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Study Finds Key To Drug Resistance

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Sophisticated “targeted” drug therapies are improving cancer care by selectively shutting down abnormal growth switches in tumor cells while avoiding toxicity to normal tissues. In some cases, though, tumors that are initially sensitive to these drugs first regress but then activate different, “backup” genetic signals that enable them to circumvent the therapy.

A new discovery by Jean Zhao, PhD, and colleagues may help physicians predict which tumors are likely to become resistant to a given drug, and identify the secondary pathways they are activating to escape the original therapy.

The discovery could lead to tests of a patient’s tumor that would tell doctors they need to utilize an additional drug during therapy to block tumor growth via the secondary gene abnormality.

“We are trying to be a step ahead so we can inform the scientists conducting the clinical trials of what to expect,” explains Zhao, of Cancer Biology. “If we can identify potential drug resistance mechanisms, we can more rapidly design combination drug therapies to overcome the resistance.”

In the report, published by Nature Medicine, researchers described how they created a genetically engineered mouse model of human breast cancer in which the most frequently occurring breast cancer “oncogene,” PIK3CA, could be turned on and off.

Surprisingly, the researchers found that while all of the PIK3CA oncogene-induced breast tumors initially shrank following inhibition of the oncogene, a large fraction of tumors shrank partially and then later resumed growth. Moreover, about half of these recurrent tumors did not respond to PI3K inhibitors currently in clinical trails for cancer therapy, meaning the cancer cells were no longer dependent on the PI3K pathway to survive.

The scientists performed genomic and genetic analyses on a large collection of recurrent tumors and found that about 30 percent of recurrent tumors have either an increased copy number or higher expression levels of another common oncogene known as c-MYC, which is independent of the PI3K pathway. These tumors were not sensitive to PI3K inhibitor treatment. When the researchers used a molecular tool to block c-MYC activity, it suppressed the growth of these recurrent tumors.

More importantly, the researchers analyzed multiple samples of human breast tumors, revealing that more than 30 percent of those tumors that carry the PIK3CA mutation also contained high levels of c-MYC.

At this time there aren’t good drugs to block c-MYC in cancer, Zhao notes. Nevertheless, she says the experimental results suggest it would be useful to test patients’ breast cancers for c-MYC when they’re being treated with PI3K inhibitors to alert doctors to the likelihood of tumor recurrence.

And eventually, Zhao adds, “I’m optimistic that we can overcome tumor resistance caused by increased c-MYC abundance.”

As a measure of the journal article’s importance, it has been picked for inclusion in a library of the top 2 percent of published articles in biology and medicine by The Faculty of 1,000, an organization of scientists that evaluates biomedical publications.

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The above story is reprinted from materials provided by Dana-Farber Cancer Institute.

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Age-Related Effects Of Multiple Sclerosis May Be Reversible

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Harvard stem cell researchers and scientists at the University of Cambridge in the United Kingdom have found that the age-related degeneration in conditions such as multiple sclerosis (MS) may be reversible.

The researchers, co-led by Associate Professor Amy Wagers of Harvard’s Department of Stem Cell and Regenerative Biology and the Harvard Stem Cell Institute, have found that impairment of the body’s ability to replace protective myelin sheaths, which surround nerve fibers and allow them to send signals properly, may be reversible, offering new hope that therapeutic strategies aimed at restoring efficient regeneration can be effective in the central nervous system throughout life.

In a proof-of-principle study published in the journal Cell Stem Cell, the researchers report that defects in the regeneration of the myelin sheaths surrounding nerves, which are lost in diseases such as MS, may be at least partially corrected after exposing an old animal to the circulatory system of a young animal. Myelin is a fatty substance that protects nerves and aids in the quick transmission of signals between nerve cells.

Using a surgical technique, the researchers introduced an experimental demyelinating injury in the spinal cord of an old mouse, creating small areas of myelin loss, and then exposed those areas to cells found in the blood of a young mouse. By doing so, they found that the influx of certain immune cells, called macrophages, from the young mouse helped resident stem cells restore effective remyelination in the old mouse’s spinal cord. This rejuvenating effect of young immune cells was aided in part by the greater efficiency of the young cells in clearing away myelin debris created by the demyelinating injury. Prior studies have shown that this debris impedes the regeneration of myelin.

