Category Archives: Gene Medicine

TORONTO Twenty-five years ago this month, the medical world was turned on its ear with the isolation of the gene that causes cystic fibrosis, a devastating inherited disease that usually killed children by their late teens.

At the helm of the research was Lap-Chee Tsui, who led the team at Torontos Hospital for Sick Children that made the seminal discovery in collaboration with scientists at the University of Michigan.

The science of human genetics was still in its infancy at that time. Pinpointing the mutated CFTR gene came about through painstaking mapping of bits of DNA to locate the root of CF symptoms thick, sticky mucus that clogs the lungs and gums up the gastrointestinal tract, requiring patients to take scores of digestive enzymes a day so they could digest food.

The cystic fibrosis defect is really a very subtle defect, Tsui (pronounced Choy), 63, said Monday during an event at Sick Kids to mark the 1989 discovery. It didnt kill the patients (right away), but the problems accumulated slowly, and at the end the patients succumbed to infection.

Using the same analogy as he used in 1989 to explain CFTRs location on chromosome 7, Tsui said researchers first narrowed it down to somewhere between Halifax and Vancouver, then further pinpointed it in Toronto, and finally zeroed in to a certain street and then the actual house that represented the defective gene.

In the ensuing years, researchers have determined there is not only one mutation in the CF gene, but about 1,900 different defects that cause greater or lesser severity of symptoms in individual patients a scientific process Tsui likened to going into the house and turning on all the lights and taps to see which ones are faulty.

The celebrated geneticist, who left Toronto 12 years ago to become vice-chancellor and president of the University of Hong Kong, from which he just retired, called progress in understanding and treating CF since the gene was isolated very exciting.

Within two years of that discovery, other Sick Kids researchers had determined that a protein that keeps epithelial cells lining the lungs, airways and digestive system nice and moist was faulty, causing the buildup of mucus that clogs the lungs and disables the digestive system.

I think the expectation when the gene was first discovered was that it would be easy to fix because the disease was caused by a single gene, and if you replaced that gene through gene therapy, then you would be able to completely reverse the consequences of the disease, said senior scientist Christine Bear, who led that team.

And it may be that gene therapy will be part of that future therapy in CF, but right now we havent developed safe ways to do that.

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Canadian researchers mark 25 years since CF gene found

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Newswise PHILADELPHIA The University of Pennsylvania today reached an important milestone in its alliance with Novartis as it unveiled plans for the construction of a first-of-its-kind Center for Advanced Cellular Therapeutics (CACT) on the Penn Medicine campus in Philadelphia. The CACT will become the epicenter for research using Chimeric Antigen Receptor technology (CAR), which enables a patients T cells to be reprogrammed outside of the body so when they are re-infused into the patient, the T cells have the ability to hunt and destroy the cancer cells. Clinical trials using this approach have made headlines around the world.

Plans for the 30,000-square foot facility cement the Penn-Novartis alliance, a marquee component of Penn's efforts in translational sciences that expedite the development of novel therapies for diseases of all kinds. The collaboration was announced in August 2012, when the two organizations entered an exclusive global research and licensing agreement to further study and commercialize novel CAR therapies.

The CACT, which will be funded in part through a $20 million investment from Novartis, will be devoted to the discovery, development and manufacturing of these personalized cellular cancer therapies, through a joint research and development program led by scientists and clinicians from Penn and Novartis.

The past five years have been a time of explosive, exciting progress in the field of cancer cellular therapy, said Carl H. June, MD, the Richard W. Vague Professor of Immunotherapy in the department of Pathology and Laboratory Medicine in the Perelman School of Medicine and director of Translational Research in Penns Abramson Cancer Center. The results weve seen among the leukemia patients weve treated using our hunter cells have accelerated our expectations for the potential of these new therapies. Today, many of those brave patients are thriving, and through our work in the CACT, we hope to offer that chance to patients with many other types of cancers.

