In a breakthrough discovery at the Children’s Medical Center Research Institute at UT Southwestern (CRI), a research team led by Ralph DeBerardinis, M.D., Ph.D., has taken a significant step in cracking the code of an atypical metabolic pathway that allows certain cancerous tumours to thrive, providing a possible roadmap for defeating such cancers.
Following up on Dr. DeBerardinis’ landmark finding in 2011, this most recent discovery identifies the triggering mechanism that plays a key role in causing a series of energy-generating chemical reactions known as the Krebs cycle to run in reverse.

‘With this finding, we have learned there are particular enzymes that work together to enable the reverse pathway to function, much like the tiny gears that turn in opposite directions to power a mechanical clock,’ said Dr. DeBerardinis, director of CRI’s Genetic and Metabolic Disease Program and associate professor in the Department of Pediatrics and the Eugene McDermott Center for Human Growth and Development at UT Southwestern Medical Center.

The identification of the mechanism could provide a future target for drugs that would attack tumours relying upon the reverse pathway for sustenance and growth. Tumours of this type, often found in the brain, lungs and kidneys, tend to be difficult for oncologists to treat because cells using the atypical pathway seem to resist existing treatments like chemotherapy.

‘Prior to this discovery, we didn’t have enough information about how to tap into the reverse metabolic pathway without disrupting the pathways that were operating in the typical, forward manner,’ said Dr. DeBerardinis, senior author of the study. ‘We now believe there is a specific enzyme critical to the reverse pathway that can be deleted without impairing normal function. If we can eliminate that enzyme, we may be able to starve tumours of their supply of building blocks for growth.’ UT Southwestern

A new theory about disorders that attack the brain and spinal column has received a significant boost from scientists at Washington University School of Medicine in St. Louis.
The theory attributes these disorders to proteins that act like prions, which are copies of a normal protein that have been corrupted in ways that cause diseases. Scientists previously thought that only one particular protein could be corrupted in this fashion, but researchers in the laboratory of Marc Diamond, MD, report that another protein linked to Alzheimer’s disease and many other neurodegenerative conditions also behaves very much like a prion.
Diamond’s lab found that the protein, known as tau, could be corrupted in different ways, and that these different forms of corruption — known as strains — were linked to distinct forms of damage to the brain.
‘If we think of these different tau strains as different pathogens, then we can begin to describe many human disorders linked to tau based on the strains that underlie them,’ said senior author Diamond, the David Clayson Professor of Neurology. ‘This may mean that certain antibodies or drugs, for example, will work better against certain disorders than others.’
Prions are composed of normal proteins that have folded into an abnormal shape. They aren’t alive, but their effects can be similar to infectious microbes such as bacteria or viruses. Their unusual structure lets prions replicate themselves through a kind of molecular peer pressure: When a prion interacts with identical but normally folded proteins, it can cause these proteins to become prions, which are small aggregates, or clumps, that can spread from cell to cell.
Prions first came to popular attention in the 1990s with the emergence of mad cow disease, a disorder that destroys the brains of cattle. Scientists linked a few cases of a similar condition in people to consumption of meat from infected cows. Researchers eventually determined that the disorder was caused by a distinct strain of prions made by the sickened cattle.
Scientists had suspected that prion-like forms of a protein called alpha-synuclein contribute to Parkinson’s disease and other conditions, and prion-like versions of proteins known as SOD1 and TDP43 may cause amyotrophic lateral sclerosis, commonly known as Lou Gehrig’s disease.
Scientists also had identified tau clumps in 25 different neurodegenerative disorders, known collectively as tauopathies. This hinted at potential prion-like behaviour on the part of tau. In 2009, Diamond’s group found that tau misfolds into several different shapes in a test tube.
‘When we infected a cell with one of these misshapen copies of tau and allowed the cell to reproduce, the daughter cells contained copies of tau misfolded in the same fashion as the parent cell,’ Diamond said. ‘Further, if we extracted the tau from an affected cell, we could reintroduce it to a naïve cell, where it would recreate the same aggregate shape. This proves that each of these differently shaped copies of the tau protein can form stable prion strains, like a virus or a bacteria, that can be passed on indefinitely.’
Diamond used the tau prions made in cells to infect mouse brains, showing that differently shaped strains caused different levels of brain damage. He isolated the prions from the mice, grew them in cell culture, and then infected other mice. Throughout these transfers, each particular prion strain continued to be misfolded in the same shape and to cause damage in the same fashion.
Finally, the researchers examined clumps of tau from the brains of 28 patients after they died. Each of the patients was known to have one of five forms of tauopathy.
‘Each disease had a unique tau prion strain or combination of strains associated with it,’ he said. ‘For example, we isolated the same tau prion strain from nearly every patient with Alzheimer’s disease we examined.’
Brain samples from patients with the progressive neurological disorders corticobasal degeneration and Pick’s disease also typically had the same tau prion strains or mixtures of strains. Washington University School of Medicine

