Prostate cancer researchers have drawn a molecular portrait that provides the first complete picture of localized, multi-focal disease within the prostate and also unveils a new gene subgroup driving it.

The discoveries are a further step along the road to personalizing prostate cancer medicine say study co-leads, Dr. Robert Bristow, a clinician-scientist at Princess Margaret Cancer Centre, and Dr. Paul Boutros, an investigator at the Ontario Institute for Cancer Research.

‘Our research shows how prostate cancers can vary from one man to another – despite the same pathology under the microscope – as well as how it can vary within one man who may have multiple tumour types in his prostate,’ says Dr. Bristow. He goes on to say, ‘these sub-types may be important to determining the response to surgery or radiotherapy between patients.’

The study involved molecular profiling of 74 patients with Gleason Score 7 index tumours. (Gleason is the classification system used to evaluate aggressiveness in prostate tumours). Of these, whole-genome sequencing was done on 23 multiple tumour specimens from five patients whose prostates were removed at surgery.  By carefully analysing the genetics of each focus of cancer within each prostate, the researchers could assign ‘aggression scores’ to each cancer which revealed that even small cancers can contain aggressive cells capable of altering a patient’s prognosis.

Dr. Boutros, explained that the more detailed analysis clearly identified that two members of the MYC cancer gene family were at play in disease development, and that one of them – ‘C-MYC’ – was the culprit driving aggressive disease. The other one – ‘L-MYC’ – is already known to be implicated in lung and other cancers.

‘This discovery of a new prostate cancer-causing gene gives researchers a new avenue to explore the biology of the disease and improve treatment,’ says Dr. Paul Boutros, a principal investigator at the Ontario Institute for Cancer Research.

‘By showing that mutations in prostate cancer vary spatially in different regions of a tumour, this study will aid in the development of new diagnostic tests that will improve treatment by allowing it to be further personalized.’ University Health Network

A landmark clinical study provides convincing evidence that a frequently overlooked therapy for genetically-caused emphysema is effective and slows the progression of lung disease.

Alpha-1 antitrypsin deficiency is an inherited disorder that can cause emphysema even without exposure to tobacco smoke.  Alpha-1 antitrypsin (AAT) is a protein made in the liver that protects the lungs. With this disorder, the AAT protein builds up in liver cells and doesn’t reach the lungs to protect them. Augmentation therapy involves regular infusions of purified AAT protein to raise the level of the protein in the blood and lungs. Although the therapy has been available for more than 25 years, it has seen limited use because doctors have been unsure that it works.

The study, ‘Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trail,’ will change how clinicians understand this treatment and encourage them to consider its early use before the condition causes severe emphysema.

By using CT scans to measure the lung density of patients in the trial, the researchers were able to overcome some of the challenges that have been associated with studying the effectiveness of the treatment.  ‘This treatment has now been studied in our centre using the most sensitive measure of lung structure – a radiologic measurement of lung density –  allowing us to detect changes far earlier than can be seen with standard breathing tests,’ said Dr. Kenneth Chapman, Director of the Asthma and Airways Centre at Toronto Western Hospital and the Canadian research lead for the multicentre trial. ‘We can now say with certainty that augmentation therapy is effective and should be given to patients with emphysema caused by this deficiency.’

According to the Canadian Medical Association Journal, up to five per cent of people with chronic obstructive pulmonary disease (COPD) are thought to have alpha-1 antitrypsin deficiency, yet only four to five per cent of those with a deficiency have been identified.  Even when the deficiency is diagnosed, there has typically been a delay of five to 10 years before this specific genetic problem has been identified as the cause of respiratory problems.

‘Augmentation therapy not only preserves lung structure, but likely adds years of life,’ said Dr. Chapman. ‘Patients with this condition need access to timely diagnosis and treatments to ensure they receive the best possible care’.  Dr. Chapman added that this treatment is used only for this specific type of emphysema and is not of benefit to those with more common types of emphysema, chronic bronchitis or COPD. University Health Network

While the overall rate of colorectal cancer (CRC) is declining, CRC specifically among young patients is increasing. Previous studies have shown that CRC in patients younger than 50 years old tends to be more aggressive than CRC in older patients. A University of Colorado Cancer Center study offers early evidence of genetic differences between CRC in young and old patients, possibly pointing toward different treatments and strategies in combating the young form of the disease.

“We saw differences in two important gene signalling pathways, PPAR and IGF1R, which are involved in regulating cell development, metabolism, and growth,” says Christopher Lieu, MD, investigator at the CU Cancer Center and assistant professor of medical oncology at the University of Colorado School of Medicine.

Alterations in these signalling pathways have been implicated in the development of several types of cancer.

The study compared the genetics of 5 colorectal cancer tumours from younger patients (median age 31) to 6 tumours from older patients (median age 73), sequencing 45 million “reads” from each tumour. The group then explored the data for significant differences between groups. In addition to the pathways PPAR and IGF1R, the study showed that younger CRC tumour samples were enriched for pathways responsible for metabolizing drugs.