The CACT will be constructed as part of the master building plan for the rear of the Perelman Center for Advanced Medicine on Penn Medicines University City campus, atop of the 8-story Jordan Medical Education Center and South Pavilion Extension, which are currently under construction. The Center for Advanced Cellular Therapeutics will adjoin the existing cancer therapeutics floor in the Smilow Center for Translational Research, allowing it to be fully integrated with Penn Medicines research and clinical operations. The Center is expected to employ 100 highly specialized professionals in this burgeoning biomedical field.

The new facility, slated for completion in 2016, will house technologically advanced rooms where patients own immune cells will be reprogramed to fight tumors, roughly doubling Penns capacity to investigate new uses for this cellular therapy technology and treat patients in clinical trials for a broad range of cancers. Functions of the space will include vaccine development, assay development and correlative studies of blood and other biospecimens to examine how trial participants respond to the therapies they receive.

We are fortunate to live in an era when fundamental discovery rapidly can become a therapeutic. Harnessing of the bodys immune system to treat cancers, as so dramatically shown with CAR T cell therapies, is the culmination of years of dedicated research, said Mark Fishman, President of the Novartis Institutes for Biomedical Research. The number of opportunities to treat heretofore lethal diseases now is legion. This new joint center is testimony to the power that comes from merging academic discovery directly to the generation of new medicines.

In July 2014, the U.S. Food and Drug Administration awarded its Breakthrough Therapy designation to the Penn-developed CTL019, an investigational CAR therapy for the treatment of relapsed and refractory adult and pediatric acute lymphoblastic leukemia (ALL). The designation followed new results presented during the American Society of Hematologys annual meeting in December 2013, when Junes team announced data from a study of nearly 60 patients with advanced blood cancers that had stopped responding to conventional treatments. The researchers reported that the reprogrammed hunter cells produced durable remissions, persisting in patients' bodies for more than three years in patients who had relapsed/refractory chronic lymphocytic leukemia. Among children and adults with relapsed/refractory acute lymphoblastic leukemia a fast-moving blood cancer that is especially deadly among patients who relapse after undergoing first-line therapies 89 percent of trial participants cancers were put into remission within just a few weeks of receiving the new cells.

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Center for Advanced Cellular Therapeutics to Rise on Penn Medicine Campus

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Newswise PHILADELPHIA - Hoping to encourage sufficient investments by pharmaceutical companies in expensive gene therapies, which often consist of a single treatment, a Penn researcher and the chief medical officer of CVS Health outline an alternative payment model in this months issue of Nature Biotechnology. They suggest annuity payments over a defined period of time and contingent on evidence that the treatment remains effective. The approach would replace the current practice of single, usually large, at-point-of-service payments.

Unlike most rare disease treatments that can continue for decades, gene therapy is frequently administered only once, providing many years, even a lifetime, of benefit, says James M. Wilson, MD, PhD, professor of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania. Under current reimbursement policies, private insurers and the government typically pay for this therapy once: when it is administered. But these individual payments could reach several million dollars each under current market conditions. Were proposing a different approach that spreads payments out and only keep coming if the patient continues to do well.

Wilson and co-author Troyen A. Brennan, MD, JD, MPH, chief medical officer of CVS Health, note that while large single payments for gene therapy may be the simplest approach, they carry substantial encumbrances. For example, approval of gene therapy treatments is unavoidably based on data derived from trials carried out over several years at most -- considerably shorter than the expected duration of the therapy. Payers may therefore be unwilling to pay large up-front sums for treatments whose long-term benefit has not been established. Additionally, large payments for medications, such as the $84,000-a-patient cost of the hepatitis C treatment Sovaldi, have been criticized in the prevailing climate of curbing health care costs. This, despite the fact that effective gene therapy may reduce the overall financial burden to the health care system.

