Category Archives: Gene Medicine

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Translational Regenerative Medicine: Market Prospects 2015-2025

CHOP study of common variable immunodeficiency finds gene crucial to immune defense

IMAGE:Dr. Hakon Hakonarson is the director of the Center for Applied Genomics of The Children's Hospital of Philadelphia. view more

Credit: The Children's Hospital of Philadelphia

Genomics researchers analyzing a rare, serious immunodeficiency disease in children have discovered links to a gene crucial to the body's defense against infections. The finding may represent an inviting target for drugs to treat common variable immunodeficiency (CVID).

A team led by Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children's Hospital of Philadelphia (CHOP), reported their findings online Feb. 10 in the Journal of Allergy and Clinical Immunology.

The researchers found 11 single nucleotide polymorphisms (SNPs) on the 16p11.2 locus of chromosome 16. SNPs are changes in one letter of DNA, compared to the more typical sequence at a given location. Of particular interest, the study team found variants in the gene ITGAM, carrying codes for an integrin protein, which regulates cellular contact and adhesion.

"This association is of high biological relevance, because ITGAM plays an important role in normal immune responses," said Hakonarson. "Other researchers have shown that mice in which this gene has been knocked out have immune deficiencies." He added that his team's findings may have broader implications for patients who do not have these specific rare variants, because the integrin protein affects many important pathways in immune function.

A child with CVID has a low level of antibodies, reducing the body's ability to fight disease, and leaving the child vulnerable to recurrent infections. CVID can first occur early or later in life, and the symptoms are highly variable. Frequent respiratory infections may lead to permanent lung damage. Patients may also suffer joint inflammation, stomach and bowel disorders, and a higher risk of cancers.

The great variability of the disease and the lack of a clear-cut diagnostic test often mean that CVID goes undiagnosed for years before doctors can begin treatment.

The study team performed an association analysis that focused on immune-related genes in a cohort of 360 CVID patients and 21,610 healthy controls. They used a genotyping chip specialized to search for gene variants previously implicated in autoimmune and inflammatory diseases, to pinpoint SNPs associated with CVID.

Read more from the original source:
Novel gene variants found in a difficult childhood immune disorder

Cancer researchers at Indiana University report that about 15 percent of people with pancreatic cancer may benefit from therapy targeting a newly identified gene signature.

Using data from the Cancer Genome Atlas, Murray Korc, M.D., the Myles Brand Professor of Cancer Research at the Indiana University School of Medicine and a researcher at the Indiana University Melvin and Bren Simon Cancer Center, and colleagues found that a sub-group of pancreatic cancer patients who possess a strong angiogenic gene signature could benefit from personalized therapies that cut off the pathways that feed the cancer's growth.

This particular gene signature enables abnormal blood vessels to form in tumors, which feeds the tumor's growth.

The finding, published online Feb. 25 in the journal Oncotarget, is new because the prevalence of this signature was not previously known. The authors also demonstrated for the first time that endothelial cells, the main type of cell found in the inside lining of blood vessels, can produce molecules that directly stimulate the growth of pancreatic cancer cells.

"We showed that endothelial cells can stimulate the growth of pancreatic cancer cells and that by silencing or inhibiting certain pathways -- JAK1-2 and STAT3 -- we can alter that effect," Dr. Korc explained. "We demonstrated that it is possible to target these pathways and prolong the survival of genetically modified mice whose pancreatic cancers also have a strong pro-angiogenic gene signature."

Thus, for people with a strong pro-angiogenic gene signature, the finding suggests that they may benefit from targeted therapy that is directed against one of these pathways.

An important feature of the study was to demonstrate that it is possible to implant in mice small biopsy samples obtained from patients undergoing endoscopic procedures and to generate human tumors in these mice. When the original human tumor had evidence for angiogenesis, the implanted human tumor also exhibited angiogenesis in the mouse. Additional studies are necessary to confirm that these approaches could guide the design of precision medicine using targeted therapies, Dr. Korc said.

The need for new therapies for pancreatic cancer patients is great as only 7 percent of people with the disease survive more than five years after diagnosis. According to the American Cancer Society, there will be an estimated 48,960 new cases of pancreatic cancer and 40,560 deaths from the disease in 2015.

