New Method Increases Accuracy of Ovarian Cancer Diagnosis

Salt Lake City, UTAH – Nearly anyone touched by ovarian cancer will tell you: it’s devastating. It’s bad enough that cancer in almost 80 percent of patients reaches advanced stages before diagnosis, and that most patients are expected to die within five years. But just as painfully, roughly one quarter of women diagnosed have no warning that they are resistant to platinum-based chemotherapy, the main line of defense, nor that they will likely have 18 months to live.

Frustratingly, the diagnosis, prognosis, and even treatment of ovarian cancer have remained largely unchanged for 30 years. Until now, the best indicator for how a woman will fare, and how her cancer should be treated, has been the tumor’s stage at diagnosis.

Now, University of Utah scientists have uncovered patterns of DNA anomalies that predict a woman’s outcome significantly better than tumor stage. In addition, these patterns are the first known indicator of how well a woman will respond to platinum therapy. Published in the journal PLOS ONE, the patterns were discovered by using a new mathematical technique in the analysis of DNA profiles from the Cancer Genome Atlas, a national database containing data from hundreds of ovarian cancer patients.

University of Utah

“We believe this is a first step toward bringing ovarian cancer into the age of precision medicine,” says team leader Orly Alter, Ph.D., associate professor of bioengineering, adjunct associate professor of human genetics, and faculty member of the Scientific Computing and Imaging Institute. Pending experimental revalidation in the clinic, the patterns could be the basis of a personalized prognostic and diagnostic laboratory test. This test would predict both the patient’s survival and the tumor’s sensitivity to platinum-based chemotherapy, and doctors could tailor treatment accordingly.

For example, among patients that were diagnosed at late stages, the DNA patterns distinguished short-term survivors, with a median survival time of three years, from long-term survivors, with a median survival time almost twice as long. Among patients treated with platinum-based chemotherapy drugs, the DNA patterns distinguished those with platinum-resistant tumors, with a median survival time of three years, from those with platinum-sensitive tumors, with a median survival time of more than seven years. Alter’s team computationally validated the results by using data from independent sets of patients.

“If we have a tool that can more accurately predict survival, and distinguish who is who, we can revamp our entire approach to how we treat patients,” says Margit-Maria Janát-Amsbury, M.D., Ph.D., research assistant professor in obstetrics and gynecology, director of gynecologic oncology research at the University of Utah School of Medicine, and faculty member of the Huntsman Cancer Institute. She is collaborating with Alter to bring her team’s results to the clinic. “For those with a poor prognosis, we can suggest other therapies, or we can focus on taking measures to improve quality of life.”

“What made our discovery possible is our new technique for mathematical modeling,” said Alter. “It may very well be that the data needed to better treat cancer are already published. The ovarian cancer data, for example, were published back in 2011. The bottleneck to discovery is in the analysis of the data.”

In Alter’s Genomic Signal Processing Lab, Ph.D. graduate students and study co-authors Katherine Aiello and Theodore Schomay of the department of bioengineering develop algorithms to uncover patterns in datasets arranged in multidimensional tables, known as tensors. Rather than simplifying the big data, as is commonly done, the algorithms make use of the complexity of the data in order to tease out the patterns within them. Here, for example, by modeling DNA profiles of tumor and normal cells from the same set of patients, they were able to separate the patterns of DNA anomalies – which occur only in tumor genomes – from those that occur in the genomes of normal cells in the body, and from variations caused by experimental inconsistencies.

The algorithms extend a mathematical technique called the singular value decomposition, or SVD. The SVD helps us understand data arranged in two-dimensional tables, known as matrices, by breaking the data down into individual components. In physics, for example, the SVD describes the activity of a prism, which splits white light into its component colors. “It seemed natural that generalizations of the SVD could separate the multidimensional data that arise in personalized medicine into mathematical patterns that have biological meaning,” explains Alter, who has a Ph.D. in applied physics.

Alter says her algorithms could just as readily be applied to any type of data. She previously used a similar mathematical technique to uncover new prognostic and diagnostic DNA indicators for patients with glioblastoma, the most common brain cancer in adults. The best predictor of glioblastoma survival prior to Alter’s discovery was the patient’s age at diagnosis.

Some of the specific genes that Alter’s team found to be perturbed in glioblastoma, and in ovarian cancer, may be actively involved in promoting or inhibiting cancer development and progression. Future work will explore whether existing drugs that target these genes are effective in treating these diseases.

- MFP News Services
- 6/16/15

Overnight Fasting Could Lower Breast Cancer Risk for Women

UNIVERSITY OF CALIFORNIA – SAN DIEGO – A decrease in the amount of time spent eating and an increase in overnight fasting reduces glucose levels and may reduce the risk of breast cancer among women, report University of California, San Diego School of Medicine researchers in the journal Cancer Epidemiology, Biomarkers & Prevention.