Wilson and Brennan further note that while a liver transplant, for example, can cost up to $300,000, physicians and hospitals that transplant livers know they will be compensated at market rates through existing contracts -- gene developers lack that assurance. Annuity payments, they say, could help address these problems.

An example of an annuity-type disbursement could be a hypothetical payment of $150,000 per year for a certain number of years for gene-therapy-based protein replacement for patients with hemophilia B -- so long as the therapy continues to work. According to the authors, the cumulative amount should be less than the cost of a one-time payment of $4-6 million, which would be the expected rate for a gene-based therapy to be comparatively priced to existing, conventional therapies for hemophilia B. One would presume, they write, that gene therapy will have to represent a discount in order for insurers to approve its use.

The annuity model that were proposing would eliminate the misguided incentive to invest in drugs and treatments with ongoing revenue streams but which require continuing, perhaps lifetime daily administration, with all the attendant inconveniences and burdens to patients and their families, as well as direct and indirect costs to the nations health system, says Wilson.

The authors point out that gene therapy differs substantially from the case of orphan drugs. Development of the latter, which target rare diseases affecting small patient populations, is supported by the Orphan Drug Act of 1983, which provides pharmaceutical manufacturers with grants, tax credits, and an extended period of market exclusivity for their medications. Whats more, in virtually all of these cases, the business costs of developing the drugs are further attenuated by ongoing administration of -- and payment for -- the medication over the lifetime of the patient. The contrast with gene therapy, especially that which produces a durable cure with one administration, the authors write, is clear.

Adding further details to their proposal, the authors write that The original annuity payment could be set with certain types of re-opener clauses, such as with patent expiration [death], or if a less expensive new therapy came on line -- thus subjecting the gene therapy annuity to the same vagaries of market competition that standard pharmaceuticals face.

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Penn Researcher and CVS Health Physician Urge New Payment Model for Costly Gene Therapy Treatments

Hoping to encourage sufficient investments by pharmaceutical companies in expensive gene therapies, which often consist of a single treatment, a Penn researcher and the chief medical officer of CVS Health outline an alternative payment model in this month's issue of Nature Biotechnology. They suggest annuity payments over a defined period of time and contingent on evidence that the treatment remains effective. The approach would replace the current practice of single, usually large, at-point-of-service payments.

"Unlike most rare disease treatments that can continue for decades, gene therapy is frequently administered only once, providing many years, even a lifetime, of benefit," says James M. Wilson, MD, PhD, professor of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania. "Under current reimbursement policies, private insurers and the government typically pay for this therapy once: when it is administered. But these individual payments could reach several million dollars each under current market conditions. We're proposing a different approach that spreads payments out and only keep coming if the patient continues to do well."

Wilson and co-author Troyen A. Brennan, MD, JD, MPH, chief medical officer of CVS Health, note that while large single payments for gene therapy may be the simplest approach, they carry substantial encumbrances. For example, approval of gene therapy treatments is unavoidably based on data derived from trials carried out over several years at most -- considerably shorter than the expected duration of the therapy. Payers may therefore be unwilling to pay large up-front sums for treatments whose long-term benefit has not been established. Additionally, large payments for medications, such as the $84,000-a-patient cost of the hepatitis C treatment Sovaldi, have been criticized in the prevailing climate of curbing health care costs. This, despite the fact that effective gene therapy may reduce the overall financial burden to the health care system.

Wilson and Brennan further note that while a liver transplant, for example, can cost up to $300,000, physicians and hospitals that "transplant livers know they will be compensated at market rates through existing contracts -- gene developers lack that assurance." Annuity payments, they say, could help address these problems.

An example of an annuity-type disbursement could be a hypothetical payment of $150,000 per year for a certain number of years for gene-therapy-based protein replacement for patients with hemophilia B -- so long as the therapy continues to work. According to the authors, the cumulative amount should be less than the cost of a one-time payment of $4-6 million, which would be the expected rate for a gene-based therapy to be comparatively priced to existing, conventional therapies for hemophilia B. "One would presume," they write, "that gene therapy will have to represent a discount in order for insurers to approve its use."