Co-authors of the study were Jesse Gore, Ph.D.; Stuart Sherman, M.D.; Harvey Cramer, M.D.; Hai Nguyen, M.D.; Kelly Craven, Monica Cheng, and Julie Wilson, all of IU School of Medicine, and Gregory Cote M.D. M.S., formerly of IU School of Medicine and now at the Medical University of South Carolina.

The study was made possible, in part, by grant CA-075059 awarded by the National Cancer Institute of the National Institutes of Health.

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Pancreatic cancer patients who benefit from personalized treatment identified

Genomics researchers analyzing a rare, serious immunodeficiency disease in children have discovered links to a gene crucial to the body's defense against infections. The finding may represent an inviting target for drugs to treat common variable immunodeficiency (CVID).

A team led by Hakon Hakonarson, M.D., Ph.D., director of the Center for Applied Genomics at The Children's Hospital of Philadelphia (CHOP), reported their findings online Feb. 10 in the Journal of Allergy and Clinical Immunology.

The researchers found 11 single nucleotide polymorphisms (SNPs) on the 16p11.2 locus of chromosome 16. SNPs are changes in one letter of DNA, compared to the more typical sequence at a given location. Of particular interest, the study team found variants in the gene ITGAM, carrying codes for an integrin protein, which regulates cellular contact and adhesion.

"This association is of high biological relevance, because ITGAM plays an important role in normal immune responses," said Hakonarson. "Other researchers have shown that mice in which this gene has been knocked out have immune deficiencies." He added that his team's findings may have broader implications for patients who do not have these specific rare variants, because the integrin protein affects many important pathways in immune function.

A child with CVID has a low level of antibodies, reducing the body's ability to fight disease, and leaving the child vulnerable to recurrent infections. CVID can first occur early or later in life, and the symptoms are highly variable. Frequent respiratory infections may lead to permanent lung damage. Patients may also suffer joint inflammation, stomach and bowel disorders, and a higher risk of cancers.

The great variability of the disease and the lack of a clear-cut diagnostic test often mean that CVID goes undiagnosed for years before doctors can begin treatment.

The study team performed an association analysis that focused on immune-related genes in a cohort of 360 CVID patients and 21,610 healthy controls. They used a genotyping chip specialized to search for gene variants previously implicated in autoimmune and inflammatory diseases, to pinpoint SNPs associated with CVID.

"Our studies identified ITGAM as an exciting candidate gene for further research," said Hakonarson. "Better understanding of its functional role may reveal opportunities for highly targeted therapies that could improve future treatment for patients with this challenging, complicated disease. This discovery fits well with the 'precision medicine' concept that is currently in its infancy but represents the future of genomic medicine."

Story Source:

The above story is based on materials provided by Children's Hospital of Philadelphia. Note: Materials may be edited for content and length.

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Novel gene variants discovered in a difficult childhood immune disorder

INDIANAPOLIS - Cancer researchers at Indiana University report that about 15 percent of people with pancreatic cancer may benefit from therapy targeting a newly identified gene signature.

Using data from the Cancer Genome Atlas, Murray Korc, M.D., the Myles Brand Professor of Cancer Research at the Indiana University School of Medicine and a researcher at the Indiana University Melvin and Bren Simon Cancer Center, and colleagues found that a sub-group of pancreatic cancer patients who possess a strong angiogenic gene signature could benefit from personalized therapies that cut off the pathways that feed the cancer's growth.

This particular gene signature enables abnormal blood vessels to form in tumors, which feeds the tumor's growth.

The finding, published online Feb. 25 in the journal Oncotarget, is new because the prevalence of this signature was not previously known. The authors also demonstrated for the first time that endothelial cells, the main type of cell found in the inside lining of blood vessels, can produce molecules that directly stimulate the growth of pancreatic cancer cells.

"We showed that endothelial cells can stimulate the growth of pancreatic cancer cells and that by silencing or inhibiting certain pathways - JAK1-2 and STAT3 - we can alter that effect," Dr. Korc explained. "We demonstrated that it is possible to target these pathways and prolong the survival of genetically modified mice whose pancreatic cancers also have a strong pro-angiogenic gene signature."

Thus, for people with a strong pro-angiogenic gene signature, the finding suggests that they may benefit from targeted therapy that is directed against one of these pathways.

