Posts Tagged ‘study’

Innovative algorithm spots interactions lethal to cancer

But a concept called “synthetic lethality” holds great promise for researchers. Two genes are considered synthetically lethal when their combined inactivation is lethal to cells, while inhibiting just one of them is not. Synthetic lethality promises to deliver personalized, more effective, and less toxic therapy. If a particular gene is found to be inactive in a tumor, then inhibiting its synthetic lethal partner with a drug is likely to kill only the cancer cells, causing little damage to healthy cells.

While this promising approach has been widely anticipated for almost two decades, its potential could not be realized due to the difficulty experimentally identifying synthetic lethal pairs in cancer. Now new research published in the journal Cell overcomes this fundamental hurdle and presents a novel strategy for identifying synthetic lethal pairs in cancer with the potential to bust cancer cells.

Tel Aviv University researchers have developed a computational data-driven algorithm, which identifies synthetic lethal interactions. In their comprehensive, multidisciplinary study, Dr. Eytan Ruppin of TAU’s Blavatnik School of Computer Science and the Sackler School of Medicine and Ms. Livnat Jerby-Arnon of TAU’s Blavatnik School of Computer Science worked together with other researchers from TAU, The Beatson Institute for Cancer Research (Cancer Research UK), and the Broad Institute of Harvard and MIT.

Taking cancer personally

Analyzing large sets of genetic and molecular data from clinical cancer samples, the scientists were able to identify a comprehensive set of synthetic lethal pairs that form the core synthetic lethality network of cancer. They have demonstrated for the first time that such a network can be used to successfully predict the response of cancer cells to various treatments and predict a patient’s prognosis based on personal genomic information.

“We started this research from a very simple observation: If two genes are synthetically lethal, they are highly unlikely to be inactive together in the same cell,” said Dr. Ruppin. “As cancer cells undergo genetic alterations that result in gene inactivation, we were able to identify synthetic lethal interactions by analyzing large sets of cancer genetic profiles. Genes that were found to be inactive in some cancer samples, but were almost never found to be inactive together in the same sample, were identified as synthetically lethal.”

The crux of the study, according to Ms. Jerby-Arnon, is the synergy between the computational research and the ensuing experiments, conducted at the Beatson Institute and the Broad Institute, to verify the predictive power of the new algorithm.

A road to new therapies

In addition to their promising role in tailoring personalized cancer treatment, the synthetic lethal pairs discovered may also be used to repurpose drugs, which are currently used to treat other non-cancer disorders, to target specific cancer types. “We applied our pipeline to search for drugs that may be used to treat certain forms of renal cancer. We identified two such drugs, currently used to treat hypertension and cardiac dysrhythmia, that may be quite effective,” said Dr. Ruppin. “Experiments in cell lines performed by the Gottlieb lab at the Beatson Institute support these findings, and we are now working on additional validations in mice.”

The researchers are hopeful that their study will help boost the experimental detection of synthetic lethality in cancer cells and offer further insight into the unique susceptibilities of these pathological cells. “In this study, we have demonstrated the clinical utility of our framework, showing that it successfully predicts the response of cancer cells to various treatments as well as patient survival,” said Ms. Jerby-Arnon. “In the long-run, we hope this research will help improve cancer treatment by tailoring the most effective treatment for a given patient.”

The researchers are in the process of forming experimental and clinical international collaborations to test key emerging leads for novel drug targets and drug repurposing.

source : http://www.sciencedaily.com/releases/2014/09/140903163532.htm

Family conflicts, other non-physical worries before cancer surgery raise patients’ complication risk

The findings are published in the Journal of Gastrointestinal Surgery.

“We know that quality of life is a very complex thing, but we can now measure it and work with it almost like blood pressure,” says lead author Juliane Bingener, M.D., a gastroenterologic surgeon at Mayo Clinic in Rochester. “We can say, ‘This is good, this is in the normal range, but this one here, that is not good, and maybe we should do something.'”