"The annuity model that we're proposing would eliminate the misguided incentive to invest in drugs and treatments with ongoing revenue streams but which require continuing, perhaps lifetime daily administration, with all the attendant inconveniences and burdens to patients and their families, as well as direct and indirect costs to the nation's health system," says Wilson.

The authors point out that gene therapy differs substantially from the case of "orphan" drugs. Development of the latter, which target rare diseases affecting small patient populations, is supported by the Orphan Drug Act of 1983, which provides pharmaceutical manufacturers with grants, tax credits, and an extended period of market exclusivity for their medications. What's more, in virtually all of these cases, the business costs of developing the drugs are further attenuated by ongoing administration of -- and payment for -- the medication over the lifetime of the patient. "The contrast with gene therapy, especially that which produces a durable cure with one administration," the authors write, "is clear."

Adding further details to their proposal, the authors write that "The original annuity payment could be set with certain types of 're-opener' clauses, such as with patent expiration [death], or if a less expensive new therapy came on line -- thus subjecting the gene therapy annuity to the same vagaries of market competition that standard pharmaceuticals face."

A crucial issue would be the calculation of the annual annuity payment. One option would be for the government to set the price through the Medicare program, since many of the patients with rare diseases are disabled and thus qualify for Medicare. The Medicare rate could in turn become a benchmark for the commercial market.

Another key test in developing an annuity model is determining the correct linkage between payments and the therapy's continued effectiveness and safety. In most diseases, this would entail identifying a biomarker reasonably correlated with efficacy, for example, plasma measures of clotting in hemophilia patients treated with gene therapy.

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New payment model for gene therapy needed, experts say

PUBLIC RELEASE DATE:

9-Sep-2014

Contact: Karen Kreeger karen.kreeger@uphs.upenn.edu 215-349-5658 University of Pennsylvania School of Medicine http://www.twitter.com/PennMedNews

PHILADELPHIA - Hoping to encourage sufficient investments by pharmaceutical companies in expensive gene therapies, which often consist of a single treatment, a Penn researcher and the chief medical officer of CVS Health outline an alternative payment model in this month's issue of Nature Biotechnology. They suggest annuity payments over a defined period of time and contingent on evidence that the treatment remains effective. The approach would replace the current practice of single, usually large, at-point-of-service payments.

"Unlike most rare disease treatments that can continue for decades, gene therapy is frequently administered only once, providing many years, even a lifetime, of benefit," says James M. Wilson, MD, PhD, professor of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania. "Under current reimbursement policies, private insurers and the government typically pay for this therapy once: when it is administered. But these individual payments could reach several million dollars each under current market conditions. We're proposing a different approach that spreads payments out and only keep coming if the patient continues to do well."

Wilson and co-author Troyen A. Brennan, MD, JD, MPH, chief medical officer of CVS Health, note that while large single payments for gene therapy may be the simplest approach, they carry substantial encumbrances. For example, approval of gene therapy treatments is unavoidably based on data derived from trials carried out over several years at most -- considerably shorter than the expected duration of the therapy. Payers may therefore be unwilling to pay large up-front sums for treatments whose long-term benefit has not been established. Additionally, large payments for medications, such as the $84,000-a-patient cost of the hepatitis C treatment Sovaldi, have been criticized in the prevailing climate of curbing health care costs. This, despite the fact that effective gene therapy may reduce the overall financial burden to the health care system.

Wilson and Brennan further note that while a liver transplant, for example, can cost up to $300,000, physicians and hospitals that "transplant livers know they will be compensated at market rates through existing contracts -- gene developers lack that assurance." Annuity payments, they say, could help address these problems.

