New throat cancer gene uncovered by UK and Japanese scientists

Public release date: 8-Mar-2012 [ | E-mail | Share ]

Contact: Katherine Barnes katherine.barnes@kcl.ac.uk 44-207-848-3076 King's College London

Researchers at King's College London and Hiroshima University, Japan, have identified a specific gene linked to throat cancer following a genetic study of a family with 10 members who have developed the condition.

The study, published today in American Journal of Human Genetics, uncovered a mutation in the ATR gene, demonstrating the first evidence of a link between abnormality in this gene and an inherited form of cancer. The researchers say this finding raises new ideas about genetic factors linked to throat cancer and provides a platform for exploring the role of ATR more generally in cancer biology.

Scientists carried out a genome-wide linkage study in a US family with an unusual hereditary condition affecting 24 members of the family over five generations. Characteristics include developmental abnormalities of hair, teeth and nails as well as dilated skin blood vessels. Strikingly, nearly every person with the condition involved in the study had developed throat cancer (oropharyngeal squamous cell carcinoma) in their 20s or 30s.

The team took blood samples from 13 members of the affected family, as well as samples from 13 unaffected people. After analysing these samples they found a single mutation in ATR was present in all the people with the condition, but none of the unaffected people had the mutation. Ten of the 13 people with the condition had developed throat cancer.

Professor John McGrath from the King's College London Genetic Skin Disease Group at St John's Institute of Dermatology, based at Guy's Hospital, said: 'This is an intriguing study which not only provides a genetic explanation for an unusual syndrome, but also provides a unique novel insight into how the ATR gene may be associated with a specific form of cancer. It is a classic example of how we can use rare conditions to give us insight into more common diseases.

'Key known risk factors for developing throat cancer include consumption of alcohol and tobacco as well as viral infections such as HPV (humanpapilloma virus). But this is the first evidence connecting abnormalities in the ATR gene with susceptibility to this type of cancer. We know that ATR encodes a protein critical to the way cells repair their DNA, and is therefore a vital mechanism. We now plan to investigate the cancer pathways in more detail to try to find new treatments.'

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CONTACT Katherine Barnes International Press Officer King's College London Tel: +44 207 848 3076 Email: katherine.barnes@kcl.ac.uk

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New throat cancer gene uncovered by UK and Japanese scientists

Setback in search for gene-based cancer treatment

Date: Thursday Mar. 8, 2012 7:17 AM ET

BOSTON Scientists are reporting what could be very bad news for efforts to customize cancer treatment based on each person's genes.

They have discovered big differences from place to place in the same tumour as to which genes are active or mutated. They also found differences in the genetics of the main tumour and places where the cancer has spread.

This means that the single biopsies that doctors rely on to choose drugs are probably not giving a true view of the cancer's biology. It also means that treating cancer won't be as simple as many had hoped.

By analyzing tumours in unprecedented detail, "we're finding that the deeper you go, the more you find," said one study leader, Dr. Charles Swanton of the Cancer Research UK London Research Institute in England. "It's like going from a black-and-white television with four pixels to a colour television with thousands of pixels."

Yet the result is a fuzzier picture of how to treat the disease.

The study is reported in Thursday's New England Journal of Medicine.

It is a reality check for "overoptimism" in the field devoted to conquering cancer with new gene-targeting drugs, Dr. Dan Longo, a deputy editor at the journal, wrote in an editorial.

About 15 of these medicines are on the market now and hundreds more are in testing, but they have had only limited success. And the new study may help explain why.

The scientists used gene sequencing to a degree that has not been done before to study primary tumours and places where they spread in four patients with advanced kidney cancer. They found that two-thirds of gene mutations they detected were not present in all areas of the same tumour. They also were stunned to see different mutations in the same gene from one part of a tumour to another.

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Setback in search for gene-based cancer treatment

Opinion: On the Gene Patent Debate

Two key patent cases that no doubt will impact the future of personalized medicine are pending review by the US Supreme Court. What will the Court decide?

By Courtenay C. Brinckerhoff | March 7, 2012

The debate over the patenting of technologies related to diagnostic and personalized medicine continues to swell with no resolution in sight. The Supreme Court heard oral arguments in Mayo Collaborative Services v. Prometheus Laboratories, Inc. last December, but has not yet issued a decision. Just last month, the US Patent and Trademark Office held public hearings to gather information for the study on genetic testing that it will use to prepare a report for Congress on this issue. And, the Supreme Court is deciding whether to review the Federal Circuit decision in Association for Molecular Pathology v. Myriad Genetics, Inc. (the BRCAI/gene patenting case), although current speculation is that the Court may defer any action on this case until it issues its decision in Prometheus. While each of these proceedings raises different legal issues, they all relate to the ability to obtain or enforce patent rights on genes, tests, and methods used in personalized medicine.

Personalized medicine is the new frontier of healthcare. It offers the promise of treatments that are tailored to a patients individual situation, including the patients genetic makeup, the specific variation of the disease the patient suffers from, and the patients specific response to a given course of treatment. With personalized medicine, a patient can be given the most effective treatment, improving prognosis and saving considerable time and money on ineffective treatments. As noted on the US Food and Drug Administrations Pharmacogentics webpage, [p]harmacogenomics can play an important role in identifying responders and non-responders to medications, avoiding adverse events, and optimizing drug dose.

The question being debated is whether these advances are most likely to flourish within the patent system or outside of it. Do patents promote investment in personalized medicine or stifle innovation by suppressing competition? Do patients benefit from patented therapies, or do they suffer without treatments because they are too expensive? The Founding Fathers established the patent system in the US Constitution as an incentive to promote the Progress of Science and useful Arts, but should a different paradigm apply to medical inventions?

