict future cancer cases. But they believe it can be a fast and useful supplement to traditional biochemical tests, which are far more time-consuming, costly and labor-intensive, and do not always yield conclusive results.

“When people are diagnosed with certain types of cancer, other family members sometimes get genetic testing to find out if they, too, are predisposed to this disease,” said Rachel Karchin, an assistant professor of biomedical engineering at Johns Hopkins and lead author of the journal article. “But sometimes, the standard tests find small genetic variations that may be harmful or benign. Our computational test may help pinpoint which one it is. We hope the system will eventually give counselors and doctors an important new tool to help them advise patients about whether they need to take preventive steps to keep cancer from developing.”

Karchin, who earned a doctorate in computer science from the University of California, Santa Cruz, joined Johns Hopkins last September as a participant in the university’s Institute for Computational Medicine. “There are some things you can do with a computer that we hope will be useful in predicting the cancer risks associated with some genetic mutations,” she said. “We’re not quite there yet, but that’s our goal.”

Karchin began working on the new computer tool as a postdoctoral fellow in the lab of Andrej Sali, a professor of biopharmaceutical sciences and pharmaceutical chemistry at the University of California, San Francisco. For the current journal article, the biochemical tests to validate the computer tool were conducted in the lab of Alvaro Monteiro at the H. Lee Moffitt Cancer Center & Research Institute in Tampa, Fla. Sali and Monteiro are co-authors of the journal article.

In their experiments, the researchers focused on inherited mutations in the BRCA1 gene. A significant number of breast and ovarian cancer cases are believed to be caused by such mutations, possibly because they disable a gene that normally suppresses cancer.

To test the computer tool, Karchin and her colleagues used it to analyze 36 “point mutants” on the BRCA1 gene, meaning locations where a single letter in a string of DNA differed from the sequence found in the general population. This mutation caused an amino acid residue change in the protein produced by the gene. “Some of these types of variations can put a woman at greater risk for developing ovarian or breast cancer,” Karchin said. “The question is: Which ones?”

To answer it, the researchers examined 16 factors in three categories. One category focused on whether the mutated genes produced proteins that performed their jobs properly. The second involved studies of the physical structure of the mutated gene. The third category was an assessment of the gene’s evolutionary history, looking at how long the changed amino acid residue position has been preserved in various organisms. The last category is important because harmful mutations tend to be eliminated by evolutionary selection because of the damage they inflict on their carriers.

The researchers plugged these factors into a computer formula that identified the gene mutations most likely to be linked with cancer. Karchin was pleased that the system was highly successful at finding harmful mutations during the blind tests in Monteiro’s lab. She believes it has a promising future. “Genetic counselors now base some of their advice on family history,” she said. “But family histories are often incomplete. If we can give genetic counselors another tool, it could be very helpful to a lot of people.”

The other co-authors of the journal paper were Sean V. Tavtigian of the International Agency for Research on Cancer in Lyon, France, and Marcelo A. Carvalho of the Moffitt Cancer Center. The research was supported by grants from the National Institutes of Health

Related Links:

Rachel Karchin’s Lab Page: karchinlab/

Institute for Computational Medicine at Johns Hopkins: icm.jhu.edu/

Johns Hopkins Department of Biomedical Engineering: bme.jhu.edu/

Contact: Phil Sneiderman

Johns Hopkins University Continue reading →

Janet Davison Rowley, MD, a founder in the field of cancer cytogenetics and a renowned leader in molecular oncology, will receive the 2009 Genetics Prize of The Peter and Patricia Gruber Foundation. She is being honored with the prestigious international award for discoveries of recurrent chromosomal abnormalities in leukemias and lymphomas – discoveries that have revolutionized how cancer is understood and treated. Currently the Blum-Riese Distinguished Service Professor at the University of Chicago, Rowley is also being honored for her critical national and international leadership in the biomedical research community. The Prize will be presented in Honolulu, Hawaii, on October 23 at the 59th Annual Meeting of the American Society of Human Genetics.

