Biomarkers for bone formation and resorption predict outcomes for men with castration-resistant prostate cancer, a team of researchers from UC Davis and their collaborators have found. Their study also found that the markers identified a small group of patients who responded to the investigational drug atrasentan. The markers’ predictive ability could help clinicians match treatments with individual patients, track their effectiveness and affect clinical trial design.
Castration-resistant prostate cancer does not respond to hormone treatments and often metastasises to bone. This led researchers to wonder if increased bone turnover markers might predict the course of the disease.
‘We found that patients with high levels of these markers in the blood had a much shorter lifespan compared to patients with low levels,’ said lead author Primo Lara, associate director for translational research at the UC Davis Comprehensive Cancer Center. ‘By measuring bone turnover in prostate cancer patients, we can determine how well they do.’
Healthy bone maintains a balance between formation and resorption, generating new bone while recycling old. Prostate cancer throws off this balance. Researchers hoped this mechanism would help them track the cancer. To investigate this potential link, the team tested blood serum in 778 patients for both resorption (N-telopeptide, pyridinoline) and formation markers (C-terminal collagen propeptide, bone alkaline phosphatase) and found elevated levels of each of the markers predicted poor prognosis.
Perhaps most interesting, elevated marker levels also predicted whether patients would respond to a specific drug. About 6 percent of patients with the highest marker levels responded to atrasentan, and investigational drug abandoned because it failed in clinical trials. Lara and colleagues believe this may be related to study design.
‘Atrasentan kept coming up short in randomised trials because the drug only works for a small group,’ Lara said. ‘Because certain drugs only succeed in a fraction of patients, drug makers need to factor in these bone metabolism markers in their trial design. They need to target the patients most likely to benefit.’
In addition to determining which patients might respond best to a specific treatment, these markers could be used to track their response during treatment. Marker status could also stratify patients equally within different study arms. Balancing these studies could potentially make them more accurate and identify the niche value of drugs like atrasentan whose effectiveness is not evident in large populations.
‘I think the days of doing empirical studies on all comers should end,’ Lara said. ‘You need to have an appropriate database of patients and perform a rigorous analysis to find the subset who will benefit from an investigational drug.’ UC Davis Comprehensive Cancer Center

The genetic disease ARVC leads to sudden cardiac death and is more common than it has been hitherto assumed. This is reported by an international team of researchers headed by Prof Dr Hendrik Milting from the Heart and Diabetes Center NRW. The molecular biologist working at the Ruhr-Universität’s clinic in Bad Oeynhausen revealed that all families who are known to be affected by the disease share the same genetic origin. There must be other families in Europe who also carry the genetic mutation but who are not yet known.
Scientists have thrown light on the genetic mutation that causes a particularly severe genetic disease (ARVC5) on the Canadian island Newfoundland in 2008. At first, they assumed that it was a genetic anomaly limited to this Canadian province. In 2010, Milting’s team – and at the same time a team of researchers from Copenhagen – proved that the ‘Newfoundland mutation’ did also occur in Europe. Today, the scientists know about affected families in Germany, Denmark, the USA and Canada. They all share common ancestors, as was demonstrated through genetic analysis. The scientists studied the environment of the TMEM43 gene in which the ARVC5-specific mutation is located. The genetic sequence in the neighbourhood of TMEM43 is typically highly variable; in all affected families, however, it was identical over long stretches. These findings verify a shared genetic origin.
The affected Danish and German families are not aware of the degree to which they are related; according to calculations, the mutation originated some 1300 to 1500 years ago. Thus, the ARVC5 mutation in the European families is not a novel mutation but an old European heritage. Therefore, there must be other families with that genetic mutation, who constitute the bridge between the patients in Europe and in North America. Two novel families with that mutation have recently been identified in Madrid. ‘In cases of sudden cardiac death in the family, people should sit up and take notice,’ says Prof Milting. ‘The families that are known to us have lost several male family members within a short space of time, even though they were under medical observation. Women frequently suffer from cardiac arrhythmias.’ Suspected cases must be looked into, warns the molecular biologist, because people carrying that mutation will definitely get the disease. Sudden cardiac death may be prevented if a defibrillator is implanted in good time.