Companies working in this field cite the high cost of developing and validating personalized medicine therapies, and emphasize the need to obtain a return on their successful investments. Without the promise of some period of market exclusivity during which they can profit from their years of research, companies will not have any incentive to work in this fieldor any resources to do so.

On the other side of the debate, some doctors organizations and patient groups believe that the patent system is bad for the healthcare system. They say that it drives up costs and may prevent patients from obtaining a second opinion, because the patent owner can prevent others from administering patented tests. Many believe that research would continueat universities and institutions like the National Institutes of Healthand that more people would benefit because the advances would be available on a more widespread basis.

At its heart, this debate may be more of a public policy question than a legal one. People deciding this issue must keep in mind that most university research is funded by government grants and that NIH is a federal agency. We may want taxpayer money to support this kind of research, but it raises the same specter of big government and taxpayer burden as health care reform. Is a country that may not be ready to provide universal access to proven therapies willing to invest substantial amounts in research programs that may take years to yield any benefits?

Turning back to the law, the US Court of Appeals for the Federal Circuit has refused to draw a line that categorically prohibits patents on personalized medicine. In Prometheus, the court found that methods of optimizing the dose of a specific type of drug was patent-eligible subject matter, not an improper attempt to patent a natural phenomenon. In Myriad, the court found that isolated DNA associated with an aggressive form of breast cancer could also be patented without violating the prohibition against patents on products of nature because DNA does not naturally occur in an isolated form. Although the Supreme Court could reach a different conclusion in either or both cases, its refusal to categorically prohibit business method patents suggests that it may also approach this issue in a similar fashioncautiously and on a case-by-case basis. That would leave it to Congress to decide if a different approach is needed (such as compulsory licensing as discussed at the Patent Office hearing), or if the current incentives and rewards are striking an adequate balance between private investment and public benefit.

Courtenay C. Brinckerhoff is a partner at Foley & Lardner LLP, vice chair of the firms Chemical, Biotechnology & Pharmaceutical Practice, and editor of Foleys PharmaPatentsBlog.com. The opinions expressed here do not represent those of Foley & Lardner LLP or its clients.

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Opinion: On the Gene Patent Debate

Is Cancer Outwitting 'Personalized Medicine'?

WEDNESDAY, March 7 (HealthDay News) -- The genetic makeup of cancer cells differs significantly from region to region within a single tumor, according to new research that raises questions about the true potential of personalized cancer medicine.

With this treatment approach, doctors study a tumor's genetic makeup to determine which drugs would work best in a particular patient. But if the genetic mutations driving the cancer cells vary widely, a single tissue sample won't necessarily give the full picture.

This "targeted therapy" involves "sticking a needle into the primary tumor site and taking a small sliver of a tumor, doing a gene analysis, and creating a genetic profile of the tumor to predict how the tumor will behave," explained Dr. Dan Longo, an oncologist and deputy editor at the New England Journal of Medicine.

"What this paper tells us is that is an oversimplification of the complexity of tumors and their heterogeneity," he said. "If you look at different sites of the very same tumor and the very same person, one site might tell you a gene profile associated with a good prognosis and the other site will tell you a gene profile associated with a bad prognosis."

Longo wrote an editorial accompanying the new study, published in the March 8 issue of the New England Journal of Medicine.

In the study, scientists from Cancer Research UK London Research Institute took 13 biopsies, or tissue samples, from a patient whose kidney cancer had spread. The biopsies were from eight regions of the kidney tumor and four tumors in the chest and lungs.

Researchers also took normal tissue, sequenced the patient's genome and compared that to what they found in the biopsies.

Genetic analysis turned up 128 mutations in the tumors. But only about one-third, or about 40 of those mutations, were present in all of the biopsies.

"The majority of mutations are not shared in every biopsy," said senior study author Charles Swanton, a professor of cancer medicine at the research institute.

Swanton and his colleagues also analyzed tumor tissue samples from another three patients with kidney cancer. From a total of 30 biopsies from all four patients, 26 tissue samples had mutations that were highly heterogenous, or varied, from one another.

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Is Cancer Outwitting 'Personalized Medicine'?

Gene-based cancer research suffers setback, scientists say

BOSTON Scientists are reporting what could be very bad news for efforts to customize cancer treatment based on each persons genes.

They have discovered big differences from place to place in the same tumor as to which genes are active or mutated. They also found differences in the genetics of the main tumor and places where the cancer has spread.

This means that the single biopsies on which doctors rely to choose drugs are probably not giving a true view of the cancers biology. It also means that treating cancer wont be as simple as many had hoped.

By analyzing tumors in unprecedented detail, Were finding that the deeper you go, the more you find, said one study leader, Dr. Charles Swanton of the London Research Institutes Cancer Research UK. Its like going from a black-and-white television with four pixels to a color television with thousands of pixels.

Yet the result is a fuzzier picture of how to treat the disease.

The study is reported in Thursdays New England Journal of Medicine.

It is a reality check for overoptimism in the field devoted to conquering cancer with new gene-targeting drugs, Dr. Dan L. Longo, a deputy editor at the journal, wrote in an editorial.

About 15 of these medicines are on the market now and hundreds more are in testing, but they have had only limited success. And the new study may help explain why.

The scientists used gene sequencing to a degree that has not been done before to study primary tumors and places where they spread in four patients with advanced kidney cancer. They found that two-thirds of gene mutations they detected were not present in all areas of the same tumor. They also were stunned to see different mutations in the same gene from one part of a tumor to another.