An important feature of the study was to demonstrate that it is possible to implant in mice small biopsy samples obtained from patients undergoing endoscopic procedures and to generate human tumors in these mice. When the original human tumor had evidence for angiogenesis, the implanted human tumor also exhibited angiogenesis in the mouse. Additional studies are necessary to confirm that these approaches could guide the design of precision medicine using targeted therapies, Dr. Korc said.

The need for new therapies for pancreatic cancer patients is great as only 7 percent of people with the disease survive more than five years after diagnosis. According to the American Cancer Society, there will be an estimated 48,960 new cases of pancreatic cancer and 40,560 deaths from the disease in 2015.

###

Co-authors of the study were Jesse Gore, Ph.D.; Stuart Sherman, M.D.; Harvey Cramer, M.D.; Hai Nguyen, M.D.; Kelly Craven, Monica Cheng, and Julie Wilson, all of IU School of Medicine, and Gregory Cote M.D. M.S., formerly of IU School of Medicine and now at the Medical University of South Carolina.

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IU researchers identify pancreatic cancer patients who benefit from personalized treatment

Children with acute lymphoblastic leukemia who had a certain gene variant experienced a higher incidence and severity of peripheral neuropathy after receiving treatment with the cancer drug vincristine, according to a study in the February 24 issue of JAMA.

Cancer remains the leading cause of death by disease in U.S. children despite major advances in the last 20 years. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and as cure rates have surpassed 85 percent, it becomes increasingly important to lessen the toxicities of treatment that adversely affect quality of life and longevity. Vincristine is one of the most widely used and effective anticancer agents for treating leukemias in both adults and children. The dose-limiting toxic effect of vincristine is peripheral neuropathy (damage to the nerves), characterized by neuropathic (nerve) pain and impaired manual dexterity, balance, and altered gait. Currently, there are no reliable means of identifying patients at high risk of vincristineinduced neuropathy nor strategies to reduce this drug toxicity, according to background information in the article.

William E. Evans, Pharm.D., of St. Jude Children's Research Hospital, Memphis, and colleagues performed a genome-wide association study to determine whether there are genetic variants associated with vincristine-induced neuropathy. The study included patients in 1 of 2 prospective clinical trials for childhood ALL that included treatment with 36 to 39 doses of vincristine. Genetic analysis and vincristine-induced peripheral neuropathy were assessed in 321 patients from whom DNA was available: 222 patients (median age, 6.0 years) enrolled in 1994-1998 in a St. Jude Children's Research Hospital cohort; and 99 patients (median age, 11.4 years) enrolled in 2007-2010 in a Children's Oncology Group (COG) cohort.

Grade 2 (moderate) to 4 (life threatening) vincristine-induced neuropathy during therapy occurred in 28.8 percent of patients (64/222) in the St. Jude cohort and in 22.2 percent (22/99) in the COG cohort. The researchers found that an inherited variant in the gene CEP72 was associated with a higher incidence and severity of vincristine-related peripheral neuropathy in children with ALL. Among patients with the gene variant, 28 of 50 (56 percent) developed at least 1 episode of grade 2 to 4 neuropathy, compared with 21 percent (58/271) of other patients.

"If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent," the authors write.

Editorial: Precision Medicine to Improve the Risk and Benefit of Cancer Care

"The study by Diouf et al has many key elements; genome-wide discovery in patients from well-conducted clinical trials, replication in a multicenter cohort, statistical robustness, and laboratory correlative findings that contribute biologic plausibility," writes Howard L. McLeod, Pharm.D., of the Moffitt Cancer Center, Tampa, Fla., in an accompanying editorial.

"However, vincristine remains a component of the most widely accepted treatment regimens for childhood ALL, although there is variation in both dose and intensity. It is not clear that vincristine can be removed from the treatment options for a child with CEP72 variants, although this study suggests that the resulting increase in leukemia cellular sensitivity makes vincristine dose reductions possible without compromising antileukemic effect."

"However, there is value in the association of CEP72 with vincristine-induced peripheral neuropathy (VIPN). The ability to objectively ascribe a degree of heightened VIPN risk will allow for greater transparency in discussions of risk and benefits of therapy with patients and their family members. This also may lead to developmental therapeutic approaches to modulate CEP72 function as either primary prevention or treatment of chronic VIPN. This study also represents an initial robust effort to generate predictors for adverse drug reactions in cancer care."