“Chemotherapies challenge cancer cells and younger people may metabolize these chemotherapies differently than older patients. This may explain why our traditional chemotherapy treatments may be less effective for younger patients with metastatic colorectal cancer,” says Todd Pitts, MS, research instructor in the Developmental Therapeutics Program at the CU Cancer Center, and the study’s lead author. (Pitts notes that this hypothesis will require additional exploration.)

The group plans to validate the finding of these differences in a larger patient population. Then, if PPAR and/or IGF1R prove to in fact be important drivers of CRC in young patients, the group hopes to explore trials of drugs targeting these potential tumour drivers. Toward this goal, the group has gathered the important resource of tumour samples grown from the tissues of young CRC patients, allowing further preclinical genetic and drug testing. University of Colorado Cancer Centre

Researchers funded by the National Institutes of Health Genotype-Tissue Expression (GTEx) project, including scientists from the Broad Institute of MIT and Harvard, have created a new and much-anticipated data resource to help establish how differences in an individual’s genomic make-up can affect gene activity and contribute to disease. The new resource will enable scientists to examine the underlying genomics of many different human tissues and cells at the same time, and promises to open new avenues to the study and understanding of human biology.
GTEx investigators reported initial findings from a two-year pilot study in several papers. These efforts provide new insights into how genomic variants – inherited spelling differences in the DNA code – control how, when, and how much genes are turned on and off in different tissues, and can predispose people to diseases such as cancer, heart disease, and diabetes.

“GTEx was designed to sample as many tissues as possible from a large number of individuals in order to understand the causal effects of genes and variants, and which tissues contribute to predisposition to disease,” said Emmanouil Dermitzakis, Ph.D., professor of genetics at the University of Geneva Faculty of Medicine, Switzerland, and a corresponding author. “The number of tissues examined in GTEx provides an unprecedented depth of genomic variation. It gives us unique insights into how people differ in gene expression in tissues and organs.”

NIH launched the GTEx Project in 2010 to create a data resource and tissue bank for scientists to study how genomic variants may affect gene activity and disease susceptibility. Investigators are collecting more than 30 tissue types from autopsy and organ donations in addition to tissue transplant programs. The DNA and RNA from those samples are then analysed using cutting-edge genomic methods. The project will eventually include tissue samples from about 900 deceased donors.

“GTEx will be a great resource for understanding human biological function, and will have many practical applications in areas such as drug development,” said NHGRI Program Director Simona Volpi, Pharm.D., Ph.D. “Scientists studying asthma or kidney cancer, for example, will be interested in understanding how specific variants influence the biological function of the lung, kidney, and other organs.” Broad Institute

You are a patient who has just been treated for a serious illness but neither you nor your doctor knows how likely it is that you – in comparison with other patients — will actually be helped by the treatment. This is often the situation with prostate cancer, one of the deadliest and most highly prevalent cancers. While hormone therapy can help, patient responses vary widely, and it’s still unclear why some types of prostate cancer seem to be resistant to the therapy.

A team led by Associate Professor Lloyd Trotman at Cold Spring Harbor Laboratory (CSHL) shows how signalling by an immune system component called interleukin-6 (IL-6) appears to play an important role in driving particularly aggressive and therapy-resistant prostate cancer.

“Our research suggests that IL-6 could be a marker for when the disease switches to a more dangerous state that is ultimately hormone therapy-resistant,” says Trotman.

The results could have important implications for human prostate cancer. “The gain could be immense, because today’s problem is that the variability in response of humans to hormone therapy is amazing,” Trotman says. “For one man this therapy might be great, might reduce disease burden dramatically for many, many, years, and be an extreme benefit,” he says. “For others there’s almost no response, and it’s still not clear to clinicians who is who.”

Being able to predict which patients would benefit from hormone therapy “would be amazing,” Trotman says. “We are really hopeful that translating the IL-6 discovery into the clinics could help us stratify patients into good responders and bad responders. For any hospital this would be a major breakthrough.”

Trotman and his team, which included Dawid Nowak, Ph.D., a postdoctoral investigator who is the paper’s first author, looked for cellular signals that led to metastasis and hormone therapy resistance in a genetically engineered mouse model for metastatic prostate cancer. They found that the combined loss of two genes, PTEN and p53 — closely associated with prostate cancer metastasis — led to the secretion of IL-6. Signalling by IL-6 was then responsible for activating a powerful cancer gene called MYC, which drives cell proliferation and disease progression.

“It suggested immediately that cell-cell communication is very, very important to make the cells resistant to therapy and very aggressive,” says Trotman.

The involvement of the MYC pathway suggests that it could potentially serve as a target of drugs against prostate cancer, Trotman says. The team’s next step is to study IL-6 signalling in humans. “IL-6 detection in blood has been developed to a high art,” Trotman says. “There are very good tools, which have been tested in the hospital setting.”  Cold Spring Harbor Laboratory