Genetic analyses are increasingly gaining in importance in healthcare settings as prevention and diagnostic tools. ‘Nevertheless, healthcare professionals are called upon to exercise great discretion when deciding which analyses must necessarily be conducted for which patients,’ stresses Hendrik Milting. ‘After all, the objective is not to stigmatise the affected families, but to prevent severe heart diseases or even sudden cardiac death.’ A team of molecular biologists, cardiologists and human geneticists is in charge of this task at the Heart and Diabetes Center NRW.
The acronym ARVC stands for arrhythmogenic right ventricular cardiomyopathy. A considerable number of patients, most of them men, suffer sudden cardiac death without having ever shown any signs of a cardiovascular disease. The average life expectancy of men who have the ARVC5 genetic mutation is about 41 years. Ruhr University Bochum

Cornell researchers report they have discovered direct genetic evidence that a family of genes, called MicroRNA-34 (miR-34), are bona fide tumour suppressors.
Previous research at Cornell and elsewhere has shown that another gene, called p53, acts to positively regulate miR-34. Mutations of p53 have been implicated in half of all cancers. Interestingly, miR-34 is also frequently silenced by mechanisms other than p53 in many cancers, including those with p53 mutations.
The researchers showed in mice how interplay between genes p53 and miR-34 jointly inhibits another cancer-causing gene called MET. In absence of p53 and miR-34, MET overexpresses a receptor protein and promotes unregulated cell growth and metastasis.
This is the first time this mechanism has been proven in a mouse model, said Alexander Nikitin, a professor of pathology in Cornell’s Department of Biomedical Sciences and the paper’s senior author. Chieh-Yang Cheng, a graduate student in Nikitin’s lab, is the paper’s first author.
In a 2011 Proceedings of the National Academy of Sciences paper, Nikitin and colleagues showed that p53 and miR-34 jointly regulate MET in cell culture but it remained unknown if the same mechanism works in a mouse model of cancer (a special strain of mice used to study human disease).
The findings suggest that drug therapies that target and suppress MET could be especially successful in cancers where both p53 and miR-34 are deficient.
The researchers used mice bred to develop prostate cancer, then inactivated the p53 gene by itself, or miR-34 by itself, or both together, but only in epithelium tissue of the prostate, as global silencing of these genes may have produced misleading results.
When miR-34 genes alone were silenced in the mice, the mice developed cancer free. When p53 was silenced by itself, there were signs of precancerous lesions early in development, but no cancer by 15 months of age. When miR-34 and p53 genes were both silenced together, the researchers observed full prostate cancer in the mice.
The findings revealed that ‘miR-34 can be a tumour-suppressor gene, but it has to work together with p53,’ Nikitin said.
In mice that had both miR-34 and p53 silenced concurrently, cancerous lesions formed in a proximal part of the prostrate ducts, in a compartment known to contain prostate stem cells. The early lesions that developed when p53 was silenced alone occurred in a distal part of the ducts, away from the compartment where the stem cell pool is located. This suggested there was another mechanism involved when p53 and miR-34 were jointly silenced.
Also, the number of stem cells in mice with both p53 and miR-34 silenced increased substantially compared with control mice or mice with only miR-34 or p53 independently silenced.
‘These results indicated that together [miR-34 and p53] regulate the prostate stem cell compartments,’ said Nikitin.
This is significant, as cancer frequently develops when stem cells become unregulated and grow uncontrollably, he said.
Researchers further found that p53 and miR-34 affect stem cell growth by regulating MET expression. In absence of p53 and miR-34, MET is overexpressed, which leads to uncontrolled growth of prostate stem cells and high levels of cancer in these mice.
Future work will further examine the role of p53/miR-34/MET genes in stem cell growth and cancer. The findings have implications for many types of cancer. Cornell University

Cardiovascular calcification (deposits of minerals in heart valves and blood vessels) is a primary contributor to heart disease, the leading cause of death among both men and women in the United States according the Centers for Disease Control and Prevention (CDC).