“Janet Rowley’s work established that cancer is a genetic disease,” says Mary-Claire King, a geneticist at the University of Washington. “She demonstrated that mutations in critical genes lead to specific forms of leukemia and lymphoma, and that one can determine the form of cancer present in a patient directly from the cancer’s genes. We are still working from her paradigm.”

Before Rowley began investigations into the chromosomal abnormalities of leukemia at the University of Chicago in the 1960s, few scientists believed that chromosomal aberrations caused tumors. The established view at the time was that abnormal chromosomes were manifestations of the generalized chaos that exists within leukemia and lymphoma cells. But Rowley believed something else was going on with those damaged pieces of DNA, and diligently pursued their study.

“I became a kind of missionary, saying that chromosome abnormalities were important and hematologists should know about them,” Rowley recalls of those early – and often lonely – years in the field. “I got sort of amused tolerance at the beginning.”

In the end, though, Rowley proved to be astonishingly prescient. Over the next decade, she made a number of remarkable discoveries, including the landmark finding that the abnormally short “Philadelphia” chromosome that had earlier been identified in hematopoietic cells of people with chronic myelogenous leukemia (CML) was not a chromosome deletion, as many scientists had thought, but an exchange (translocation) of segments between two chromosomes. She soon uncovered translocations in other types of leukemia and lymphoma cells, and then, as new technology became available, began to clone the translocation abnormalities, or breakpoints, of these chromosomes and to identify their oncogenes (the mutated genes that help transform a normal cell into a cancerous one). By 1980, she had redefined the field of cancer cytogenetics.

Rowley’s contributions to identifying chromosomal abnormalities in leukemias and lymphomas have changed the way these diseases are diagnosed and treated. Today, such cytogenetic techniques as fluorescence in situ hybridization (FISH) and polymerase chain reaction (PRC) can identify the DNA damage within individual cells, offering a much more precise diagnosis of disease – and more effective treatments. For example, the development of the drug imatinib (Gleevec) – one of the most successful targeted cancer therapies to date – stems directly from Rowley’s work on the chromosomal translocation associated with CML. Imatinib blocks the abnormal protein produced by that translocation.

Rowley’s research continues at her lab at the University of Chicago, the institution where she received her undergraduate and medical degrees six decades ago and where she has inspired and generously mentored countless students and postgraduate fellows during the ensuing years. Cancer cytogenetics continues to fascinate – and challenge – her. “We’re still working on the leukemias,” she says. “There’s a lot of evidence that translocations and other chromosome abnormalities aren’t sufficient to make a cell malignant. We’re looking for the other mechanisms involved.”

“As Chair of this year’s Selection Committee for the Gruber Prize in Genetics, I am delighted that the Committee recognized such a distinguished scientist and individual as Dr. Rowley,” says Elizabeth Blackburn, the Morris Herzstein Professor of Biology and Physiology in the Department of Biochemistry and Biophysics at the University of California, San Francisco. “Her major contributions to the understanding of the underpinnings of cancer make her an outstanding choice for this important Prize and truly reflect the goal of this Prize in celebrating the field of Genetics.”

Source:
Alyson O’Mahoney

Robin Leedy & Associates, Inc.

View drug information on Gleevec. Continue reading →

Cancer Research UK has launched a multimillion pound programme, alongside the Technology Strategy Board’s Innovation Platform, to help turn the genetic revolution into better treatment for cancer patients.

Cancer Research UK will work with hospitals and labs to improve genetic testing services. The charity will also collect genetic data from tumours and information on how gene faults affect patient survival for use in research to discover new cancer drugs targeted at specific genetic mutations.

The programme has been set up in partnership with the Technology Strategy Board – a government body that aims to support technology in areas that will boost the economy.

The Technology Strategy Board announced that they will be investing up to ??50 million in a new Stratified Medicines Innovation Platform to develop stratified medicine* in the UK, including funding to develop new and innovative ways to genetically test tumours. They want to make the process cheaper and more efficient.

James Peach, director of Cancer Research UK’s stratified medicine programme, said: “The aim of our programme is to improve genetic testing in the NHS while collecting valuable research data. So when personalised treatments targeting specific genes become available in the future, doctors will have access to the best possible tests to help them decide which cancer patients are suitable for these drugs.