That means a single biopsy would reveal only a minority of mutations. Still, its not clear whether doing more biopsies would improve accuracy, or how many or how often they should be done.

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Gene-based cancer research suffers setback, scientists say

Gene study suggests treating cancer is more complex than many had hoped

BOSTON - Scientists are reporting what could be very bad news for efforts to customize cancer treatment based on each person's genes.

They have discovered big differences from place to place in the same tumour as to which genes are active or mutated. They also found differences in the genetics of the main tumour and places where the cancer has spread.

This means that the single biopsies that doctors rely on to choose drugs are probably not giving a true view of the cancer's biology. It also means that treating cancer won't be as simple as many had hoped.

By analyzing tumours in unprecedented detail, "we're finding that the deeper you go, the more you find," said one study leader, Dr. Charles Swanton of the Cancer Research UK London Research Institute in England. "It's like going from a black-and-white television with four pixels to a colour television with thousands of pixels."

Yet the result is a fuzzier picture of how to treat the disease.

The study is reported in Thursday's New England Journal of Medicine.

It is a reality check for "overoptimism" in the field devoted to conquering cancer with new gene-targeting drugs, Dr. Dan Longo, a deputy editor at the journal, wrote in an editorial.

About 15 of these medicines are on the market now and hundreds more are in testing, but they have had only limited success. And the new study may help explain why.

The scientists used gene sequencing to a degree that has not been done before to study primary tumours and places where they spread in four patients with advanced kidney cancer. They found that two-thirds of gene mutations they detected were not present in all areas of the same tumour. They also were stunned to see different mutations in the same gene from one part of a tumour to another.

That means a single biopsy would reveal only a minority of mutations. Still, it's not clear whether doing more biopsies would improve accuracy, or how many or how often they should be done.

Go here to read the rest:
Gene study suggests treating cancer is more complex than many had hoped

Cancer gene mutation more complex than previously thought -study

LONDON (Reuters) - Taking a sample or biopsy from just one part of a tumour might not give a full picture of its genetic diversity and may explain why doctors, despite using genetically targeted drugs, are often unable to save patients whose cancer has spread, scientists said.

A study by British researchers found there are more genetic differences than similarities between biopsies taken from separate areas of the same tumour, and yet further gene differences in samples taken from secondary tumours.

That might help explain why, despite recent development of a wave of highly targeted drugs designed to tackle cancers of specific genetic types, the prognosis remains poor for many patients with so-called solid-tumour disease like breast, lung, or kidney cancer that has spread to others parts of the body.

But the researchers, whose study was partly funded by charity Cancer Research UK and published in the New England Journal of Medicine, said it also pointed to a way forward.

The team carried out the first ever genome-wide analysis of the genetic changes or faults in different regions of the same tumour.

They looked at four patients with cancer in their kidneys, taking samples from different regions of the primary tumour and also from other organs where the tumour had spread.

They found that the majority of gene faults, around two-thirds, were not the same in one sample as in another, even when the biopsies were taken from the same tumour.

Samples taken from secondary tumours - which are a result of the disease spreading to other parts of the body - had yet more different genetic faults, suggesting that basing treatment decisions on just one primary tumour sample is not sufficient.

"We've known for some time that tumours are a patchwork of faults, but this is the first time we've been able to use cutting-edge genome sequencing technology to map out the genetic landscape of a tumour in such exquisite detail," said Charles Swanton, of University College London's cancer institute, who led the study and presented its results at a briefing in London on Tuesday.

He said they had uncovered "an extraordinary amount of diversity" at a genetic level both within tumours and within a single patient, with more differences between biopsies from the same tumour than similarities.

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Cancer gene mutation more complex than previously thought -study

Cost of Gene Sequencing Falls, Raising Hopes for Medical Advances

MOUNTAIN VIEW, Calif. -- In Silicon Valley, the line between computing and biology has begun to blur in a way that could have enormous consequences for human longevity.

Bill Banyai, an optical physicist at Complete Genomics, has helped make that happen. When he began developing a gene sequencing machine, he relied heavily on his background at two computer networking start-up companies. His digital expertise was essential in designing a factory that automated and greatly lowered the cost of mapping the three billion base pairs that form the human genome.

The promise is that low-cost gene sequencing will lead to a new era of personalized medicine, yielding new approaches for treating cancers and other serious diseases. The arrival of such cures has been glacial, however, although the human genome was originally sequenced more than a decade ago.

Now that is changing, in large part because of the same semiconductor industry manufacturing trends that opened up consumer devices like the PC and the smartphone: exponential increases in processing power and transistor density are accompanied by costs that fall at an accelerating rate.

As a result, both new understanding and new medicines will arrive at a quickening pace, according to the biologists and computer scientists.

"For all of human history, humans have not had the readout of the software that makes them alive," said Larry Smarr, director of the California Institute of Telecommunications and Information Technology, a research center that is jointly operated by the University of California, San Diego, and the University of California, Irvine, who is a member of the Complete Genomics scientific advisory board. "Once you make the transition from a data poor to data rich environment, everything changes."

Complete Genomics, based in Mountain View, is one of more than three dozen firms hastening to push the cost of sequencing an entire human genome below $1,000. The challenge is part biology, part chemistry, part computing, and in Complete Genomics' case, part computer networking.

Complete Genomics is a classic Silicon Valley start-up story. Even the gene sequencing machines, which are housed in a 4,000-square-foot room bathed in an eerie blue light, appear more like a traditional data center than a biology lab.

