Monthly Archives: November 2016

New Target for Treating Glioblastoma

“These findings change our fundamental understanding of the molecular basis of glioblastoma, and how to treat it,” said co-senior author Dr. Robert Bachoo, Associate Professor of Neurology and Neurotherapeutics, Internal Medicine, and with the Annette G. Strauss Center for Neuro-Oncology at UT Southwestern Medical Center. “We may have identified a set of critical genes we can target with drugs that are shared across nearly all glioblastomas.”

The study, published in Cell Reports, represents research from UT Southwestern’s precision medicine campaign in neuro-oncology.

For the past decade, patients diagnosed with glioblastoma have been treated with the current standard of care regimen: surgery followed by chemotherapy and radiation. This regimen improves median survival by an average of four to six months, followed by recurrence of the tumor. There are currently no successful therapies available to treat glioblastoma patients when the tumor recurs. Five-year survival rates are around 5 percent.

Faced with these prospects, the brain tumor research and clinical communities turned to genetic studies to guide possible treatment strategies.

“Our work shows that the gene mutations which the pharmaceutical industry and clinicians have been focusing on are essential only for starting tumor growth. Once the tumor has advanced to the stage where patients seek treatment, these mutations are no longer required for continued tumor growth; they are in effect redundant,” said Dr. Bachoo, a member of the Simmons Cancer Center and O’Donnell Brain Institute, who holds the Miller Family Professorship in Neuro?Oncology. Previously, proteins called receptor tyrosine kinase were considered the drivers of glioblastoma; however, drugs that inhibit these proteins have not been effective in treating this type of cancer.

“We learned that, instead, it is neurodevelopmental transcription factors (master proteins that regulate the activity of hundreds of genes during normal brain development), which are reactivated to drive the growth of glioblastoma. We can inhibit these transcription factors and prevent further tumor growth with the chemotherapy drug mithramycin, a drug that has not been in clinical use for years due to its side effects,” said co-senior author Dr. Ralf Kittler, Assistant Professor of Pharmacology in the Eugene McDermott Center for Human Growth and Development. “Our discovery has the potential for the development of a new therapy that may increase survival time for glioblastoma patients.”

The researchers caution that repurposing mithramycin, which is known to cause liver toxicity in some patients, with safer and more effective treatments for brain tumor patients may take years.

Risk-taking behaviour in adolescents

Reckless driving, binge drinking, drug taking — it is well known that adolescents are more likely than adults to engage in risky and impulsive behavior. A study conducted at the Max Planck Institute for Human Development provides new insights into these risky decisions. The findings show that, relative to children and adults, adolescents are less interested in information that would help them to gauge the risks of their behavior. They are less motivated to seek out such information and better able to tolerate a lack of knowledge. “It’s not that they are cognitively incapable of processing the issues. They are simply driven to seek new experiences and try out new things,” says lead author Wouter van den Bos, researcher in the Center for Adaptive Rationality at the Max Planck Institute for Human Development.

The patterns of adolescent risk-taking behaviors observed in previous experimental studies deviate sharply from those seen in real life. In these earlier laboratory experiments, participants were often given all the information they needed to make a decision. When adolescents test their luck by experimenting with drugs or having unprotected sex, however, they may have only a vague idea of the possible consequences of their actions and the likelihoods of those consequences. But they often have the opportunity to learn more about those consequences before making a decision — metaphorically speaking, they can look before they leap. “Ours was the first developmental study to use experimental tasks that afforded decision makers this opportunity to reduce uncertainty by searching for more information,” adds van den Bos.

In the study, 105 children, adolescents, and young adults aged 8-22 years old played various lotteries, each offering a chance of winning a certain amount of money. Players either had full information on the value of the prize and the probability of winning it (choices under risk), or they were told the value of the prize but had incomplete information on its probability (choices under ambiguity), or they were not told the value of the prize or its probability but had the opportunity to access further information (choices under uncertainty). Additionally, participants were asked about their real-life risk-taking behavior.

It emerged that teenagers were more ready to accept ambiguity and also searched for less information in the context of uncertainty. This tolerance of the unknown peaked around age 13-15 years. Unlike adolescents’ choices in the context of full information, their behavior under ambiguity and uncertainty also correlated with their self-reported risk-taking in the real world.

The study findings could also explain why information campaigns designed to educate young people about the risks of certain behaviors — such as drug abuse — often fall on deaf ears. Even when information is easily available to young people, they show little motivation to engage with it. “If we really want to get through to young people, we need to take these insights into account when designing interventions,” says coauthor Ralph Hertwig, Director of the Center for Adaptive Rationality at the Max Planck Institute for Human Development. “A promising alternative to information campaigns would be to give adolescents the opportunity to experience the consequences of their risky behavior

Serum micoRNAs may serve as biomarkers

MicroRNAs are small RNA molecules that influence basic cellular processes and have been proposed as biomarkers for the diagnosis, progression and treatment of multiple sclerosis. In a new study conducted at the Ann Romney Center of Neurologic Diseases at Brigham and Women’s Hospital, researchers have found that serum microRNAs are linked to MRI findings in the brain and spinal cord in patients with MS. These findings suggest that microRNAs could serve as promising biomarkers for monitoring the progression of MS and could help to identify distinct underlying disease processes, such as inflammation and tissue destruction.

The study was published on January 23, 2017 in JAMA Neurology.

In a large study, researchers examined the connection between serum microRNAs and MRI measures to evaluate the severity of MS, which included looking at lesions and atrophy, a measure of degeneration of the cells, in the central nervous system. Among the findings, the researchers identified that the expression of certain microRNAs were linked to MRI measures. The authors showed that these associations could be protective or harmful to patients (depending upon the function of the microRNA). They also found that different mechanisms were linked to different locations of MS changes, such as in the brain or spinal cord. Additionally, the study suggested certain sets of microRNAs were linked to lesions, while others were linked to atrophy, which is known to cause more devastating effects to MS patients.

“These findings tell us the disease is heterogeneous. There’s a complex set of mechanisms at play, and it may vary from patient to patient,” says senior co-author Rohit Bakshi, MD, MA. “Another implication of this research is that it could eventually lead to us having a blood test to identify the subtype of MS in a patient, to help guide therapeutic decisions and prognosis,” says Bakshi, also a neurologist at BWH.

“MicroRNAs could serve as biomarkers of the underlying MS disease processes, once validated and standardized for clinical settings. In addition, these markers have the potential to provide novel treatment targets,” says Roopali Gandhi, PhD, senior co-author and an assistant professor at BWH.