Posts Tagged ‘cancer’

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

Prostate cancer: Pioneering new imaging method

Severely ill prostate cancer patients are helping researchers test a diagnostic tool that involves injecting a radioactive substance into their bodies. Norway has the fifth highest mortality rate for prostate cancer in Europe.

Four doses of a radioactive tracer called 18F- FACBC are on their way from Oslo to Trondheim in a private jet. Three NTNU researchers, one doctor, two radiographers and a bioengineer fidget nervously as they wait. They check the time.

The plane cannot be delayed. Today is a bad day for fog to descend around Oslo’s main airport, Gardermoen, or for there to be a traffic jam between the Trondheim airport and the city hospital, St. Olavs. Everything has to be on time.

Radioactive decay

From the second that 18F- FACBC is injected into its container, it begins to degrade. In 110 minutes, half of the radioactive substance is gone. If the plane is delayed too much, there won’t be any radioactivity left for the last patient. Then more doses have to be flown up from Oslo.

Now the plane is 20 minutes late. Time really is money when it comes to this radioactive substance. One dose costs NOK 30 000 (3700 Euros). The first patient is already on the table, ready for the procedure. He has an aggressive form of prostate cancer. Doctors fear that it has spread to his lymph nodes.

Now he is waiting to be examined with the most advanced imaging technology that can be found in Norway, a combined PET MRI scan with a price tag of NOK 50 million. He will have to lie still in what boils down to a tiny cave for over an hour while the machine scans and makes images of his blood, bones, and cancer cells.

Finding its way through the body

But this kind of advanced imaging requires a radioactive tracer. With its short half-life, 18F- FACBC (which is an abbreviation for 1-amino-3-fluorine 18-fluorocyclobutane-1-carboxylic acid) has just the right characteristics for the job.

The medical team works quickly when the doses finally arrive at the hospital.

Fortunately, the timing is perfect. First the patient is given an injection of the tracer in his arm, and then placed into the machine, where the tracer finds its way into his veins.

For the radioactive substance to find its way into cancer cells, it needs to have a carrier, a kind of pilot that is able to lead the way to the tumours. In this case, an amino acid acts as the carrier. This is because of cancer cells’ appetite for certain amino acids. A cancer cell is much more active than other cells. It needs more building blocks than other cells, more food. As a result, it attracts and absorbs the amino acid that has been injected into the body.

The radioactive tracer is picked up by detectors that are placed in a ring around the patient in the scanner, and the machine makes images of the cancer cells that light up from the tracer. At the same time, MRI photos of the area are taken, so that doctors get a unique package of information to help them determine which type of treatment is appropriate.

Eight private jets

After an hour, the scan is over and the patient is backed out of the PET MRI. A day later, all of the radioactivity will have left his body. In a few days, he will be in surgery. Hopefully, he has a number of healthy years left to live.

It will take a few years, however, before researchers will be able to conclude how PET MRI scans can be used to improve the diagnosis and treatment of prostate cancer. First, they need to conduct their study with 32 patients. Eight private jets of radioactive tracer will need to be flown to Trondheim, at a cost of NOK 960 000 for this substance.

Shorter, less surgery

This is the first research study in the world where amino acids and PET MRI are being used to try to improve the diagnosis of prostate cancer.[faktaboks=”1″ stillopp=”hoyre” storrelse=”liten”/]

Currently, doctors remove the lymph nodes found in the pelvis of patients with aggressive prostate cancer, without really knowing if it is necessary. Only by cutting into the lymph nodes after they have been removed can doctors determine if the cancer had actually spread.

The NTNU researchers’ goal is for PET MRI to be able to do this detective work before the patient has to undergo surgery, so that surgeons know whether or not removing a patient’s lymph nodes is actually necessary. As a result, some patients should be able to have shorter, less involved surgery, which means less side effects and potential complications.