In 2005 ,when Clifford Reid, a successful Silicon Valley software entrepreneur, began to assemble his team, he approached Dr. Banyai and asked if he was interested in joining a gene sequencing start-up. Dr. Reid, who was also trained in physics and math, had spent a year as an entrepreneur-in-residence at the Massachusetts Institute of Technology, where he had become a convert to bioinformatics, the application of computer science and information technologies to biology and medicine.

Dr. Banyai had even less experience in biology.

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Cost of Gene Sequencing Falls, Raising Hopes for Medical Advances

Cancer gene mutation more complex than previously thought

Taking a sample or biopsy from just one part of a tumor might not give a full picture of its genetic diversity and may explain why doctors, despite using genetically targeted drugs, are often unable to save patients whose cancer has spread, scientists said.

A study by British researchers found there are more genetic differences than similarities between biopsies taken from separate areas of the same tumor, and yet further gene differences in samples taken from secondary tumors.

That might help explain why, despite recent development of a wave of highly targeted drugs designed to tackle cancers of specific genetic types, the prognosis remains poor for many patients with so-called solid-tumor disease like breast, lung, or kidney cancer that has spread to others parts of the body.

But the researchers, whose study was partly funded by charity Cancer Research UK and published in the New England Journal of Medicine, said it also pointed to a way forward.

The team carried out the first ever genome-wide analysis of the genetic changes or faults in different regions of the same tumor.

They looked at four patients with cancer in their kidneys, taking samples from different regions of the primary tumor and also from other organs where the tumor had spread.

They found that the majority of gene faults, around two-thirds, were not the same in one sample as in another, even when the biopsies were taken from the same tumor.

Samples taken from secondary tumors - which are a result of the disease spreading to other parts of the body - had yet more different genetic faults, suggesting that basing treatment decisions on just one primary tumor sample is not sufficient.

"We've known for some time that tumors are a patchwork of faults, but this is the first time we've been able to use cutting-edge genome sequencing technology to map out the genetic landscape of a tumor in such exquisite detail," said Charles Swanton, of University College London's cancer institute, who led the study and presented its results at a briefing in London on Tuesday.

He said they had uncovered "an extraordinary amount of diversity" at a genetic level both within tumors and within a single patient, with more differences between biopsies from the same tumor than similarities.

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Cancer gene mutation more complex than previously thought

TEDxOU – Courtney Griffin – Epigenetics and the Influence of Our Genes – Video

23-02-2012 10:18 Because we want to understand what genes are required for blood vessel development, Courtney Griffin studies certain enzymes that help turn genes on and off. These enzymes are specifically involved in relaxing DNA that is normally tightly coiled up in our cells. Dr. Griffin is now an Assistant Member in the Cardiovascular Biology Research Program at the Oklahoma Medical Research Foundation after receiving her BA from Harvard University and her Ph. D. from the University of California San Francisco School of Medicine

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TEDxOU - Courtney Griffin - Epigenetics and the Influence of Our Genes - Video

Newly Published Meta-Analysis Study Finds that IL-1 Gene Variations Contained in Interleukin Genetics’ PST Test are …

WALTHAM, Mass.--(BUSINESS WIRE)--

Interleukin Genetics, Inc. (OTCQB: ILIU.PK - News) announced today the publication of a peer-reviewed study which found that Interleukin-1 (IL-1) gene variations are associated with increased risk of periodontal disease. The study, which appears on the Journal of Periodontologys website, in advance of appearing in the print edition, was led by Nadeem Y. Karimbux, D.M.D., Associate Professor of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine.

The study assessed the potential value of IL-1 genetic variations in the risk for developing severe periodontal disease. The IL-1 genetic variations in the published study are included in Interleukin Genetics PST Genetic Test, the first genetic test to analyze genes for variations that identify an individuals predisposition for over-expression of inflammation and risk for periodontal disease. Researchers reviewed 27 published studies on IL-1 genetics and periodontal disease from 1997 through June 2011 which examined Caucasian adults, 35 years or older with adult periodontal disease, to determine whether there was a significant association between the presence of the IL-1 gene variations and the severity and progression of periodontal disease. Thirteen studies qualified for the quantitative meta-analysis, which found significant effects for the two individual gene variations (IL1A OR=1.48; and IL1B OR= 1.54) and for a composite genotype that combines minor alleles at each locus (OR= 1.51). Some heterogeneity was evident, but there was no indication of publication bias.

This review and meta-analysis show that IL1A and IL1B genetic variations are significant contributors to chronic periodontitis in Caucasians, said Dr. Karimbux. Having this actionable information can assist dentists in establishing more aggressive treatment protocols for patients at increased risk.

Periodontal disease is caused by a chronic bacterial infection that activates inflammation which destroys the gums and bone supporting the teeth. If left untreated, periodontitis leads to tooth loss. Studies have shown that people with chronic and prolonged inflammatory periodontal disease are at an increased risk of several systemic conditions, such as heart disease, strokes, rheumatoid arthritis and certain chronic pulmonary diseases.

Periodontal disease is one of the most common chronic diseases worldwide, but fortunately most individuals develop only a mild form of periodontitis that when caught early, can be easily treated. We now know that approximately 8 to 13 percent of the adult population will develop more destructive forms of periodontitis, and most of those at risk can be identified early based on smoking, IL-1 genetics and diabetes, said Kenneth Kornman D.D.S., PhD., study author and Chief Scientific Officer of Interleukin Genetics. While additional studies should be undertaken to look at specific periodontal conditions and additional ethnicities, this study reaffirms the role genetics plays in adult oral and overall health.