An example of an annuity-type disbursement could be a hypothetical payment of $150,000 per year for a certain number of years for gene-therapy-based protein replacement for patients with hemophilia B -- so long as the therapy continues to work. According to the authors, the cumulative amount should be less than the cost of a one-time payment of $4-6 million, which would be the expected rate for a gene-based therapy to be comparatively priced to existing, conventional therapies for hemophilia B. "One would presume," they write, "that gene therapy will have to represent a discount in order for insurers to approve its use."

"The annuity model that we're proposing would eliminate the misguided incentive to invest in drugs and treatments with ongoing revenue streams but which require continuing, perhaps lifetime daily administration, with all the attendant inconveniences and burdens to patients and their families, as well as direct and indirect costs to the nation's health system," says Wilson.

The authors point out that gene therapy differs substantially from the case of "orphan" drugs. Development of the latter, which target rare diseases affecting small patient populations, is supported by the Orphan Drug Act of 1983, which provides pharmaceutical manufacturers with grants, tax credits, and an extended period of market exclusivity for their medications. What's more, in virtually all of these cases, the business costs of developing the drugs are further attenuated by ongoing administration of -- and payment for -- the medication over the lifetime of the patient. "The contrast with gene therapy, especially that which produces a durable cure with one administration," the authors write, "is clear."

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Penn researcher and CVS Health physician urge new payment model for gene therapy

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Newswise New York, NYSeptember 9, 2014Led by Itsik Peer, associate professor of computer science at Columbia Engineering, a team of researchers has created a data resource that will improve genomic research in the Ashkenazi Jewish population and lead to more effective personalized medicine. The team, which includes experts from 11 labs in the New York City area and Israel, focused on the Ashkenazi Jewish population because of its demographic history of genetic isolation and the resulting abundance of population-specific mutations and high prevalence of rare genetic disorders. The Ashkenazi Jewish population has played an important role in human genetics, with notable successes in gene mapping as well as prenatal and cancer screening. The study was published online on Nature Communications today.

Our study is the first full DNA sequence dataset available for Ashkenazi Jewish genomes, says Peer, who is also a co-chair of the Health Analytics Center at Columbias Institute for Data Sciences and Engineering, as well as a member of its Foundations of Data Science Center. With this comprehensive catalog of mutations present in the Ashkenazi Jewish population, we will be able to more effectively map disease genes onto the genome and thus gain a better understanding of common disorders. We see this study serving as a vehicle for personalized medicine and a model for researchers working with other populations.

To help in his hunt for disease genes, Peer founded The Ashkenazi Genome Consortium (TAGC) in September 2011 with Todd Lencz, an investigator at The Feinstein Institute for Medical Research, director of the Laboratory of Analytic Genomics at the Zucker Hillside Hospital, and associate professor of molecular medicine and psychiatry at the Hofstra North Shore-LIJ School of Medicine. The other TAGC members, who are providing expertise in the diseases they are studying, are: Gil Atzmon, associate professor of medicine and genetics, Albert Einstein College of Medicine (genetics of longevity and diabetes); Lorraine Clark, associate professor of clinical pathology and cell biology and co-director, Personalized Genomic Medicine Laboratory, Columbia University Medical Center, Laurie Ozelius, associate professor at Icahn School of Medicine at Mount Sinai, and Susan Bressman, chair of neurology at Mount Sinai Beth Israel (Parkinsons disease and related neurological phenotypes); Harry Ostrer, professor of pathology, genetics, and pediatrics, Albert Einstein College of Medicine (radiogenomics, cancers and rare genetic disorders); Ken Offit, chief of clinical genetics at Memorial Sloan Kettering Cancer Center (breast, ovarian, colon and prostate cancers, lymphoma); Inga Peter, associate professor of genetics and genomic sciences, and Judy Cho, professor of medicine and professor of genetics and genomic sciences, both at The Mount Sinai Hospital(inflammatory bowel disease); and Ariel Darvasi, vice-dean of The Faculty of Life Sciences at The Hebrew University of Jerusalem (multiple diseases).