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Gene variant, risk, severity of nerve disorder linked to cancer drug

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Newswise Children with acute lymphoblastic leukemia who had a certain gene variant experienced a higher incidence and severity of peripheral neuropathy after receiving treatment with the cancer drug vincristine, according to a study in the February 24 issue of JAMA.

Cancer remains the leading cause of death by disease in U.S. children despite major advances in the last 20 years. Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, and as cure rates have surpassed 85 percent, it becomes increasingly important to lessen the toxicities of treatment that adversely affect quality of life and longevity. Vincristine is one of the most widely used and effective anticancer agents for treating leukemias in both adults and children. The dose-limiting toxic effect of vincristine is peripheral neuropathy (damage to the nerves), characterized by neuropathic (nerve) pain and impaired manual dexterity, balance, and altered gait. Currently, there are no reliable means of identifying patients at high risk of vincristineinduced neuropathy nor strategies to reduce this drug toxicity, according to background information in the article.

William E. Evans, Pharm.D., of St. Jude Children's Research Hospital, Memphis, and colleagues performed a genome-wide association study to determine whether there are genetic variants associated with vincristine-induced neuropathy. The study included patients in 1 of 2 prospective clinical trials for childhood ALL that included treatment with 36 to 39 doses of vincristine. Genetic analysis and vincristine-induced peripheral neuropathy were assessed in 321 patients from whom DNA was available: 222 patients (median age, 6.0 years) enrolled in 1994-1998 in a St. Jude Children's Research Hospital cohort; and 99 patients (median age, 11.4 years) enrolled in 2007-2010 in a Children's Oncology Group (COG) cohort.

Grade 2 (moderate) to 4 (life threatening) vincristine-induced neuropathy during therapy occurred in 28.8 percent of patients (64/222) in the St. Jude cohort and in 22.2 percent (22/99) in the COG cohort. The researchers found that an inherited variant in the gene CEP72 was associated with a higher incidence and severity of vincristine-related peripheral neuropathy in children with ALL. Among patients with the gene variant, 28 of 50 (56 percent) developed at least 1 episode of grade 2 to 4 neuropathy, compared with 21 percent (58/271) of other patients.

If replicated in additional populations, this finding may provide a basis for safer dosing of this widely prescribed anticancer agent, the authors write. (doi:10.1001/jama.2015.0894; Available pre-embargo to the media at http://media.jamanetwork.com)

Editors Note: Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

Editorial: Precision Medicine to Improve the Risk and Benefit of Cancer Care

The study by Diouf et al has many key elements; genome-wide discovery in patients from well-conducted clinical trials, replication in a multicenter cohort, statistical robustness, and laboratory correlative findings that contribute biologic plausibility, writes Howard L. McLeod, Pharm.D., of the Moffitt Cancer Center, Tampa, Fla., in an accompanying editorial.

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Gene Variant and Risk and Severity of Nerve Disorder Linked to Cancer Drug

Mutation of one gene is all it takes to get cystic fibrosis (CF), but disease severity depends on many other genes and proteins. For the first time, researchers at the UNC School of Medicine have identified genetic pathways -- or clusters of genes -- that play major roles in why one person with CF might never experience the worse kinds of symptoms while another person will battle severe airway infection for a lifetime.

The finding, published in the American Journal of Human Genetics, opens avenues of research toward new personalized or precision treatments to lessen pulmonary symptoms and increase life expectancy for people with cystic fibrosis.

"Right now, there are drugs being developed to fix the function of the CFTR protein that is disrupted in cystic fibrosis, but even then, some patients will respond very well to therapy and some won't," said Michael Knowles, MD, professor of pulmonary and critical care medicine and senior author of the paper. "Why is that? We think it's the genetic background -- the pathways that we identified contain genes that likely interact with the main CFTR gene mutation."

Knowles's team found that when these pathways or groups of genes are highly expressed, CF patients have less severe symptoms. When these pathways are expressed in lower amounts, patients experience a more severe form of the disease and are more likely to be hospitalized.

Wanda O'Neal, PhD, associate professor of medicine and first author, said, "Now that we've found these pathways, we need to dig into the biology to see how specific genes within them influence disease severity. This could help us not only to predict which patients will respond to a given therapy but it may also provide drug targets to lessen the severity of disease for all patients."

