Predicting and preventing prostate cancer spread

Published in the journal Cancer Research, the discovery has potential to lead to the development of a blood test that could predict whether cancer will spread from the prostate tumour to other parts of the body. The research also reveals potential new targets for drugs that may inhibit the spread of cancer.

“Prostate cancers only kill men after they have spread or ‘metastasised’ from the prostate,” says project leader Dr Luke Selth, Senior Research Fellow at the University of Adelaide’s Dame Roma Mitchell Cancer Research Laboratories and a member of the Freemasons Foundation Centre for Men’s Health.

“The identification of markers that accurately predict, at an early stage, prostate tumours that are likely to metastasise could guide the urgency and aggressiveness of treatment — and this could save lives.”

The international research team — led by the University of Adelaide and including members from the University of Michigan, Vancouver Prostate Centre, the Mayo Clinic and Johns Hopkins University — showed that a specific microRNA (a type of molecule involved in regulating the level and activity of genes) called miR-194 promotes cancer metastasis by inhibiting a key protein called SOCS2. SOCS2 can suppress the spread of cancer cells.

“In previous work, we had found that a high level of miR-194 in a patient’s blood was associated with rapid relapse of prostate cancer following surgical removal of the tumour,” says Dr Selth. “This new work explains why miR-194 is associated with a poor outcome, and in the process reveals a completely novel pathway regulating prostate cancer metastasis.

“Importantly, measuring miR-194 in a patient’s blood at the time of diagnosis could become a test for the likelihood of metastasis. Patients with high levels of miR-194 in their blood could receive more aggressive treatment to reduce the chance of the cancer spreading to other parts of the body.” Dr Selth’s team is currently testing this idea using larger patient groups to validate their findings.

Dr Selth says miR-194 also represents a potential therapeutic target. “There are currently no drugs that effectively inhibit the spread of prostate cancer,” he says. “We propose that inhibiting miR-194 could reduce rates of metastasis in patients with aggressive disease, but the development of a drug to achieve this goal is still a long way off.”

Obesity on the rise in adults with a history of cancer

Results were based on data from a nationally representative sample of 538,969 non-institutionalized adults aged 18 to 85 years with or without a history of cancer who participated in the annual National Health Interview Survey from 1997 to 2014. Obesity was defined as body mass index of 30 kg/m2 for non-Asians and of 27.5 kg/m2 for Asians.

Among 32,447 cancer survivors, the most common diagnoses were cancers of the breast followed by prostate, and colorectal cancers. Populations with the highest rates of increasing obesity were colorectal cancer survivors followed by breast cancer survivors. African-American survivors of all three cancers were particularly affected.

“Our study identified characteristics of cancer survivors at the highest risk of obesity, which are important patient populations in which oncology care providers should focus their efforts,” said Heather Greenlee, ND, PhD, assistant professor of Epidemiology at the Mailman School, and principal investigator.

From 1997 to 2014, prevalence of obesity increased from 22 percent to 32 percent in cancer survivors and from 21 percent to 29 percent of adults without a history of cancer. During this time, rates of obesity grew more rapidly in women cancer compared to both male cancer survivors and compared to women with no history of cancer.

In female colorectal cancer survivors, those who are young and non-Hispanic black and had been diagnosed within 2 to 9 years had the highest increasing rates of obesity. Similarly, among female breast cancer survivors, those who are young, were diagnosed within the past year, and are non-Hispanic white had the highest increasing obesity rate. Among male colorectal cancer survivors, the highest increases in obesity were among older men, non-Hispanic blacks, and those at or greater than 10 years from diagnosis. In contrast, prostate-cancer survivors with the highest increases in obesity were younger, non-Hispanic whites, and 2 to 9 years from diagnosis.

“While our findings can be partially explained by the growing population of patients with breast and colorectal cancer — the two cancers most closely linked to obesity — we identified additional populations of cancer survivors at risk of obesity not as well understood and which require further study,” observed Dr. Greenlee.

“These results suggest that obesity is a growing public health burden for cancer survivors, which requires targeted interventions including weight management efforts to stave off the increasing obesity trends we are seeing in cancer survivors,” noted Dr. Greenlee.

Link between common prostate cancer treatment, dementia detailed in new study

The team compiled data from four different global databases looking at studies on ADT patients and dementia and Alzheimer’s. An analysis of more than 50,000 patients worldwide showed a consistent statistical link between men who underwent ADT for prostate cancer and men who developed dementia. Nead says the numbers show correlation, not causation at this point, but that there is evidence of a direct connection.

“Research shows androgens play a key role in neuron maintenance and growth, so the longer you undergo this therapy to decrease androgens, the more it may impact the brain’s normal functions,” Nead said.

The analysis was less conclusive on the question of Alzheimer’s. While there was still a connection, it was not as clearly defined as the link to dementia. Nead says evidence for a link between ADT and neurocognitive dysfunction is growing and should be part of the conversation between doctors and patients.

“There’s enough evidence of these links that patients should know about them when considering their options,” Nead said.

Novel genes identified that help suppress prostate and other cancers

Reported in Nature Genetics, this research sheds light on new pathways involved in cancer development — these could be possible drug targets for cancers with a faulty PTEN gene. The methods developed could also identify other genes that cooperate to suppress cancer growth.

Prostate cancer is the second most common cancer in men in the UK with around 47,000 men diagnosed each year. More than half of prostate cancers have an altered or missing PTEN gene, as do many other cancers, including brain tumours, and endometrial cancers.

Tumour suppressor genes such as PTEN help prevent cancer development in healthy people. PTEN regulates an important cell pathway for growth and division. However, little is known about which other genes and pathways cooperate with PTEN to prevent cancer.

In this study, researchers designed a new method in mice in which part of the Pten gene was converted into a mobile DNA element known as a transposon. When this was mobilized from the Pten gene it was inactivated. Importantly the transposon carrying a piece of Pten would land randomly throughout the genome, damaging genes into which it inserted. Cancers would grow when the transposon damaged a tumour suppressor gene that co-operated with Pten.

Dr Jorge de la Rosa, the first author on the study from the Wellcome Trust Sanger Institute, said: “We developed a new method that coupled Pten inactivation with mobilization of the transposon. We inserted the transposon directly inside the Pten gene, so that whenever it jumped out and inserted into another part of the genome, it inactivated Pten at the same time. By analysing which genes were disrupted in the cancers that grew, we were able to pinpoint genes that cooperate with Pten in suppressing tumours.”