“Aging impairs regenerative potential in the central nervous system,” said Wagers, who is based at the Joslin Diabetes Center, and who co-led the study with Professor Robin Franklin, director of the MS Society’s Cambridge Centre for Myelin Repair at the University of Cambridge. “This impairment can be reversed, however, suggesting that the eventual development of cell-based or drug-based interventions that mimic the rejuvenation signals found in our study could be used therapeutically.”

This could be particularly useful, she said, in treating MS, which typically spans many decades of life, and thus is likely to be influenced by age-dependent reductions in the ability of myelin to regenerate. In MS, the body’s own immune system attacks the myelin sheath and prevents nerve fibers in the brain from sending signals properly, which can cause mild symptoms such as limb numbness or more serious ones like losing the ability to walk or speak. As people with MS age, remyelination decreases significantly, eventually causing permanent loss of nerve fibers.

“For MS sufferers,” said Franklin, “this means that, in theory, regenerative therapies will work throughout the duration of the disease. Specifically, it means that remyelination therapies do not need to be based on stem cell transplantation, since the stem cells already present in the brain and spinal cord can be made to regenerate myelin, regardless of a person’s age.”

Other Harvard co-authors of the study were Tata Nageswara Rao and Jennifer L. Shadrach of Wagers’ lab.

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Cysteamine Will Be Tested As Treatment For Fatty Liver Disease In Children

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NIH study to test treatment for fatty liver disease in children

With the launch of a new clinical trial supported by the National Institutes of Health, researchers are working to determine whether treating children diagnosed with the most severe form of fatty liver disease with a drug called cysteamine will help improve the liver.

The trial, called Cysteamine Bitartrate Delayed-Release for the Treatment of Nonalcoholic Fatty Liver Disease in Children (CyNCh),will enroll 160 boys and girls ages 8 to 17 with nonalcoholic fatty liver disease (NAFLD).  The participants will receive cysteamine or placebo by mouth twice a day for a year.  There are no weight cutoffs or percentiles for the children participating in CyNCh.  However, more than 90 percent of the children are expected to be overweight or obese.  Participants need a baseline biopsy that confirms severe NAFLD to be eligible for the study.   Children with poorly managed diabetes, heart disease, and other chronic liver diseases will be excluded.

NAFLD covers a range of severity from simple liver disease without injury, called steatosis, to the more concerning nonalcoholic steatohepatitis, or NASH, which includes fat accumulation, inflammation, and liver injury.  Most children with fatty liver disease are overweight and resistant to insulin, a hormone that regulates energy.  The only way to distinguish NASH from other forms of fatty liver disease is with a liver biopsy.

“We did not see fatty liver disease in children until recently,” said Edward Doo, M.D., NASH Clinical Research Network project scientist and director of the Liver Diseases Program at NIH’s National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), which is funding the study in collaboration with Raptor Pharmaceutical of Novato, Calif., which makes the drug and will provide it to the trial. “Fatty liver disease affects about 17 percent of children in the United States. This rise in the number of children with NAFLD most likely mirrors the increase in obesity, which affects more than 16 percent of American children and teens,” Dr. Doo said.

Results from a small pilot study using cysteamine in 11 children with NASH suggest that it improves liver enzymes by reducing toxins that can damage the liver.  Cysteamine is approved to treat cystinosis, a genetic disease that causes the amino acid cystine to accumulate in the kidneys, liver, eyes, brain, and white blood cells.  Modest weight loss through diet and physical activity may help some children with fatty liver disease, but it is a treatment option that seldom helps people meet their goals.  “We know that following a weight loss plan for many children and adults can be daunting, especially if they have limited access to healthy food options that are low in fat, added sugars, and calories, and infrequent opportunities for physical activity,” said Joel E. Lavine, M.D., Ph.D., a CyNCh principal investigator and professor of pediatrics at Columbia University, New York City.  “Hopefully, this trial will move us closer to finding a safe and effective treatment that helps children with fatty liver disease.”

NAFLD can be a precursor to NASH, which may progress to cirrhosis, liver failure and liver cancer.  NAFLD may also increase a patient’s risk of developing heart disease.  A healthy liver helps the body remove harmful chemicals from the blood, fight infection and digest food.  If too much scar tissue forms, the liver could fail.  Then a liver transplant is required.   “We are concerned that the disease may advance as children become adults and increase their risk for cirrhosis, liver failure, liver transplantation, and death as adults,” said Stephen P. James, M.D., director of the NIDDK’s Digestive Diseases and Nutrition Division.  “This multicenter, double-blind trial offers researchers and NIDDK an opportunity to rigorously assess how safe and effective cysteamine is in treating children with NASH, as well as to reveal new avenues worthy of scientific study.”