About Interleukin Genetics, Inc. Interleukin Genetics, Inc. (OTCQB: ILIU.PK - News) develops and markets a line of genetic tests under the Inherent Health and PST brands.The products empower individuals to prevent certain chronic conditions and manage their existing health and wellness through genetic-based insights with actionable guidance. Interleukin Genetics leverages its research, intellectual property and genetic panel development expertise in metabolism and inflammation to facilitate the emerging personalized healthcare market. The Company markets its tests through partnerships with health and wellness companies, healthcare professionals and other distribution channels. Interleukin Genetics flagship products include its proprietary PST genetic risk panel for periodontal disease and tooth loss susceptibility sold through dentists and the Inherent Health Weight Management Genetic Test that identifies the most effective diet and exercise program for an individual based on genetics. Interleukin Genetics is headquartered in Waltham, Mass. and operates an on-site, state-of-the-art DNA testing laboratory certified under the Clinical Laboratory Improvement Amendments (CLIA). For more information, please visit http://www.ilgenetics.com.

About PST The PST Genetic Test identifies individuals with increased risk for severe and progressive periodontal disease and significant tooth loss based on a proprietary panel of genetic variations that predispose an individual to over-express inflammation. In August 2010, Interleukin Genetics announced the initiation of a landmark clinical study on risk factors predictive of periodontal disease progression to tooth loss using a new version of the PST Genetic Test. This clinical studybeing conducted at the University of Michigan School of Dentistry and led by Dr. William Giannobile, Director of the Michigan Center for Oral Health Researchis designed to test whether risk factors, including genetic information, can guide more successful intervention and thus reduce the adverse outcomes of periodontal disease, such as tooth loss.

Certain statements contained herein are forward-looking statements, including statements that the clinical studies have the potential to expand the use of the PST Genetic Test. Because such statements include risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Factors that could cause actual results to differ materially from those expressed or implied by such forward-looking statements include, but are not limited to, those risks and uncertainties described in the Interleukin Genetics annual report on Form 10-K for the year ended December 31, 2010 and other filings with the Securities and Exchange Commission. Interleukin Genetics disclaims any obligation or intention to update these forward-looking statements.

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Newly Published Meta-Analysis Study Finds that IL-1 Gene Variations Contained in Interleukin Genetics’ PST Test are ...

UCLA scientists uncover mechanism for melanoma drug resistance

Public release date: 6-Mar-2012 [ | E-mail | Share ]

Contact: Kim Irwin kirwin@mednet.ucla.edu 310-206-2805 University of California - Los Angeles Health Sciences

Cancer is tough to kill and has many ways of evading the drugs used by oncologists to try and eliminate it.

Now, researchers at UCLA's Jonsson Comprehensive Cancer Center have uncovered how an advanced form of melanoma gets around an inhibitor, Zelboraf, which targets the mutated BRAF gene.

By examining the part of the melanoma genome that encodes proteins, called the exome, Jonsson Cancer Center scientists discovered that in some patients with BRAF-mutated metastatic melanoma, the mutated BRAF gene driving the cancer becomes amplified as the cancer develops resistance to a BRAF inhibitor. Quite simply, by increasing the copies of the mutated BRAF gene, the melanoma is trying to over produce the drug target protein and outnumber the inhibitor. The findings may lead to alternative ways of preventing or treating resistant melanomas.

"Understanding and solving the problem of how cancer gets around targeted drugs is arguably one of the highest priorities in modern day cancer medicine. In this study, we found that in some patients, the cancer simply makes more of the target, the mutated BRAF gene, so that the drug dose becomes too weak to fight the cancer," said study senior author Dr. Roger Lo, an assistant professor of dermatology and molecular and medical pharmacology and a Jonsson Cancer Center scientist. "If you think of the mutation as a right hand and the BRAF inhibitor as a left hand and the two clasp to be effective, there's clearly an optimal radio to ensure the mutated gene is fully inhibited. Here, we get more of the drug target, which has the same effect as dropping the drug level."

The one-year study is published March 6, 2012, in the peer-reviewed journal Nature Communications.

About 50 percent of patients with metastatic melanoma, or 4,000 people a year, have the BRAF mutation and can be treated with Zelboraf, two pills taken twice a day. Zelboraf was approved by the U.S. Food and Drug Administration for use in metastatic melanoma in August of 2011. Many other common human cancers, including colon, thyroid and lung, also harbor BRAF-mutated subsets, Lo said.

Oncologists cannot give more Zelboraf to these patients to combat the increased number of mutated BRAF genes because the dose approved by the FDA is the maximum tolerated dose, Lo said. However, Zelboraf could perhaps be given with inhibitors of other cell signaling pathways in metastatic melanoma to try and stop patients from becoming resistant.

Lo and his team examined samples of 20 patients for this study, taking their normal tissue, their tumor tissue before treatment with Zelboraf and a sample when the cancer had responded earlier but subsequently became resistant. Using high-throughput DNA sequencing technology, the scientists examined the entire cancer exome to see what changes were occurring that may point to resistant mechanisms. Lo found that five of the 20 patients showed increased copies of the mutated BRAF gene. Cell lines developed from melanoma patients also showed pathways downstream of the amplified gene that could be blocked with inhibitors to fight resistance.

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UCLA scientists uncover mechanism for melanoma drug resistance

Stanford scientists develop gene therapy approach to grow blood vessels in ischemic limbs

Public release date: 6-Mar-2012 [ | E-mail | Share ]

Contact: Cody Mooneyhan cmooneyhan@faseb.org 301-634-7104 Federation of American Societies for Experimental Biology

Bethesda, MDA new research discovery by a team of Stanford and European scientists offers hope that people with atherosclerotic disease may one day be able to avoid limb amputation related to ischemia. A new research report appearing online in the FASEB Journal suggests that the delivery of genes for two molecules naturally produced by the body, called "PDGF-BB" and "VEGF" may successfully cause the body to grow new blood vessels that can save ischemic limbs.