Quality of life as measured in the study is about more than happiness and how well people feel physically, Dr. Bingener says. It also includes the financial, spiritual, emotional, mental and social aspects of their lives and whether their needs are being met.

Researchers studied 431 colon cancer surgery patients and found that before surgery, 13 percent had a quality of life deficit, defined as an overall quality of life score of less than 50 on a 100-point scale.

Nearly three times as many patients who entered surgery with a quality of life deficit experienced serious post-surgery complications as those with a normal or good quality of life score. Patients with a postoperative complication spent 3.5 days longer in the hospital on average than those who didn’t.

“The question I’m exploring is whether, if we understand before surgery that someone is in the red zone for quality of life, can we do something to help them cope with the new stress that’s going to come, so they’re better equipped to go through surgery?” Dr. Bingener says.

Preventing complications by intervening with behavioral therapy or other assistance would likely cost much less than an ICU stay for an infection after major surgery, Dr. Bingener notes.

Stress can weaken patients’ immune response, putting them at higher risk of infection. A patient’s outlook on life can also influence how active they are in working to recover.

“You have a surgery, you’re lying there in pain, now you wonder, ‘Why should I even get up and walk around? Why do I have to do these deep-breathing exercises? I don’t feel like it.’ You might get pneumonia much faster than somebody who says, ‘Oh, I have to get up. There’s something worth living for, my quality of life is good and I need to get back to that,'” Dr. Bingener says.

The study is part of ongoing work by Mayo to identify and address factors that can influence patients’ recovery from cancer surgery, to help improve their outcomes. Years ago, physicians were just concerned with whether patients survived cancer, because survival was so hard to achieve, Dr. Bingener says. Now, there is growing awareness of the mind’s influence on the body’s health.

“We’re understanding much better now that patients are not just a body with a disease: There’s a whole person with that, and everything plays together,” Dr. Bingener says. “Now that survival is possible, we want to achieve it in a way that preserves normal life for patients as much as possible. And we think that’s probably also the most economical way to go.”

source : http://www.sciencedaily.com/releases/2014/09/140902114416.htm

Sabotage as therapy: Aiming lupus antibodies at vulnerable cancer cells

The findings were published recently in Nature‘s journal Scientific Reports.

The study, led by James E. Hansen, M.D., assistant professor of therapeutic radiology at Yale School of Medicine, found that cancer cells with deficient DNA repair mechanisms (or the inability to repair their own genetic damage) were significantly more vulnerable to attack by lupus antibodies.

“Patients with lupus make a wide range of autoantibodies that attack their own cells and contribute to the signs and symptoms associated with lupus. Some of these antibodies actually penetrate into cell nuclei and damage DNA, and we suspected that we may be able to harness the power of these antibodies for use in targeted cancer therapy,” Hansen said.

The genetic code that determines how a cell develops is written in DNA. Damage to this code can cause a cell to malfunction, die, or transform into a cancer cell. Normal cells are equipped to repair damaged DNA and preserve the genetic code, but many cancer cells have defective DNA repair machinery and accumulate genetic mutations.

This difference between normal cells and certain cancer cells creates an opportunity to develop therapies that damage DNA and only kill cancer cells that cannot repair the damage. However, DNA is sequestered inside cell nuclei, where delivery of therapies can be challenging. Yale Cancer Center researchers are finding that naturally occurring lupus antibodies just may be a solution to this problem.

“Lupus antibody-based cancer therapy is an emerging new concept, and I believe we are just seeing the tip of the iceberg in terms of the potential of this approach,” said Hansen.

The researchers previously found that a lupus antibody called 3E10 inhibits DNA repair and sensitizes cancer cells to DNA damage, and they have now found that the DNA-damaging lupus antibody 5C6 is toxic to DNA repair-deficient cancer cells.

“Now that we know that more than one lupus antibody has a selective effect on cancer cells, I am confident that additional lupus autoantibodies with even greater therapeutic potential await discovery,” Hansen said.

source : http://www.sciencedaily.com/releases/2014/09/140902151302.htm