Before the TAGC study, data was available for a limited number of DNA markers (only approximately one in every 3000 letters of DNA) that are mostly common in Europeans. The TAGC researchers performed high-depth sequencing of 128 complete genomes of Ashkenazi Jewish healthy individuals. They compared their data to European samples, and found that Ashkenazi Jewish genomes had significantly more mutations that had not yet been mapped. Peer and his team analyzed the raw data and created a comprehensive catalog of mutations present in the Ashkenazi Jewish population.

The TAGC database is already proving useful for clinical genomics, identifying specific new mutations for carrier screening. Lencz explains: TAGC advances the goal of bringing personal genomics to the clinic, as it tells the physician whether a mutation in a patients genome is shared by healthy individuals, and can alleviate concerns that it is causing disease. Without our work, a patients genome sequence is much harder to interpret, and more prone to create false alarms. We have eliminated two thirds of these false alarms.

The TAGC study further enables more effective discovery of disease-causing mutations, since some genetic factors are observable in Ashkenazi individuals but essentially absent elsewhere. Moreover, the demography of the Ashkenazi population, the largest isolated population in the U.S., enables large-scale recruitment of study patients and hence more genetic discoveries than in other well-known isolated populations like the Amish and Hutterites locally, or the Icelanders overseas. The researchers expect that medical insights from studies of specific populations will also be relevant to general populations as well.

The TAGC teams findings also shed light on the long-debated origin of Ashkenazi Jews and Europeans. The genetic data indicates that the Ashkenazi Jewish population was founded in the late medieval times by a small number, effectively only hundreds of individuals, whose descendants expanded rapidly while remaining mostly isolated genetically.

Our analysis shows that Ashkenazi Jewish medieval founders were ethnically admixed, with origins in Europe and in the Middle East, roughly in equal parts, says Shai Carmi, a post-doctoral scientist who works with Peer and who conducted the analysis. TAGC data are more comprehensive than what was previously available, and we believe the data settle the dispute regarding European and Middle Eastern ancestry in Ashkenazi Jews. In addition to illuminating medieval Jewish history, our results further pave the way to better understanding European origins, millennia before. For example, our data provides evidence for todays European population being genetically descendant primarily from late mid-eastern migrations that took place after the last ice age, rather than from the first humans to arrive to the continent, more than 40,000 years ago.

Originally posted here:
Mapping the DNA Sequence of Ashkenazi Jews

Researchers from the UNC School of Medicine have discovered that the protein RBM4, a molecule crucial to the process of gene splicing, is drastically decreased in multiple forms of human cancer, including lung and breast cancers. The finding, published today in the journal Cancer Cell, offers a new route toward therapies that can thwart the altered genetic pathways that allow cancer cells to proliferate and spread.

"Historically, scientists haven't targeted the proteins in cancer cells that are involved in gene splicing," said Zefeng Wang, PhD, associate professor in the department of pharmacology and senior author of the Cancer Cell paper. "This is a whole new ballgame in terms of gene regulation in cancer."

There are approximately 25,000 genes in the human genome -- the same amount as in a fruit fly. But in humans, these genes are spliced together in different ways to create various kinds of messenger RNA to produce the many different proteins humans require. It's like a filmmaker splicing together bits of movie scenes to create alternative cuts of a movie. In genetics, this process is called alternative splicing.

Wang's lab found that RBM4 is an important film editor.

Wang, a member of the UNC Lineberger Comprehensive Cancer Center, studies how alternative splicing happens in normal cells and in cancer cells. Through a series of biochemical experiments and high-throughput screening methods, his team identified about 20 proteins that are involved in regulating alternative splicing. Then his team conducted further experiments to pinpoint changes in the activity of these proteins in various kinds of human cancer cells and in mouse models. Such "misregulated" protein expression would provide evidence that the proteins are involved in cancer development or metastasis.