“Our initiative will pilot new ways of genetic testing over the next two years to develop examples that the NHS can then adopt nationally.”

At the moment, some NHS hospitals are able to test the tumours of cancer patients for faulty genes. But they are not able to test for more than a few gene faults at a time. And because there is not a centralised way of collecting samples for testing, it is often done on a few samples at a time, rather than on a large scale.

The Stratified Medicines Innovation Platform is offering grants to industry-led groups to develop tests that can cover many of the known mutations of the most common types of cancers, making genetic testing cheaper, more reliable, and improving their commercial availability. Or companies can pitch to develop IT systems that can link clinical and genetic data together. Up to ??5.6 million in grant funding is available**.

Cancer Research UK and commercial companies, including Life Technologies and Pfizer, will provide the money for tumour samples to be collected from some lung, breast, colorectal, prostate, ovarian and skin cancer patients being treated in selected Cancer Research UK/Department of Health Experimental Cancer Medicines Centres (ECMCs) when they are diagnosed or if they have relapsed.

Funding for this part of the programme will be announced in the coming months and the first patient will be genetically tested through the programme in the first half of next year.

James Peach continued: “Although the programme won’t change the drugs patients can get straight away we know that this information on the mutations inside tumours is going to become more and more important in the future.

“We are looking forward to a time when we can match up cancer patients with the best treatments for them. They’ll get the drugs that work on the unique DNA patterns of their tumours first time round, and spare those patients who will not respond from having unnecessary treatment.”

Rob Day, head of Pfizer Oncology, UK, said: “Personalised medicines are likely to transform the way cancer is treated in the future. As a company dedicated to advancing oncology research, Pfizer Oncology is focused on discovering gene-specific targeted medicines to improve outcomes for patients with cancer. This is only part of the solution though; the first step is creating the infrastructure and clinical pathways to identify and follow up those patients who will benefit most from each individual medicine. Pfizer fully supports the work of Cancer Research UK and the Technology Strategy Board in advancing the role of genetic testing in cancer diagnosis and treatment selection.”

Peter Silvester, general manager for Life Technologies in Europe, said: “At Life Technologies we are proud to be part of this partnership in developing personalised cancer care, which helps bring about our goal of driving innovation in molecular medicine. This programme will lead to the application of innovative technologies, help contribute to better patient outcomes in the future and enable cost savings in the NHS. We commend Cancer Research UK and the Technology Strategy Board for their bold thinking in shaping this programme.”

Care services minister Paul Burstow said: “Improved cancer survival rates and patient experience are key priorities for the Coalition Government.

“This funding will help develop new testing techniques for doctors to work out which drugs are the most effective for different cancer patients. The research will also help in the development of new targeted drugs. The aim is to save cancer patients from unnecessary side effects from treatments and to improve cancer survival rates. The scope for stratified medicine is enormously exciting.”

Kate Law, Cancer Research UK’s director of clinical research, said: “It’s important that the NHS is ready to deal with the new generation of targeted drugs that are emerging, and that research is hardwired into the day-to-day treatment of patients.

“We hope that investing in the infrastructure to make this happen now will make a real difference for cancer patients in the future.”

Notes

* Stratified medicine means looking at large groups of cancer patients to try and find ways of predicting which treatments cancers are likely to respond to. This is one step towards ‘personalised medicine’. Once we have carried out research with large groups of cancer patients, we may be able to predict response to treatments. Then we hope we will be able to tailor cancer treatment very precisely to an individual person’s cancer.

** The rest of the ??50 million will be invested over the coming 5 years, including a further ??5.5 million this year to advance the development of biomarkers for Chronic Obstructive Pulmonary Disease (COPD) and Rheumatoid Arthritis (RA), and to help develop business models in stratified medicines.

Source:

Cancer Research UK Continue reading →

Scientists from The Scripps Research Institute have determined for the first time that prions, bits of infectious protein devoid of DNA or RNA that can cause fatal neurodegenerative disease, are capable of Darwinian evolution.