The following clinical centers are conducting the CyNCh trial:

  • Children’s Memorial Hospital, Chicago
  • Cincinnati Children’s Hospital Medical Center
  • Columbia University, New York City
  • Indiana University, Indianapolis
  • Mount Sinai Medical Center, New York City
  • St. Louis University
  • Texas Children’s Hospital, Houston
  • University of California, San Diego
  • University of California,  San Francisco
  • University of Washington, Seattle

For more information:

The NIDDK, a component of the NIH, conducts and supports research on diabetes and other endocrine and metabolic diseases; digestive diseases, nutrition and obesity; and kidney, urologic and hematologic diseases. Spanning the full spectrum of medicine and afflicting people of all ages and ethnic groups, these diseases encompass some of the most common, severe and disabling conditions affecting Americans. For more information about the NIDDK and its programs, see www.niddk.nih.gov. Education programs for diabetes and kidney disease offer information and resources for patients and health professionals.

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The above story is reprinted from materials provided by NIH.

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Novel Approach To View Inner Workings Of Viruses, Identified By NIH Scientists

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Since the discovery of the microscope, scientists have tried to visualize smaller and smaller structures to provide insights into the inner workings of human cells, bacteria and viruses.  Now, researchers at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health, have developed a new way to see structures within viruses that were not clearly seen before.  Their findings are reported in the Jan. 13 issue of Science.

Cryo-electron microscopy (cryo-EM) is a technique that allows scientists to image very small particles, like structures on the surface of viruses. This method has been useful in helping researchers understand how vaccines work.  But, despite the success of cryo-EM, scientists have been unable to clearly visualize structures inside of viruses, because radiation is used to image them.   “With lower doses of radiation, it is not possible to see inside the organism,” said lead author Dr. Alasdair Steven of the NIAMS Laboratory of Structural Biology Research.  “However, higher doses of radiation damage the virus, destroying the very structures that we would like to view.”

Working in collaboration with the group of Dr. Lindsay Black at the University of Maryland Medical School, Baltimore, Steven and his team were able to turn the problem of radiation damage into an asset.  Viruses, one of the simplest life forms, are made up of nucleic acids (DNA or RNA) and the proteins encoded by the nucleic acid instruction manual.  The researchers realized that proteins inside the virus are more sensitive to damage than DNA.

“We first used low doses of radiation and recorded images in which the inner structure of the virus was invisible,” said Steven. “Next, we used high doses of radiation, and found that the inner structure could be seen as a cylinder of bubbles.”  While the inner structure was damaged, the team was able to superimpose the images, using three-dimensional computer reconstruction.  As a result, they were able to clearly visualize the viral structure. The investigators call this technique bubblegram imaging.

Moving forward, the team members anticipate many uses of bubblegram imaging.  Ideally, this technique will allow a better understanding of the inner workings of viruses, providing more opportunities for developing novel therapies. Beyond studying viral structure, cryo-EM could be used to visualize interactions of proteins with DNA in human cells. One exciting prospect lies in using this approach to visualize differences in cancer vs. non-cancer cells. “This new cryo-EM procedure renders previously invisible proteins visible and, thus, will provide new understanding of cell biology,” said  Steven.

For more information on the NIAMS Laboratory of Structural Biology Research, visit http://www.niams.nih.gov/Research/Ongoing_Research/Branch_Lab/Structural_Biology/default.asp.

The mission of the NIAMS, a part of the U.S. Department of Health and Human Services’ National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about the NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at http://www.niams.nih.gov.

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The above story is reprinted from materials provided by NIH.

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NIH Scientists Find The Cause Of Cold Urticaria

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Genetic mutation leads to cold allergy, immune deficiency and autoimmunity

Investigators at the National Institutes of Health have identified a genetic mutation in three unrelated families that causes a rare immune disorder characterized by excessive and impaired immune function. Symptoms of this condition include immune deficiency, autoimmunity, inflammatory skin disorders and cold-induced hives, a condition known as cold urticaria.

The study was led by Joshua Milner, M.D., in the Laboratory of Allergic Diseases at the National Institute of Allergy and Infectious Diseases (NIAID), and Daniel Kastner, M.D., Ph.D., scientific director at the National Human Genome Research Institute (NHGRI). It will appear in the online edition of the New England Journal of Medicine on Jan. 11, 2012.