"We hope that our findings will ultimately develop into a safe and effective therapy for the many patients, suffering from blocked arteries in the limbs, who are currently not adequately treated by surgery or drugs," said Helen M. Blau, Ph.D., a senior researcher involved in the work and Associate Editor of the FASEB Journal from the Baxter Laboratory for Stem Cell Biology at the Institute for Regenerative Medicine and Stem Cell Biology at Stanford. "This could help avoid the devastating consequences of limb amputations for both patients and their families."

To make this discovery, Blau and colleagues, including Andrea Banfi (now at Basel University), introduced the genes for PDGF-BB and VEGF into the muscles of mice, either independently or together. When high doses of VEGF alone were produced, they caused the growth of vascular tumors. When the two factors were produced in unbalanced amounts, tumor growth also occurred. When VEGF and PDGF were delivered in a fixed ratio relative to one another, however, no tumors occurred, and blood flow was restored to ischemic muscle tissue and damage repaired without any toxic effects. To achieve a "balanced" delivery of PDGF-BB and VEGF, scientists placed both genes in a single gene therapy delivery mechanism, called a "vector."

Although the report shows the feasibility of growing robust and safe new blood vessels that restore blood flow to diseased tissues, Blau points out that "there are multiple challenges to correcting peripheral vasculature disease by using proangiogenic gene therapy strategies. Two important challenges are what to deliver and how to get it to where it can have beneficial effects. Clinical success will require both delivering a gene therapy construct that encodes for effective angiogenic factors and ensuring that the sites of delivery are where the construct can have the greatest clinical benefit."

"This ingenious work, based on the latest techniques of molecular biology, tells us that it is possible to reinvigorate parts of our body that can't get enough blood to keep them going," said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal. "The next question is whether this approach will work in humans and exactly how to deliver the new treatment to places that need it the most."

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Receive monthly highlights from the FASEB Journal by e-mail. Sign up at http://www.faseb.org/fjupdate.aspx. The FASEB Journal is published by the Federation of the American Societies for Experimental Biology (FASEB) and is the most cited biology journal worldwide according to the Institute for Scientific Information. In 2010, the journal was recognized by the Special Libraries Association as one of the top 100 most influential biomedical journals of the past century. FASEB is composed of 26 societies with more than 100,000 members, making it the largest coalition of biomedical research associations in the United States. Celebrating 100 Years of Advancing the Life Sciences in 2012, FASEB is rededicating its efforts to advance health and well-being by promoting progress and education in biological and biomedical sciences through service to our member societies and collaborative advocacy.

Details: Andrea Banfi, Georges von Degenfeld, Roberto Gianni-Barrera, Silvia Reginato, Milton J. Merchant, Donald M. McDonald, and Helen M. Blau. Therapeutic angiogenesis due to balanced single-vector delivery of VEGF and PDGF-BB. FASEB J. doi:10.1096/fj.11-197400 ; http://www.fasebj.org/content/early/2012/03/05/fj.11-197400.abstract

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Stanford scientists develop gene therapy approach to grow blood vessels in ischemic limbs

Fasudil bypasses genetic cause of spinal birth defect

Public release date: 6-Mar-2012 [ | E-mail | Share ]

Contact: Dr. Hilary Glover hilary.glover@biomedcentral.com 44-203-192-2370 BioMed Central

Spinal muscular atrophy (SMA) is an incurable, and progressive, disease caused by an inheritable defect in the gene SMN1. Depending on the severity of the mutation it can result in the loss of spinal cord motor neurons, muscle wasting (atrophy) and even death of an affected child. A new study published in Biomed Central's open access journal BMC Medicine shows that Fasudil, a ROCK inhibitor, can improve both the size of muscle fibers and their connection to motor neurons. Fasudil also increased the lifespan and improved the movement of SMA mice.

SMA affects 1 in 6,000 births and is the leading cause of death in young children. In its less severe form the muscle wasting of SMA traps bright young children within their bodies. Researchers from the Ottawa Hospital Research Institute and the University of Ottawa realized that SMA caused problems in regulation of the ROCK intracellular signaling pathway and that inhibiting this pathway could increase the lifespan of SMA mice.

By targeting the ROCK pathway in spinal cord and muscles, Fasudil bypasses the genetic defect SMN1. Dr Kothary, who led the team, explained, "Fasudil increased the lifespan of SMA mice from 30 to 300 days, allowing them to survive well into adulthood. Although it had no apparent effect on the damaged neurons themselves, Fasudil increased muscle size and the endplate junction between muscles and their motor neurons. Consequently, the mice were also better coordinated, better groomed, and could move about more freely than untreated SMA mice."

Melissa Bowerman from the Ottawa Hospital Research Institute continued, "Finding a cure for SMA is still a long way off, however we hope that treatment with drugs like Fasudil, which goes some way towards restoring normal developmental, or HDAC inhibitors, which alter how genes are regulated, along with nutrition and physiotherapy will provide a package of therapy to improve the quality and length of life of SMA children."

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Notes to Editors

1. Fasudil improves survival and promotes skeletal muscle development in a mouse model of spinal muscular atrophy Melissa Bowerman, Lyndsay M Murray, Justin G Boyer, Carrie L Anderson and Rashmi Kothary BMC Medicine (in press)

Please name the journal in any story you write. If you are writing for the web, please link to the article. All articles are available free of charge, according to BioMed Central's open access policy.