The CFTR gene was discovered in 1989, and since then researchers have found about 1,800 different mutations in the CFTR gene that cause cystic fibrosis. There is a new drug that works very well to correct a mutation found in about 4 percent of CF patients. There is still no FDA approved drug to correct the mutation found in about 70 percent of patients (called the DF508 mutation), though a drug company has recently shown that a combination therapy of two new drugs modestly improved lung function in some CF patients. Still, this combination therapy may not work or wouldn't work well enough for some patients, and the reason could be the complex interaction between the CFTR gene and the genetic pathways uncovered by Knowles, O'Neal, and co-senior author Fred Wright, PhD, a professor of bioinformatics and director of the bioinformatics program at North Carolina State University.

In a normal epithelial cell, the CFTR gene creates the protein that transits from the cell nucleus to the cell membrane, where it then works to maintain proper lung function. As the protein transits, there are many genes that interact with it in various ways so that it can complete the journey to the membrane and work properly in the end. In CF patients with the DF508 mutation, the CFTR gene does not fold into its correct form and cannot make it to the cell surface. In order for CF patients to be out of the woods, the DF508 protein would need help from a complex network of genes and proteins to get to the membrane.

Over the past decade, Knowles has teamed with scientists from the United States and Canada to gather thousands of genetic and blood cell samples from CF patients. One of the research goals has been to identify genes and cellular proteins that often have subtle effects inside cells but that can produce dramatic differences in disease severity. Decades of research on protein functions has allowed genes to be grouped into pathways based on common biological roles.

For this current study, Knowles and O'Neal used gene expression data from the cells collected from 750 patients gathered over the past decade from 40 sites across the United States. Along with Wright and other authors, they analyzed data on more than 4,000 pathways to find pathways that identified severe CF patients as compared to mild CF patients. They found significant genetic variation in only broad types of pathways: endomembrane pathways and HLA pathways.

This finding was telling because endomembrane genes are responsible for transporting the DF508 protein from the cell nucleus to the cell membrane and for regulating the way that proteins such as CFTR are folded into the proper functioning form. The HLA genes are widely known to have roles in immune function; they're important for protection against pathogens, such as Pseudomonas -- the commonly seen bacteria that causes pneumonia in CF patients.

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Genetic pathways linked to CF disease severity pinned down

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Newswise CHAPEL HILL, NC Mutation of one gene is all it takes to get cystic fibrosis (CF), but disease severity depends on many other genes and proteins. For the first time, researchers at the UNC School of Medicine have identified genetic pathways or clusters of genes that play major roles in why one person with CF might never experience the worse kinds of symptoms while another person will battle severe airway infection for a lifetime.

The finding, published in the American Journal of Human Genetics, opens avenues of research toward new personalized or precision treatments to lessen pulmonary symptoms and increase life expectancy for people with cystic fibrosis.

Right now, there are drugs being developed to fix the function of the CFTR protein that is disrupted in cystic fibrosis, but even then, some patients will respond very well to therapy and some wont, said Michael Knowles, MD, professor of pulmonary and critical care medicine and senior author of the paper. Why is that? We think its the genetic background the pathways that we identified contain genes that likely interact with the main CFTR gene mutation.

Knowless team found that when these pathways or groups of genes are highly expressed, CF patients have less severe symptoms. When these pathways are expressed in lower amounts, patients experience a more severe form of the disease and are more likely to be hospitalized.

Wanda ONeal, PhD, associate professor of medicine and first author, said, Now that weve found these pathways, we need to dig into the biology to see how specific genes within them influence disease severity. This could help us not only to predict which patients will respond to a given therapy but it may also provide drug targets to lessen the severity of disease for all patients.

The CFTR gene was discovered in 1989, and since then researchers have found about 1,800 different mutations in the CFTR gene that cause cystic fibrosis. There is a new drug that works very well to correct a mutation found in about 4 percent of CF patients. There is still no FDA approved drug to correct the mutation found in about 70 percent of patients (called the DF508 mutation), though a drug company has recently shown that a combination therapy of two new drugs modestly improved lung function in some CF patients. Still, this combination therapy may not work or wouldnt work well enough for some patients, and the reason could be the complex interaction between the CFTR gene and the genetic pathways uncovered by Knowles, ONeal, and co-senior author Fred Wright, PhD, a professor of bioinformatics and director of the bioinformatics program at North Carolina State University.