The mutation discovered occurs in a gene for phospholipase C-gamma2 (PLCG2), an enzyme involved in the activation of immune cells. The investigators have named the condition PLCG2-associated antibody deficiency and immune dysregulation, or PLAID. “Investigating rare diseases gives researchers more clues about how the healthy immune system functions,” says NIAID Director Anthony S. Fauci, M.D. “More importantly, identifying the genetic cause of these disorders opens up possibilities for better disease management and potentially a cure for people who may have spent their entire lives debilitated by severe and unexplained symptoms.”

The NIH study involved 27 people from three separate families who all suffered from an inherited form of cold urticaria, an allergic disease characterized by the formation of itchy, sometimes painful hives, episodes of fainting and, in certain cases, life-threatening reactions in response to cold temperatures.

Blood sample analysis revealed that many patients produced antibodies to their own cells and tissues (autoantibodies), making them more susceptible to developing autoimmune disease. More than half had a history of recurrent infections, and laboratory tests revealed that most had low levels of infection-fighting antibodies and low numbers and reduced activity of circulating immune B cells — all symptoms of immune deficiency disease. In three cases, patients had common variable immunodeficiency, a disease that requires frequent intravenous infusions of immune globulin to prevent severe infections. Seven patients suffered from granulomas, inflamed masses of tissue, which formed on their fingers, ears, nose and other parts of their skin.

“This is one of few examples in which the allergy symptom directed us to a genetic syndrome,” says Dr. Milner. “In trying to understand the link between this group of conditions — autoimmunity, chronic infections and cold urticaria—we not only identified a disease-causing mutation but uncovered a unique and fascinating genetic mechanism at the crux of allergy, immune defense and self-tolerance.”

“This study illustrates the power of multidisciplinary teamwork involving clinicians, geneticists and basic immunologists to get to the heart of seemingly insoluble medical mysteries,” says Dr. Kastner. “Our team and colleagues working in the field now have much better odds of improving health outcomes for people with PLAID and for understanding this gene’s role in other disorders.”

The NIAID investigators teamed up with gene hunting experts in Dr. Kastner’s laboratory and found the PLCG2 mutation after performing gene analysis and DNA sequencing studies. The mutation caused the PLCG2 enzyme to function without shutting off. Despite the fact that the enzyme was constantly turned on, immune cells ignored its signaling and did not activate normally.

Investigators performed a series of laboratory experiments to understand how the PLCG2 mutation affects B cells and mast cells, immune cells that contain histamine and other chemicals that are released during an allergic response. Patients’ B cells containing the mutated gene fail to turn on normally, leading to their inability to produce antibody, but also an inability to sense when they are producing autoantibodies. Laboratory-developed mast cells containing the mutated gene released chemicals on exposure to cool temperatures, which could explain why the patients developed cold-induced hives.

According to the investigators, their findings suggest that inhibiting PLCG2 activity could be a therapeutic strategy to treat cold-induced hives, autoimmunity and immune deficiency in people with PLAID, but more studies are needed. The study findings also suggest that people previously diagnosed with common variable immunodeficiency disease or with granulomatous diseases could have a PLCG2 gene mutation. Further study is needed to understand PLAID and how mutations in PLCG2 could contribute to other allergic and immunologic disorders.

“These findings are gratifying both for researchers and for people with this disorder,” says NHGRI Director Eric Green, M.D., Ph.D. “Furthermore, this study illustrates how genome-analysis methods can empower efforts to unravel the molecular basis of rare genetic diseases.”

Additional support for this work was provided by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, part of the NIH.

The mission of the NIAMS, a part of the U.S. Department of Health and Human Services’ National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about the NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS website at http://www.niams.nih.gov.

NIAID conducts and supports research  — at NIH, throughout the United States, and worldwide — to study the causes of infectious and immune-mediated diseases, and to develop better means of preventing, diagnosing and treating these illnesses. News releases, fact sheets and other NIAID-related materials are available on the NIAID Web site at http://www.niaid.nih.gov.

NHGRI is one of the 27 institutes and centers at the NIH, an agency of the Department of Health and Human Services. The NHGRI Division of Intramural Research develops and implements technology to understand, diagnose and treat genomic and genetic diseases. Additional information about NHGRI can be found at its website, www.genome.gov.

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The above story is reprinted from materials provided by NIH.

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

Disclaimer: Views expressed in this article do not necessarily reflect those of PreventiveMedicineDaily or its staff.