Wang found that the protein RBM4 was decreased, as compared with normal tissue. In lung and breast cancer patients, RBM4 was drastically "down regulated."

"In normal cells, RBM4 inhibits alternative splicing," Wang says. "It makes genes splice from a long form into a short form. For one of the genes we study, which is called Bcl-x, we want the short form because it has anti-cancer properties."

When RBM4 is low, the longer form of Bcl-x is produced, which plays a role in promoting cancer development and metastasis. "In mouse models, we showed that activating RBM4 can reverse cancer progression," Wang said.

Wang's group also found that RBM4 played a role in controlling another splicing regulator called SRSF1, which is highly expressed in some cancer cells. "What's interesting is that RBM4 actually inhibits the expression of SRSF1 and therefore controls the splicing of many SRSF1 targets in an opposite fashion. This again showed us why RBM4 has activity as a tumor suppressor.

Wang said that RBM4 is needed in the proper amount so that these genes are spliced properly and don't contribute to cancer development and metastasis. This means that the level of RBM4 in cancer patients can actually be used to predict their chances of survival.

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New genetic target for a different kind of cancer drug found

PUBLIC RELEASE DATE:

8-Sep-2014

Contact: Mark Derewicz mark.derewicz@unchealth.unc.edu 919-923-0959 University of North Carolina Health Care http://www.twitter.com/UNC_Health_Care

CHAPEL HILL, NC Researchers from the UNC School of Medicine have discovered that the protein RBM4, a molecule crucial to the process of gene splicing, is drastically decreased in multiple forms of human cancer, including lung and breast cancers. The finding, published today in the journal Cancer Cell, offers a new route toward therapies that can thwart the altered genetic pathways that allow cancer cells to proliferate and spread.

"Historically, scientists haven't targeted the proteins in cancer cells that are involved in gene splicing," said Zefeng Wang, PhD, associate professor in the department of pharmacology and senior author of the Cancer Cell paper. "This is a whole new ballgame in terms of gene regulation in cancer."

There are approximately 25,000 genes in the human genome the same amount as in a fruit fly. But in humans, these genes are spliced together in different ways to create various kinds of messenger RNA to produce the many different proteins humans require. It's like a filmmaker splicing together bits of movie scenes to create alternative cuts of a movie. In genetics, this process is called alternative splicing.

Wang's lab found that RBM4 is an important film editor.

Wang, a member of the UNC Lineberger Comprehensive Cancer Center, studies how alternative splicing happens in normal cells and in cancer cells. Through a series of biochemical experiments and high-throughput screening methods, his team identified about 20 proteins that are involved in regulating alternative splicing. Then his team conducted further experiments to pinpoint changes in the activity of these proteins in various kinds of human cancer cells and in mouse models. Such "misregulated" protein expression would provide evidence that the proteins are involved in cancer development or metastasis.

Wang found that the protein RBM4 was decreased, as compared with normal tissue. In lung and breast cancer patients, RBM4 was drastically "down regulated."

"In normal cells, RBM4 inhibits alternative splicing," Wang says. "It makes genes splice from a long form into a short form. For one of the genes we study, which is called Bcl-x, we want the short form because it has anti-cancer properties."

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UNC researchers find new genetic target for a different kind of cancer drug

COLUMBUS, Ohio - Cancer research goes beyond medicine at The Ohio State University's James Cancer Hospital.

Doctors conduct genetic testing at Ohio State, unraveling the genetic code of a specific cancer.

"The idea is can we identify what these cancers are, what's wrong with these cancers, and what's the right therapy for them?" said Dr. Sameek Roychowdhury.

Roychowdhury leads the precision cancer medicine program at the James. The focus of the program is just that precision.

Doctors have been analyzing tumors for years, but now it's so specific down to the genetic mutation.

"So if we saw 100 patients with breast cancer, we could literally find 100 different types of breast cancer," Roychowdhury said.