The findings were presented recently the American Association of Cancer Research’s annual meeting in Philadelphia.

“Increasing the duration of overnight fasting could be a novel strategy to reduce the risk of developing breast cancer,” said Catherine Marinac, UC San Diego doctoral candidate and first author on the paper. “This is a simple dietary change that we believe most women can understand and adopt. It may have a big impact on public health without requiring complicated counting of calories or nutrients.”

University of California - San Diego

Women who fasted for longer periods of time overnight had significantly better control over blood glucose concentrations. The data shows that each three hour increase in nighttime fasting was associated with a 4 percent lower postprandial glucose level, regardless of how much women ate.

“The dietary advice for cancer prevention usually focuses on limiting consumption of red meat, alcohol and refined grains while increasing plant-based foods,” said co-author Ruth Patterson, PhD, UC San Diego Moores Cancer Center associate director for population sciences and program leader of the cancer prevention program. “New evidence suggests that when and how often people eat can also play a role in cancer risk.”

Women in the study reported eating five times per day with a mean nighttime fasting of 12 hours. Those who reported longer fast durations also indicated they consumed fewer calories per day, ate fewer calories after 10 p.m. and had fewer eating episodes.

Researchers recommend large-scale clinical trials to confirm that nighttime fasting results in favorable changes to biomarkers of glycemic control and breast cancer risk.

- MFP News Serives
- 5/24/15

Cancer drug Might Be a Possible Cure for Hepatitis B

MELBOURNE, AUSTRALIA – Scientists have found a potential cure for hepatitis B virus (HBV) infections, with a promising new treatment proving 100 per cent successful in eliminating the infection in preclinical models.

Australian patients are now the first in the world to have access to the potential treatment – a combination of an antiviral drug and an anti-cancer drug – which is in phase 1/2a clinical trials in Melbourne, Perth and Adelaide.

Walter and Eliza Hall Institute

Scientists from Melbourne’s Walter and Eliza Hall Institute developed the combination treatment using birinapant, a drug developed by US biotech company TetraLogic Pharmaceuticals for treating cancer. Hepatitis B is a chronic viral disease that is currently incurable.

Dr Marc Pellegrini, Dr Greg Ebert and colleagues at the institute used their studies of the behaviour of hepatitis B virus in infected cells as a basis for the treatment. The research was published today in two papers in the journal Proceedings of the National Academy of Sciences.

Dr Pellegrini said the treatment was successful in curing infections in preclinical models, leading to a human trial that began in December 2014. “We were 100 per cent successful in curing HBV infection in hundreds of tests in preclinical models,” Dr Pellegrini said.

“Birinapant enabled the destruction of hepatitis B-infected liver cells while leaving normal cells unharmed. Excitingly, when birinapant was administered in combination with current antiviral drug entecavir, the infection was cleared twice as fast compared with birinapant alone. We are hopeful these promising results will be as successful in human clinical trials, which are currently underway in Melbourne, Perth and Adelaide.”

The combination treatment, developed in collaboration with TetraLogic Pharmaceuticals based in Malvern, Pennsylvania, US, targets the cell signalling pathways that the hepatitis B virus uses to keep host liver cells alive.

Chronic infectious diseases such as HBV live within the host’s cells, enabling them to persist within the body for many months or years, Dr Pellegrini said.

“Normally, liver cells would respond to infection by switching on a signal that tells the cell to destroy itself ‘for the greater good’, preventing further infection,” he said. “However our research showed that the virus commandeers the liver cells’ internal communications, telling the cells to ignore the infection and stay alive. Birinapant flips the cell survival ‘switch’ used by the virus, causing the infected cell to die.”

More than two billion people worldwide are infected with hepatitis B and approximately 400 million have a chronic HBV infection. The virus infects liver cells and can lead to complications including cirrhosis and liver cancer, resulting in more than 780,000 deaths annually.

Treatments that enable the host cell to rid itself of the virus, rather than targeting the virus itself, may prevent drug-resistant strains of HBV emerging, Dr Pellegrini said. “It is relatively easy for an organism to adapt to a drug, but it is very difficult to adapt to a change in the host cell,” he said. “The virus relies on the survival mechanisms of the host, so if it can’t exploit them, it dies. Such a monumental change in the virus’ environment may be too big a hurdle for it to adapt to.”

Dr Pellegrini and colleagues will now investigate if the same strategy could be applied to other chronic infectious diseases. “Pathogens that infect and reside inside host cells, including viral diseases such as HIV, herpes simplex and dengue fever, and bacterial infections such as tuberculosis, could all potentially be cured in a similar way,” he said.

Patients are currently being recruited for the clinical trial in Melbourne by Nucleus Network, situated at the Alfred Hospital; in Perth by Linear Clinical Research, located at Sir Charles Gardiner Hospital; and in Adelaide by IDT CMAX, situated at the Royal Adelaide Hospital.

- MFP News Services
- 5/22/15