The study from Scripps Florida in Jupiter shows that prions can develop large numbers of mutations at the protein level and, through natural selection, these mutations can eventually bring about such evolutionary adaptations as drug resistance, a phenomenon previously known to occur only in bacteria and viruses. These breakthrough findings also suggest that the normal prion protein – which occurs naturally in human cells – may prove to be a more effective therapeutic target than its abnormal toxic relation.

The study was published in the December 31, 2009 issue of the journal Science Express, an advance, online edition of the prestigious journal Science.

“On the face of it, you have exactly the same process of mutation and adaptive change in prions as you see in viruses,” said Charles Weissmann, M.D., Ph.D., the head of Scripps Florida’s Department of Infectology, who led the study. “This means that this pattern of Darwinian evolution appears to be universally active. In viruses, mutation is linked to changes in nucleic acid sequence that leads to resistance. Now, this adaptability has moved one level down – to prions and protein folding – and it’s clear that you do not need nucleic acid for the process of evolution.”

Infectious prions (short for proteinaceous infectious particles) are associated with some 20 different diseases in humans and animals, including mad cow disease and a rare human form, Creutzfeldt-Jakob disease. All these diseases are untreatable and eventually fatal. Prions, which are composed solely of protein, are classified by distinct strains, originally characterized by their incubation time and the disease they cause. Prions have the ability to reproduce, despite the fact that they contain no nucleic acid genome.

Mammalian cells normally produce cellular prion protein or PrPC. During infection, abnormal or misfolded protein – known as PrPSc – converts the normal host prion protein into its toxic form by changing its conformation or shape. The end-stage consists of large assemblies (polymers) of these misfolded proteins, which cause massive tissue and cell damage.

“It was generally thought that once cellular prion protein was converted into the abnormal form, there was no further change,” Weissmann said. “But there have been hints that something was happening. When you transmit prions from sheep to mice, they become more virulent over time. Now we know that the abnormal prions replicate, and create variants, perhaps at a low level initially. But once they are transferred to a new host, natural selection will eventually choose the more virulent and aggressive variants.”

Drug Resistance

In the first part of the study, Weissmann and his colleagues transferred prion populations from infected brain cells to culture cells. When transplanted, cell-adapted prions developed and out-competed their brain-adapted counterparts, confirming prions’ ability to adapt to new surroundings, a hallmark of Darwinian evolution. When returned to brain, brain-adapted prions again took over the population.

To confirm the findings and to explore the issue of evolution of drug resistance, Weissmann and his colleagues used the drug swainsonine or swa, which is found in plants and fungi, and has been shown to inhibit certain prion strains. In cultures where the drug was present, the team found that a drug-resistant sub-strain of prion evolved to become predominant. When the drug was withdrawn, the sub-strain that was susceptible to swainsonine again grew to become the major component of the population.

Weissmann notes that the findings have implications for the development of therapeutic targets for prion disease. Instead of developing drugs to target abnormal proteins, it could be more efficient to try to limit the supply of normally produced prions – in essence, reducing the amount of fuel being fed into the fire. Weissmann and his colleagues have shown some 15 years ago that genetically engineered mice devoid of the normal prion protein develop and function quite normally (and are resistant to prion disease!).

“It will likely be very difficult to inhibit the production of a specific natural protein pharmacologically,” Weissmann said, “You may end up interfering with some other critical physiological process, but nonetheless, finding a way to inhibit the production of normal prion protein is a project currently being pursued in collaboration with Scripps Florida Professor Corinne Lasmezas in our department.”

Quasi-Species

Another implication of the findings, according to the study, is that drug-resistant variants either exist in the prion population at a low level prior to exposure or are generated during exposure to the drug. Indeed, the researchers found some prions secreted by infected cells were resistant to the drug before exposure, but only at levels less than one percent.

The scientists show that prion variants constantly arise in a particular population. These variants, or “mutants”, are believed to differ in the way the prion protein is folded. As a consequence, prion populations are, in fact, comprised of multiple sub-strains.