Diagnoses and the answer key

Researcher will go through the images of all 32 study participants, and then compare these images to their “answer key,” which in this case are the lymph nodes that were removed and biopsied from the patients. Comparing the nodes with the PET MRI images will show whether or not the scans can be used to help in the diagnosis of prostate cancer.

source : http://www.sciencedaily.com/releases/2014/09/140904084500.htm

Breast conserving therapy shows survival benefit compared to mastectomy in early-stage patients with hormone receptor positive disease

The study findings defy the conventional belief that the two treatment interventions offer equal survival, and show the need to revisit some standards of breast cancer practice in the modern era.

The research was presented at the 2014 Breast Cancer Symposium by Catherine Parker, MD, formerly a fellow at MD Anderson, now at the University of Alabama Birmingham.

In the 1980s, both US-based and international randomized clinical studies found that BCT and mastectomy offered women with early stage breast cancer equal survival benefit. However, those findings come from a period in time when very little was understood about breast cancer biology, explains Isabelle Bedrosian, M.D., associate professor, surgical oncology at MD Anderson.

“Forty years ago, very little was known about breast cancer disease biology — such as subtypes, differences in radio-sensitivities, radio-resistances, local recurrence and in metastatic potential,” explains Bedrosian, the study’s senior author. “Since then, there’s been a whole body of biology that’s been learned — none of which has been incorporated into patient survival outcomes for women undergoing BCT or a mastectomy.

“We thought it was important to visit the issue of BCT versus mastectomy by tumor biology,” Bedrosian continues.

The researchers hypothesized that they would find that patients’ surgical choice would matter and impact survival with tumor biology considered.

For the retrospective, population-based study, the researchers used the National Cancer Database (NCDB), a nation-wide outcomes registry of the American College of Surgeons, the American Cancer Society and the Commission on Cancer that captures approximately 70 percent of newly-diagnosed cases of cancer in the country. They identified 16,646 women in 2004-2005 with Stage I disease that underwent mastectomy, breast conserving surgery followed by six weeks of radiation (BCT), or breast conserving surgery without radiation (BCS). Bedrosian notes that it was important that the study focused solely on women with Stage I disease in order to keep the study group homogenous and because in this cohort few would be ineligible for BCT.

Since estrogen receptor (ER) and progesterone receptor (PR) data were available and HER2 status was not, the researchers categorized the tumors as ER or PR positive (HR positive), or both ER and PR negative (HR negative). Patients were rigorously matched using propensity-score for a broad range of variables, including age, receiving hormone therapy and/or chemotherapy, as well as type of center where patients were treated and comorbidities.

Of the 16,646 women: 1,845 (11 percent) received BCS; 11,214 (67 percent) received BCT and 3,857 (22 percent) underwent a mastectomy. Women that had BCT had superior survival to those that had a mastectomy or BCS — the five-year overall survival was 96 percent, 90 percent and 87 percent, respectively. After adjusting for other risk factors, the researchers again found an overall survival benefit for BCT compared to BCS and mastectomy. In a matched cohort of 1,706 patients in each arm, the researchers still found an overall survival benefit with BCT over mastectomy in the HR positive subset but not in the HR negative subset.

While provocative, Bedrosian cautions that the findings are not practice changing, as the study is retrospective. Still, the research complements other recent studies that showed BCT was associated with a survival benefit compared to mastectomy. Also, she points to the delivery of radiation therapy as the possible driver of the overall survival benefit.

“We’ve historically considered surgery and radiation therapy as tools to improve local control,” says Bedrosian. Yet recent studies suggest that there are survival-related benefits to radiation in excess of local control benefits. Therefore, radiation may be doing something beyond just helping with local control. Also, we know hormone receptive positive tumors are much more sensitive to radiation, which could explain why we found the survival benefit in this group of patients.”

As follow up, Bedrosian and her team hope to mine the randomized controlled trial findings from the 1980s, matching those cohorts to current NCDB patients to see if a similar survival benefit could be observed.

“While retrospective, I think our findings should give the breast cancer community pause. In the future, we may need to reconsider the paradigm that BCT and mastectomy are equivalent,” she says. “When factoring in what we know about tumor biology, that paradigm may no longer hold true.”

source : http://www.sciencedaily.com/releases/2014/09/140904103336.htm