Getting to the genetic heart of the cancer, knowing what drives it and makes it grow and spread, is the key to finding the cancer, stopping it, and saving lives.

"It's going to be much more focusedon the exact gene that's disruptive," Roychowdhury said.

For example, Jared Gordon was diagnosed with stage four lung cancer at age 51.

The father of three was told that he had six months to live.

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Ohio State Gene Testing Could Unlock Key To Curing Cancer

Researchers at UT Southwestern Medical Center and the Gill Center for Cancer and Blood Disorders at Children's Medical Center, Dallas, have made significant progress in defining new genetic causes of Wilms tumor, a type of kidney cancer found only in children.

Wilms tumor is the most common childhood genitourinary tract cancer and the third most common solid tumor of childhood.

"While most children with Wilms tumor are thankfully cured, those with more aggressive tumors do poorly, and we are increasingly concerned about the long-term adverse side effects of chemotherapy in Wilms tumor patients. We wanted to know -- what are the genetic causes of Wilms tumor in children and what are the opportunities for targeted therapies? To answer these questions, you have to identify genes that are mutated in the cancer," said Dr. James Amatruda, Associate Professor of Pediatrics, Molecular Biology, and Internal Medicine at UT Southwestern and senior author for the study.

The new findings appear in Nature Communications. Collaborating with Dr. Amatruda on the study were UT Southwestern faculty members Dr. Dinesh Rakheja, Associate Professor of Pathology and Pediatrics; Dr. Kenneth S. Chen, Assistant Instructor in Pediatrics; and Dr. Joshua T. Mendell, Professor of Molecular Biology. Dr. Jonathan Wickiser, Associate Professor in Pediatrics, and Dr. James Malter, Chair of Pathology, are also co-authors.

Previous research has identified one or two mutant genes in Wilms tumors, but only about one-third of Wilms tumors had these mutations.

"We wanted to know what genes were mutated in the other two-thirds. To accomplish this goal, we sequenced the DNA of 44 tumors and identified several new mutated genes," said Dr. Amatruda, who holds the Nearburg Family Professorship in Pediatric Oncology Research and is an Attending Physician in the Pauline Allen Gill Center for Cancer and Blood Disorders at Children's Medical Center. "The new genes had not been identified before. The most common, and in some ways the most biologically interesting, mutations were found in genes called DROSHA and DICER1. We found that these mutations affected the cell's production of microRNAs, which are tiny RNA molecules that play big roles in controlling the growth of cells, and the primary effect was on a family of microRNAs called let-7."

"Let-7 is an important microRNA that slows cell growth and in Wilms tumors in which DROSHA or DICER1 were mutated, let-7 RNA is missing, which causes the cells to grow abnormally fast," Dr. Amatruda said.

These findings have implications for future treatment of Wilms tumor and several other childhood cancers, including neuroblastoma, germ cell tumor, and rhabdomyosarcoma.

"What's exciting about these results is that we can begin to understand what drives the growth of different types of Wilms tumors. This is a critical first step in trying to treat the cancer based on its true molecular defect, rather than just what a tumor looks like under a microscope," Dr. Amatruda said. "Most importantly, we begin to think in concrete terms about a therapy, which is an exciting translational goal of our work in the next few years. This study also is a gratifying example of great teamwork. As oncologists, Dr. Chen and I were able to make rapid progress by teaming up with Dr. Rakheja, an expert pathologist, and with Dr. Mendell, a leading expert on microRNA biology."

According to the American Cancer Society, an estimated 510 cases of Wilms tumor will be diagnosed among children in 2014. Also called nephroblastoma, Wilms tumor is an embryonal tumor of the kidney that usually occurs in children under age 5, and 92 percent of kidney tumors in this age group are Wilms tumor. Survival rates for Wilms tumor have increased from 75 percent in 1975-1979 to 90 percent in 2003-2009.

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New gene mutations for Wilms tumor found