This, Weissmann noted, is reminiscent of something he helped define some 30 years ago – the evolutionary concept of quasi-species. The idea was first conceived by Manfred Eigen, a German biophysicist who won the Nobel Prize in Chemistry in 1967. Basically stated, a quasi-species is a complex, self-perpetuating population of diverse and related entities that act as a whole. It was Weissmann, however, who provided the first confirmation of the theory through the study of a particular bacteriophage – a virus that infects bacteria – while he was director of the Institut f??r Molekularbiologie in Z??rich, Switzerland.

“The proof of the quasi-species concept is a discovery we made over 30 years ago,” he said. “We found that an RNA virus population, which was thought to have only one sequence, was constantly creating mutations and eliminating the unfavorable ones. In these quasi-populations, much like we have now found in prions, you begin with a single particle, but it becomes very heterogeneous as it grows into a larger population.”

There are some unknown dynamics at work in the prion population that leads to this increased heterogeneity, Weissmann added, that still need to be explored.

“It’s amusing that something we did 30 years has come back to us,” he said. “But we know that mutation and natural selection occur in living organisms and now we know that they also occur in a non-living organism. I suppose anything that can’t do that wouldn’t stand much of a chance of survival.”

The joint first authors of the Science study, “Darwinian Evolution of Prions in Cell Culture,” are Jiali Li and Shawn Browning of The Scripps Research Institute. Other authors include Sukhvir P. Mahal and Anja M. Oelschlegel also of The Scripps Research Institute. Weissmann notes that after the manuscript was accepted by Science, an article by Ghaemmanghami et al. appeared in PLoS Pathogens that described emergence of prions resistant to a completely different drug, quinacrine, providing additional support to the Scripps Research team’s conclusions.

The Scripps Research study was supported by a grant from the National Institutes of Health and by a generous donation to the Weissmann laboratory from the Alafi Family Foundation.

Source: Keith McKeown

Scripps Research Institute Continue reading →

Gene therapy for a severe inherited blindness, which produced dramatic improvements last year in 12 children and young adults who received the treatment in a clinical trial, has cleared another hurdle. The same research team that conducted the human trial now reports that a study in animals has shown that a second injection of genes into the opposite, previously untreated eye is safe and effective, with no signs of interference from unwanted immune reactions following the earlier injection.

These new findings suggest that patients who benefit from gene therapy in one eye may experience similar benefits from treatment in the other eye for Leber’s congenital amaurosis (LCA), a retinal disease that progresses to total blindness by adulthood. Researchers had exercised caution by treating only one eye in the human trial.

In the current study, the study team found no evidence of toxic side effects in the blood or the eyes of the 10 animals six dogs and four monkeys that received the gene therapy. Each animal received an injection first in the right eye, then in the left eye 14 days later. All six dogs, which had been specially bred to have congenital blindness, had improved vision, in addition to showing no toxic effects from the gene therapy.

Researchers from The Children’s Hospital of Philadelphia and from the University of Pennsylvania School of Medicine, and colleagues from two other institutions published their study in the journal Science Translational Medicine. The first authors are Defne Amado, of the F.M. Kirby Center for Molecular Ophthalmology at Penn, and Federico Mingozzi, Ph.D., of the Center for Cellular and Molecular Therapeutics at Children’s Hospital.

“We designed this study to investigate the immunological consequences of administering the gene therapy injection to the second eye after treating the first one,” said corresponding author Jean Bennett, M.D., Ph.D., F.M. Kirby professor of Ophthalmology at the University of Pennsylvania School of Medicine. “The good news is that in animals, the second injection, like the first, is benign.”

As in the human trials of this gene therapy, the researchers packaged a normal version of the gene that is missing in LCA inside a genetically engineered vector, adeno-associated virus (AAV). The vector delivers the gene to cells in the retina, where the gene produces an enzyme that restores light receptors. Although the virus used does not cause human disease, it previously set off an immune response that cut short the initial benefits of gene therapy, notably in a 2002 human trial of gene therapy for the bleeding disorder hemophilia.

“Our current study in large animals provides encouraging indications that immune responses will not interfere with human gene therapy in both eyes,” said co-author Katherine A. High, M.D., a pioneer in gene therapy who helped lead the hemophilia trial. “Like humans, monkeys generate neutralizing antibodies against both naturally occurring and injected AAV, but these antibodies did not prevent the injected gene from producing the desired enzyme.” High is director of the Center for Cellular and Molecular Therapeutics (CCMT) at Children’s Hospital, which manufactured the vector used in the current study and the previous human trial for LCA.