Improved diagnosis and management of one of the most common cancers in men – prostate cancer – could result from research at the University of Adelaide, which has discovered that seminal fluid (semen) contains biomarkers for the disease.
Results of a study have shown that the presence of certain molecules in seminal fluid indicates not only whether a man has prostate cancer, but also the severity of the cancer.
Speaking in the lead-up to Men’s Health Week (9-15 June), University of Adelaide research fellow and lead author Dr Luke Selth says the commonly used PSA (prostate specific antigen) test is by itself not ideal to test for the cancer.
‘While the PSA test is very sensitive, it is not highly specific for prostate cancer,’ Dr Selth says. ‘This results in many unnecessary biopsies of non-malignant disease. More problematically, PSA testing has resulted in substantial over-diagnosis and over-treatment of slow growing, non-lethal prostate cancers that could have been safely left alone.
‘Biomarkers that can accurately detect prostate cancer at an early stage and identify aggressive tumours are urgently needed to improve patient care. Identification of such biomarkers is a major focus of our research,’ he says.
Dr Selth, a Young Investigator of the Prostate Cancer Foundation (USA), is a member of the Freemasons Foundation Centre for Men’s Health at the University of Adelaide and is based in the University’s Dame Roma Mitchell Cancer Research Laboratories.
Using samples from 60 men, Dr Selth and colleagues discovered a number of small ribonucleic acid (RNA) molecules called microRNAs in seminal fluid that are known to be increased in prostate tumours. The study showed that some of these microRNAs were surprisingly accurate in detecting cancer.
‘The presence of these microRNAs enabled us to more accurately discriminate between patients who had cancer and those who didn’t, compared with a standard PSA test,’ Dr Selth says. ‘We also found that the one specific microRNA, miR-200b, could distinguish between men with low grade and higher grade tumours. This is important because, as a potential prognostic tool, it will help to indicate the urgency and type of treatment required.’ University of Adelaide

Hakon Hakonarson, MD, PhDA large new analysis of DNA from thousands of patients has uncovered several underlying gene networks with potentially important roles in autism. These networks may offer attractive targets for developing new autism drugs or repurposing existing drugs that act on components of the networks.

Furthermore, one of the autism-related gene pathways also affects some patients with attention-deficit hyperactivity disorder (ADHD) and schizophrenia — raising the possibility that a class of drugs may treat particular subsets of all three neurological disorders.

‘Neurodevelopmental disorders are extremely heterogeneous, both clinically and genetically,’ said study leader Hakon Hakonarson, MD, PhD, director of the Center for Applied Genomics at The Children’s Hospital of Philadelphia (CHOP). ‘However, the common biological patterns we are finding across disease categories strongly imply that focusing on underlying molecular defects may bring us closer to devising therapies.’