‘Unfortunately, there currently is no medical treatment for cardiovascular calcification, which can lead to acute cardiovascular events, such as myocardial infarction and stroke, as well as heart failure,’ says Elena Aikawa, MD, PhD, Director of the Vascular Biology Program at the Center for Interdisciplinary Cardiovascular Sciences at Brigham and Women’s Hospital (BWH) and Associate Professor of Medicine at Harvard Medical School. ‘We have not found a way to reverse or slow this disease process, which is associated with ageing and common chronic conditions like atherosclerosis, diabetes, and kidney disease.’
Led by Dr. Aikawa, a team of researchers at BWH and Kowa Company, Ltd., a Japanese pharmaceutical company, has discovered certain proteins in osteoclasts, a precursor to bone, that may be used in helping to destroy cardiovascular calcification by dissolving mineral deposits. The research suggests a potential therapeutic avenue for patients with cardiovascular calcification.
Mature osteoclasts are not typically found in the vasculature. Using unbiased global proteomics (study of proteins), the researchers were able to examine osteoclast-like cells in the vasculature to determine which proteins induced osteoclast formation. They identified more than 100 proteins associated with osteoclast development. Follow-up study validated six candidate proteins, which serve as targets for possible medications that may help promote osteoclast development in the vasculature.
‘To advance this research, we need to further understand why osteoclasts are not prevalent in the vaculature, despite active calcification of the heart valves and blood vessels, and determine the difference between calcification in vasculature compared with calcification in bone,’ said Dr. Aikawa. ‘Then, we may examine ways to form osteoclasts in the vasculature.’ Brigham and Women’s Hospital

A team of cardiovascular researchers from the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai, Sanford-Burnham Medical Research Institute, and University of California, San Diego have identified a small, but powerful, new player in the onset and progression of heart failure. Their findings also show how they successfully blocked the newly discovered culprit to halt the debilitating and chronic life-threatening condition in its tracks.
In the study, investigators identified a tiny piece of RNA called miR-25 that blocks a gene known as SERCA2a, which regulates the flow of calcium within heart muscle cells. Decreased SERCA2a activity is one of the main causes of poor contraction of the heart and enlargement of heart muscle cells leading to heart failure. Using a functional screening system developed by researchers at Sanford-Burnham, the research team discovered miR-25 acts pathologically in patients suffering from heart failure, delaying proper calcium uptake in heart muscle cells.
‘Before the availability of high-throughput functional screening, our chance of teasing apart complex biological processes involved in disease progression like heart failure was like finding a needle in a haystack,’ says study co-senior author Mark Mercola, PhD, professor in the Development, Aging, and Regeneration Program at Sanford-Burnham and professor of Bioengineering at UC San Diego Jacobs School of Engineering. ‘The results of this study validate our approach to identifying microRNAs as potential therapeutic targets with significant clinical value.’
Dr. Mercola’s laboratory has pioneered the use of robotic high-throughput methods of drug discovery to identify new targets for heart failure. According to co-lead study authors Christine Wahlquist and Agustin Rojas Muñoz, PhD, developers of the approach and researchers in Mercola’s lab at Sanford-Burnham, they used high-throughput robotics to sift through the entire genome for microRNAs involved in heart muscle dysfunction.
Subsequently, the researchers at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai found that injecting a small piece of RNA to inhibit the effects of miR-25 dramatically halted heart failure progression in mice. In addition, it also improved their cardiac function and survival.
‘In this study, we have not only identified one of the key cellular processes leading to heart failure, but have also demonstrated the therapeutic potential of blocking this process,’ says co-lead study author Dongtak Jeong, PhD, a post-doctoral fellow at the Cardiovascular Research Center at Icahn School of Medicine at Mount Sinai in the laboratory of the study’s co-senior author Roger J. Hajjar, MD.
Nearly 6 million Americans suffer from heart failure, which is when the heart becomes weak and cannot pump enough blood and oxygen throughout the body. Heart failure is a leading cause of hospitalisation in the elderly. Often, a variety of medications are used to provide heart failure patients temporary relief of their debilitating symptoms. However, these medications do not improve cardiac function or halt the progression of the disease. Mount Sinai Health System