In a normal epithelial cell, the CFTR gene creates the protein that transits from the cell nucleus to the cell membrane, where it then works to maintain proper lung function. As the protein transits, there are many genes that interact with it in various ways so that it can complete the journey to the membrane and work properly in the end. In CF patients with the DF508 mutation, the CFTR gene does not fold into its correct form and cannot make it to the cell surface. In order for CF patients to be out of the woods, the DF508 protein would need help from a complex network of genes and proteins to get to the membrane.

Over the past decade, Knowles has teamed with scientists from the United States and Canada to gather thousands of genetic and blood cell samples from CF patients. One of the research goals has been to identify genes and cellular proteins that often have subtle effects inside cells but that can produce dramatic differences in disease severity. Decades of research on protein functions has allowed genes to be grouped into pathways based on common biological roles.

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Researchers Pin Down Genetic Pathways Linked to CF Disease Severity

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Newswise Working with cells taken from children with a very rare but ferocious form of brain cancer, Johns Hopkins Kimmel Cancer Center scientists have identified a genetic pathway that acts as a master regulator of thousands of other genes and may spur cancer cell growth and resistance to anticancer treatment.

Their experiments with cells from patients with atypical teratoid/rhabdoid tumor (AT/RT) also found that selumetinib, an experimental anticancer drug currently in clinical trials for other childhood brain cancers, can disrupt part of the molecular pathway regulated by one of these factors, according to a research team led by Eric Raabe, M.D., Ph.D., an assistant professor of oncology at the Johns Hopkins University School of Medicine.

AT/RT mostly strikes children 6 and younger, and the survival rate is less than 50 percent even with aggressive surgery, radiation and chemotherapy, treatments that can also disrupt thinking, learning and growth. AT/RT accounts for 1 percent of more than 4,500 reported pediatric brain tumors in the U.S., but it is more common in very young children, and it represents 10 percent of all brain tumors in infants.

Whats exciting about this study is that it identifies new ways we can treat AT/RT with experimental drugs already being tested in pediatric patients, Raabe says. Because few outright genetic mutations and potential drug targets have been linked to AT/RT, Raabe and his colleagues turned their attention to genes that could regulate thousands of other genes in AT/RT cancer cells. Experiments in fruit flies had already suggested a gene known as LIN28 could be important in regulating other genes involved in the development of brain tumors. Specifically, the LIN28 protein helps regulate thousands of RNA molecules in normal stem cells, giving them the ability to grow, proliferate and resist damage.

These factors provide stem cells with characteristics that cancer cells also have, such as resistance to environmental insults. These help tumor cells survive chemotherapy and radiation, says Raabe. These proteins also help stem cells move around the body, an advantage cancer cells need to metastasize.

In a report on one of their studies, published Dec. 26 in the journal Oncotarget, the researchers examined cell lines derived from pediatric AT/RT patients and the tumors themselves. They found that the two members of the LIN28 family of genes were highly expressed in 78 percent of the samples, and that blocking LIN28 expression with specially targeted gene silencers called short hairpin RNAs curbed the tumor cells growth and proliferation and triggered cell death. When Raabe and colleagues blocked LIN28A in AT/RT tumor cells transplanted into mice, they were able to more than double the mices life span, from 48 to 115 days.

Using selumetinib in cell line experiments, the scientists cut AT/RT tumor cell proliferation in half and quadrupled the rate of cell death in some cell lines. Raabe says the drug appeared to be disrupting a key molecular pathway controlled by LIN28.

In a second study, described in the Journal of Neuropathology and Experimental Neurology, Raabe and his colleagues examined another factor in the LIN28 pathway, called HMGA2, which is also highly expressed in AT/RT tumors. They again used short pieces of RNA to silence HMGA2, which led to lower levels of cell growth and proliferation and increased cell death. Blocking HMGA2 also doubled the survival rate of mice implanted with tumors derived from pediatric AT/RT cell lines from 58 to 153 days.

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Master Gene Regulatory Pathway Revealed as Key Target for Therapy of Aggressive Pediatric Brain Cancer