In the human trial for LCA reported last year, the CHOP/Penn researchers, led by Bennett, High and retina specialist Albert M. Maguire, M.D., injected the vector into only one eye in each of their 12 patients. Because the treatment was experimental, researchers left one eye untreated in the event of unexpected complications. After the subjects experienced partially restored eyesight in their treated eyes, many were eager to receive the same treatment in the other eye. The current study advances that possibility, and the research team is planning another clinical trial of LCA gene therapy, which may include some of the subjects from the first group.

Additionally, the results may set the stage for gene therapy in LCA patients who were excluded from the previous trial. Adopting a conservative approach, the researchers did not treat patients who already had neutralizing antibodies against AAV in their blood. As many as a quarter of all people may carry these antibodies by their teenage and young adult years. Fortunately, unlike other organs, both human and animal eyes are insulated from these circulating antibodies. (Co-author Stephen Orlin, M.D., of Penn’s Scheie Eye Institute, led studies of human samples and showed that even when antibodies to AAV were at high levels in the blood, antibodies within the eye remained at or near background levels). The authors conclude that the presence of those antibodies in the blood will most likely not prevent effective gene transfer in human eyes.

“Safety and Efficacy of Subretinal Readministration of a Viral Vector in Large Animals to Treat Congenital Blindness” Science Translational Medicine, published online March 3, 2010.

Funding support came from the CCMT, the Foundation Fighting Blindness sponsored CHOP-PENN Pediatric Center for Retinal Degenerations, the National Institutes of Health, Research to Prevent Blindness, Hope for Vision, the Paul and Evanina Mackall Foundation Trust at the Scheie Eye Institute, and the F.M. Kirby Foundation. Dr. High is an Investigator of the Howard Hughes Medical Institute, which also provided support.

About The Children’s Hospital of Philadelphia: The Children’s Hospital of Philadelphia was founded in 1855 as the nation’s first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals and pioneering major research initiatives, Children’s Hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country, ranking second in National Institutes of Health funding. In addition, its unique family-centered care and public service programs have brought the 430-bed hospital recognition as a leading advocate for children and adolescents.

About PENN Medicine: Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, and excellence in patient care. Penn Medicine consists of the University of Pennsylvania School of Medicine (founded in 1765 as the nation’s first medical school) and the University of Pennsylvania Health System, which together form a $3.6 billion enterprise. Penn’s School of Medicine is currently ranked #3 in U.S. News & World Report’s survey of research-oriented medical schools, and is consistently among the nation’s top recipients of funding from the National Institutes of Health, with $367.2 million awarded in the 2008 fiscal year.

Source: Children’s Hospital of Philadelphia Continue reading →

One of the most common human genomic disorders, DiGeorge syndrome, occurs in one of every 2,000-4,000 live births and involves a deletion on chromosome 22. The deletion is mediated by rare repetitive sequences that flank genes crucial for proper development of the heart, face, and upper thorax.

Dr. Bernice Morrow and her colleagues describe in this month’s issue of Genome Research how they examined these flanking repetitive sequences for patterns of polymorphisms. “Our results show that there are intervals with more frequent traffic of genetic material – regions with higher rates of gene conversion or recombination – that are indicative of genomic instability,” explains Morrow.

“With this knowledge in hand, we hope to screen our patients and identify the genomic mechanism underlying this important disease,” says Morrow.

Bernice Morrow, Ph.D.
Professor, Albert Einstein College of Medicine

Studies on human genome variation provide insight into disease – The International HapMap Project was initiated with the primary goal of facilitating medical studies and understanding the genomic basis for human diseases. To coordinate with the journal Nature’s publication describing the HapMap, the journal Genome Research is announcing a special issue entitled “Human Genome Variation,” which is entirely devoted to studies using these data to provide insight into human biology and disease.

Maria A. Smit
smitcshl.edu
Cold Spring Harbor Laboratory
cshl Continue reading →