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Fasudil bypasses genetic cause of spinal birth defect

ASF Grantee Rhonda Charles uses mouse models to examine social behaviors in autism – Video

14-02-2012 14:36 Rhonda Charles is a 2010 ASF Grant Winner and a PhD Student in the Department of Genetics and Genomic Sciences at the Mt. Sinai School of Medicine. Ms. Charles' work focuses on the AVPR1A gene, which affects social behavior and anxiety in autism spectrum disorder. Her ASF- funded study puts the human AVPR1A gene into a mouse model, a key step that must occur before we can introduce pharmacological treatments for individuals with autism affected by AVPR1A gene mutations.

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ASF Grantee Rhonda Charles uses mouse models to examine social behaviors in autism - Video

Gene therapy approach to grow blood vessels in ischemic limbs

ScienceDaily (Mar. 6, 2012) A new research discovery by a team of Stanford and European scientists offers hope that people with atherosclerotic disease may one day be able to avoid limb amputation related to ischemia. A new research report appearing online in the FASEB Journal suggests that the delivery of genes for two molecules naturally produced by the body, called "PDGF-BB" and "VEGF" may successfully cause the body to grow new blood vessels that can save ischemic limbs.

"We hope that our findings will ultimately develop into a safe and effective therapy for the many patients, suffering from blocked arteries in the limbs, who are currently not adequately treated by surgery or drugs," said Helen M. Blau, Ph.D., a senior researcher involved in the work and Associate Editor of the FASEB Journal from the Baxter Laboratory for Stem Cell Biology at the Institute for Regenerative Medicine and Stem Cell Biology at Stanford. "This could help avoid the devastating consequences of limb amputations for both patients and their families."

To make this discovery, Blau and colleagues, including Andrea Banfi (now at Basel University), introduced the genes for PDGF-BB and VEGF into the muscles of mice, either independently or together. When high doses of VEGF alone were produced, they caused the growth of vascular tumors. When the two factors were produced in unbalanced amounts, tumor growth also occurred. When VEGF and PDGF were delivered in a fixed ratio relative to one another, however, no tumors occurred, and blood flow was restored to ischemic muscle tissue and damage repaired without any toxic effects. To achieve a "balanced" delivery of PDGF-BB and VEGF, scientists placed both genes in a single gene therapy delivery mechanism, called a "vector."

Although the report shows the feasibility of growing robust and safe new blood vessels that restore blood flow to diseased tissues, Blau points out that "there are multiple challenges to correcting peripheral vasculature disease by using proangiogenic gene therapy strategies. Two important challenges are what to deliver and how to get it to where it can have beneficial effects. Clinical success will require both delivering a gene therapy construct that encodes for effective angiogenic factors and ensuring that the sites of delivery are where the construct can have the greatest clinical benefit."

"This ingenious work, based on the latest techniques of molecular biology, tells us that it is possible to reinvigorate parts of our body that can't get enough blood to keep them going," said Gerald Weissmann, M.D., Editor-in-Chief of the FASEB Journal. "The next question is whether this approach will work in humans and exactly how to deliver the new treatment to places that need it the most."

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The above story is reprinted from materials provided by Federation of American Societies for Experimental Biology, via EurekAlert!, a service of AAAS.

Note: Materials may be edited for content and length. For further information, please contact the source cited above.

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Gene therapy approach to grow blood vessels in ischemic limbs

Researchers Find Five Novel Gene Mutations Linked to Platelet Counts in African Americans

--Findings could be a step toward developing better drugs for coronary artery disease and preventing heart attacks

Newswise Researchers, led by scientists from Johns Hopkins, have found five previously unknown gene mutations believed to be associated with elevated blood platelet counts in African-Americans, findings they say could someday lead to the development of new drugs to help prevent coronary artery disease.

The study is believed to be the first of its size to focus on platelet genetics in African Americans, who have a higher risk of stroke than other racial groups. They also have relatively higher platelet counts and average platelet volume, and worse outcomes than whites after a heart attack.

Improving our understanding of the biology and genetics of platelets and how they function will aid us in developing better treatments and more individualized treatments to reduce risk of heart disease associated with platelets, says study leader Rehan Qayyum, M.D., an assistant professor in the division of general internal medicine at the Johns Hopkins University School of Medicine.

Qayyum cautions that there are believed to be many more genes involved in platelet function that remain unknown.

Platelets are cells produced in bone marrow, smaller than red or white blood cells, which foster blood clotting. While clotting is critical to stop bleeding after injuries, it can also cause harm by allowing clumps of blood cells to clog blood vessels leading to the heart, brain and other organs, cutting off blood flow.

Studies have shown that the greater the platelet volume or count in the blood, and the larger platelets are, the greater the risk of dangerous clot formation. Qayyum notes that the number of platelets in a given amount of blood (platelet count) and the size of these platelets (measured as average platelet count) vary from person to person in much the way that height, weight and eye color traits differ. Thus, he said, the search for genes that control this variation is a potentially fruitful line of scientific inquiry.

Qayyum and his colleagues, publishing in the online journal PLoS Genetics, report that they conducted a meta-analysis and genomewide association study, looking at genetic data from 16,000 African-American participants from seven separate studies. They compared information from each study, tracking 2.5 million single possible changes in the human genetic code to see which genes stood out across the entire group as significantly associated with increased or decreased platelet counts.

