Prostate cancer is a leading cause of cancer-related death in men in the United States. The development and progression of the disease depend on the actions of male sex hormones called androgens, which bind to the androgen receptor to activate signalling pathways involved in cell growth and survival. Therefore, there is a strong need to identify novel drug targets to alter androgen-receptor signalling and treat this often deadly disease.

Sanford-Burnham researchers have discovered that a protein called NWD1 affects androgen-receptor signalling to control the growth of prostate cancer cells. ‘A very limited number of proteins have been shown to specifically and exclusively affect androgen-receptor signalling, so our findings represent a major advance in the field,’ said lead study author Ricardo Correa, Ph.D., staff scientist at Sanford-Burnham. ‘NWD1 could represent a new biomarker for predicting patient prognosis as well as a therapeutic target for a novel class of prostate cancer drugs.’
High levels of androgens are critical for the growth of prostate cancer cells in early disease stages, and one major type of therapy focuses on inhibiting androgens. But over time, prostate cancer cells often respond to hormone therapy by expressing high levels of the androgen receptor, allowing these castration-resistant cells to grow even when androgen levels are low. Castration-resistant prostate cancer is an advanced form of the disease associated with poor survival rates. However, both early and advanced stages of prostate cancer depend on androgen-receptor signalling, highlighting the value of targeting this pathway for treating a broad range of patients.

While searching for novel modulators of androgen-receptor signalling, Correa and his team became interested in the nucleotide-binding domain and leucine-rich repeat (NLR) family of proteins. These proteins are involved in recognising pathogens and cell-injury signals and activating immune-defence pathways, but they have also been implicated in a variety of cancers. In particular, the researchers were intrigued by an NLR-related protein called NWD1, which was previously identified in zebrafish but had not yet been analyzed in humans.

In the new study, Correa and his colleagues found that the expression of the human NWD1 gene was very high in prostate tissue and other parts of the male reproductive system. Moreover, NWD1 expression was higher than normal in human prostate cancer cell lines, especially in castration-resistant and highly metastatic cell lines. Similarly, NWD1 protein levels were higher than normal in advanced-stage and castration-resistant prostate tumour tissue from patients.

Taken together, the findings suggest that NWD1 could be a potential prostate cancer biomarker because high levels of the protein are associated with malignant progression. ‘We believe that NWD1 could represent a promising biomarker because changes in NWD1 expression happen at stages where the levels of prostate-specific antigen (PSA), a protein that is widely used to screen men for prostate cancer, are not very accurate in the clinic,’ Correa said.
In addition to its potential use for predicting patient prognosis, NWD1 could represent a promising therapeutic target. When the researchers inhibited the activity of the NWD1 gene in prostate cancer cells, they noticed a drop in androgen-receptor levels as well as a decrease in cell growth and survival. On the other hand, an increase in NWD1 activity led to a rise in androgen-receptor levels in these cells.

Their experiments also shed light on the molecular mechanisms by which NWD1 affects androgen-receptor signalling. NWD1 silencing fed the activity of cancer-related genes such as PDEF (prostate-derived epithelial factor), which is known to bind to androgen receptors and belongs to a family of proteins that regulate cell growth and survival. Moreover, a protein called sex-determining region Y (SRY), which controls sex determination during fetal development, affected the activity of the NWD1 gene. Thus, the findings not only reveal a novel molecular pathway involved in prostate cancer, but also suggest that drugs targeting NWD1 could eventually become a new class of treatments for the disease. Sanford-Burnham

Findings should help narrow the search for genetic contributions of autism and suggest new routes for therapy
‘Aha’ moments are rare in medical research, scientists say. As rare, they add, as finding mice with Mohawk-like hairstyles.
But both events happened in a lab at NYU Langone Medical Center, months after an international team of neuroscientists bred hundreds of mice with a suspect genetic mutation tied to autism spectrum disorders.
Almost all the grown mice, the NYU Langone team observed, had sideways,’overgroomed’ hair with a highly stylised centre hairline between their ears and hardly a tuft elsewhere. Mice typically groom each other’s hair.
Researchers say they knew instantly they were on to something, as the telltale overgrooming — a repetitive motor behaviour — had been linked in other experiments in mice to the brain condition that prevents children from developing normal social, behavioural, cognitive, and motor skills. People with autism, the researchers point out, exhibit noticeably dysfunctional behaviours, such as withdrawal, and stereotypical, repetitive movements, including constant hand-flapping, or rocking.
Now and for what NYU Langone researchers believe to be the first time, an autistic motor behaviour has been traced to specific biological pathways that are genetically determined.
The findings, says senior study investigator Gordon Fishell, PhD, the Julius Raynes Professor of Neuroscience and Physiology at NYU Langone, could with additional testing in humans lead to new treatments for some autism, assuming the pathways’ effects as seen in mice are reversible.
In the study, researchers knocked out production in mice of a protein called Cntnap4. This protein had been found in earlier studies in specialized brain cells, known as interneurons, in people with a history of autism.
Researchers found that knocking out Cntnap4 affected two highly specialized chemical messengers in the brain, GABA and dopamine. Both are so-called neurotransmitters, chemical signals released from one nerve cell to the next to stimulate similar sensations throughout the body. GABA, short for gamma-aminobutyric acid, is the main inhibitory neurotransmitter in the brain. It not only helps control brain impulses, but also helps regulate muscle tone. Dopamine is a well-known hormonal stimulant, highly touted for producing soothing, pleasing sensations.
Among the researchers’ key findings was that in Mohawk-coiffed mice, reduced Cntnap4 production led to depressed GABA signalling and overstimulation with dopamine. Researchers say the lost protein had opposite effects on the neurotransmitters because GABA is fast acting and quickly released, so interfering with its action decreases signalling, while dopamine’s signalling is longer-acting, so impairing its action increases its release.
‘Our study tells us that to design better tools for treating a disease like autism, you have to get to the underlying genetic roots of its dysfunctional behaviours, whether it is overgrooming in mice or repetitive motor behaviours in humans,’ says Dr. Fishell. ‘There have been many candidate genes implicated in contributing to autism, but animal and human studies to identify their action have so far not led to any therapies. Our research suggests that reversing the disease’s effects in signalling pathways like GABA and dopamine are potential treatment options.’
The U.S. Centers for Disease Control and Prevention estimate that one in 68 American children under age 8 has some form of autism, with five times as many boys as girls suffering from the spectrum of disorders.
As part of their study, researchers performed dozens of genetic, behavioural, and neural tests with growing mice to isolate and pinpoint where Cntnap4 acted in their brains, and how it affected chemical signalling among specific interneuron brain cells, which help relay and filter chemical signals between neurons in localised areas of the brain.
They found that Cntnap4 in mature interneurons strengthened GABA signalling, but did not do so in younger interneurons. When researchers traced where Cntnap4 acted in immature brain cells, Dr. Fishell says tests showed that it stimulated ‘a big bolus of dopamine.’
As part of testing to confirm the hereditary link among Cntnap4, the two pathways, and grooming behaviours, researchers exposed young mice with normal levels of Cntnap4, who did not groom each other, to mature mice with and without Cntnap4. Only mature mice deficient in Cntnap4 preened the hairstyle on other mice. Further tests in young mice without Cntnap4 showed that other, mature mice with normal amounts of Cntnap4 largely let them be, without any particular grooming or hairstyle. EurekAlert

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