The study by Hakonarson and colleagues draws on gene data from CHOP’s genome center as well as from the Autism Genome Project and the AGRE Consortium, both part of the organisation Autism Speaks.

Autism spectrum disorders (ASDs), of which autism is the best known, are a large group of heritable childhood neuropsychiatric conditions characterised by impaired social interaction and communication, as well as by restricted behaviours. The authors note that recent investigations suggest that up to 400 distinct ASDs exist.

The current research is a genome-wide association study comparing more than 6,700 patients with ASDs to over 12,500 control subjects. It was one of the largest-ever studies of copy number variations (CNVs) in autism. CNVs are deletions or duplications of DNA sequences, as distinct from single-base changes in DNA.

The study team focused on CNVs within defective gene family interaction networks (GFINs) — groups of disrupted genes acting on biological pathways. In patients with autism, the team found three GFINs in which gene variants perturb how genes interact with proteins. Of special interest to the study group was the metabotropic glutamate receptor (mGluR) signalling pathway, defined by the GRM family of genes that affects the neurotransmitter glutamate, a major chemical messenger in the brain regulating functions such as memory, learning, cognition, attention and behaviour.

Hakonarson’s team and other investigators previously reported that 10 percent or more of ADHD patients have CNVs in genes along the glutamate receptor metabotropic (GRM) pathway, while other teams have implicated GRM gene defects in schizophrenia.

Based on these findings, Hakonarson is planning a clinical trial in selected ADHD patients of a drug that activates the GRM pathway. ‘If drugs affecting this pathway prove successful in this subset of patients with ADHD, we may then test these drugs in autism patients with similar gene variants,’ he said.

In ASDs and other complex neurodevelopmental disorders, common gene variants often have very small individual effects, while very rare gene variants exert stronger effects. Many of these genes with very rare defects belong to gene families that may offer druggable targets.

The three gene families found in the current study have notable functional roles. The CALM1 network includes the calmodulin family of proteins, which regulate cell signaling and neurotransmitter function. The MXD-MYC-MAX gene network is involved in cancer development, and may underlie links reported between autism and specific types of cancer. Finally, members of the GRM gene family affect nerve transmission, neuron formation, and interconnections in the brain — processes highly relevant to ASDs. Children’s Hospital of Philadelphia

A new Moffitt Cancer Center study shows that counselling from a genetic health care provider before genetic testing educates patients and may help reduce unnecessary procedures.

Up to 10 percent of cancers are inherited, meaning a person was born with an abnormal gene that increases their risk for cancer. ‘Pre-test genetic counselling in which a health care provider takes a thorough family history and discusses the potential risks and benefits of genetic testing is standard of care as recommended by the American Society of Clinical Oncology and National Society of Genetic Counselors,’ said Tuya Pal, M.D., a board-certified geneticist at Moffitt and senior author of the paper.

In the Moffitt study, researchers surveyed 473 patients who had genetic testing for BRCA1 and BRCA2 gene mutations, which are associated with an increased risk of breast and ovarian cancers. Among study participants who saw a board-certified geneticist or genetic counsellor, almost all recalled having a pre-test discussion, compared to only 59 percent of those who did not. These findings suggest large differences in quality of care across providers who order testing.

The researchers also suggest there may be cost-of-care implications when genetic health care providers are involved. ‘Our results suggest that genetic health care providers are less likely to order more expensive comprehensive genetic testing, when less expensive testing may be appropriate,’ said Deborah Cragun, Ph.D., lead study author and post-doctoral fellow at Moffitt. ‘Our study found that in cases where less expensive testing may be appropriate, genetic health care providers ordered comprehensive testing for 9.5 percent of participants, compared to 19.4 percent when tests were ordered by other health care providers. At the time of data collection, comprehensive genetic testing cost approximately $4,000, compared to $400 for the less expensive testing.’

The findings are important, noted researchers, because costs and quality of care are often the focus of policy-level decisions in health care. Moffitt Cancer Center