The researchers found five such alterations, involving the addition or deletion of a single piece of genetic code, across the studied genomes that had not been identified in other populations. When they checked their findings against data from Caucasian and Hispanic groups, they found three of the novel gene mutations in those populations, too. Four of the previously unknown gene mutations were later found in the genetic code of platelet cells, but one was not. That one, however, was found close to a gene that is known to be essential in the formation of normal platelets. The exact role played by each of these mutations still needs to be determined, Qayyum says.

Qayyum says one goal of their research is to identify new targets for drugs that decrease platelet aggregation in the arteries and prevent clot formation. Blood thinners, including aspirin, clopidogrel and warfarin, are widely used antiplatelet medications. But some people cant tolerate the side effects, which include bleeding, bruising and gastrointestinal upset.

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Researchers Find Five Novel Gene Mutations Linked to Platelet Counts in African Americans

Unlocking The Mysteries Of Single Gene Mutations

Yale researchers recently received a DNA sample from Turkey of twin newborns whose brains weren't developing properly. The physician figured it was a genetic problem, but had no way of analyzing it further.

"We identified a mutation in the folic acid receptor of the brain," said Murat Gunel, professor of genetics and neurobiology, adding that it's a very rare abnormality that forms during pregnancy. Most problems with brain development, he said, don't have an easy cure. In this case, though, Gunel and his fellow researchers at Yale immediately called the physician in Turkey and instructed him to give the babies very high doses of folic acid, which reverses the problem.

It was one of the first cases handled in a four-university project designed to solve the mysteries of thousands of disorders caused by inherited single-gene mutations, known as Mendelian diseases, named for the Austrian botanist and monk Gregor Mendel. The four-year project is funded by a $48 million grant from National Institutes of Health grant awarded in December. The other recipients are researchers at the University of Washington and a collaborative team of researches from Baylor College of Medicine in Houston and Johns Hopkins University in Baltimore. Yale's share of the grant -- $11.2 million goes to the university's new Center for Mendelian Disorders.

By collecting and analyzing DNA samples of these disorders from around of the world, the researchers hope to shed some light on how to treat them. To coordinate, the researchers talk by phone every weeks and will meet in person three or four times a year.

"We're identifying the disease-causing mutations in as many genes and as many diseases as possible," Gunel said.

Single gene mutations cause thousands of diseases, about 3,000 of which are still unexplained. Individually, the diseases are fairly rare, but together affect some 25 million people in the U.S.

James Lupski, professor of molecular genetics at Baylor, said many of these diseases are more common in parts of the world where more children are born to parents who are related, which increases the risk of recessive genetic disorders.

This kind of work would have been nearly impossible just a few years ago, when it could take months and millions of dollars to map a human genome. Today, new technology can get the job done in days, and the next generation of machines promises to map an entire genome within 24 hours for $1,000. But there's still a matter of analyzing the data.

"It takes a couple of months to do analysis," said Shrikant Mane, who runs the Center for Genome Analysis at Yale. "It's one thing to generate the data, but then the rest of it is analysis."

The Yale researchers will make use of exome sequencing, a process developed at Yale that selectively sequences the region of the genome that contains genes that code for proteins.

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Unlocking The Mysteries Of Single Gene Mutations

Researchers find 5 novel gene mutations linked to platelet counts in African Americans

Public release date: 1-Mar-2012 [ | E-mail | Share ]

Contact: Stephanie Desmon sdesmon1@jhmi.edu 410-955-8665 Johns Hopkins Medical Institutions

Researchers, led by scientists from Johns Hopkins, have found five previously unknown gene mutations believed to be associated with elevated blood platelet counts in African-Americans, findings they say could someday lead to the development of new drugs to help prevent coronary artery disease.

The study is believed to be the first of its size to focus on platelet genetics in African Americans, who have a higher risk of stroke than other racial groups. They also have relatively higher platelet counts and average platelet volume, and worse outcomes than whites after a heart attack.

"Improving our understanding of the biology and genetics of platelets and how they function will aid us in developing better treatments and more individualized treatments to reduce risk of heart disease associated with platelets," says study leader Rehan Qayyum, M.D., an assistant professor in the division of general internal medicine at the Johns Hopkins University School of Medicine.

Qayyum cautions that there are believed to be many more genes involved in platelet function that remain unknown.

Platelets are cells produced in bone marrow, smaller than red or white blood cells, which foster blood clotting. While clotting is critical to stop bleeding after injuries, it can also cause harm by allowing clumps of blood cells to clog blood vessels leading to the heart, brain and other organs, cutting off blood flow.

Studies have shown that the greater the platelet volume or count in the blood, and the larger platelets are, the greater the risk of dangerous clot formation. Qayyum notes that the number of platelets in a given amount of blood (platelet count) and the size of these platelets (measured as average platelet count) vary from person to person in much the way that height, weight and eye color traits differ. Thus, he said, the search for genes that control this variation is a potentially fruitful line of scientific inquiry.

Qayyum and his colleagues, publishing in the online journal PLoS Genetics, report that they conducted a meta-analysis and genomewide association study, looking at genetic data from 16,000 African-American participants from seven separate studies. They compared information from each study, tracking 2.5 million single possible changes in the human genetic code to see which genes stood out across the entire group as significantly associated with increased or decreased platelet counts.

The researchers found five such alterations, involving the addition or deletion of a single piece of genetic code, across the studied genomes that had not been identified in other populations. When they checked their findings against data from Caucasian and Hispanic groups, they found three of the novel gene mutations in those populations, too. Four of the previously unknown gene mutations were later found in the genetic code of platelet cells, but one was not. That one, however, was found close to a gene that is known to be essential in the formation of normal platelets. The exact role played by each of these mutations still needs to be determined, Qayyum says.

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Researchers find 5 novel gene mutations linked to platelet counts in African Americans