Posts Tagged ‘science’

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.

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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.

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‘K-to-M’ Histone Mutations: How Repressing Repressors May Drive Tissue-Specific Cancers

In 2012, investigators from multiple research institutions studying the sequence of the genome from cancer patients rocked the “chromatin world” when they independently reported that mutations in the gene that encodes histone H3.3 occurred in aggressive pediatric brain tumors. This finding was stunning, as researchers had never before associated histone mutations with any disease, much less a deadly tumor. What followed was a race by cancer researchers worldwide to discover how histone mutations might promote tumorigenesis.

Now a paper from a laboratory at the Stowers Institute of Medical Research reports the first animal model created to assess the molecular effects of two different histone H3.3 mutations in the fruit fly Drosophila. The study from a team led by Investigator Ali Shilatifard, Ph.D. published in the August 29, 2014 issue of Science, strongly suggests that these mutations actually could drive cancer and identifies interacting partners and pathways that could be targeted for the treatment of cancer.

Molecular biologists categorize these mutations as “K-to-M,” because a normal lysine residue (symbolized by K) in the protein is replaced by methionine (M) through mutations in the DNA sequence. In pediatric tumors, K-to-M mutations occurred at lysine residue 27 (K27) of histone H3.3. Researchers suggested that the presence of even a small population of these damaged proteins in the nucleus muffled a large repressor complex called PRC2. Normally, PRC2 acts as an enzyme to decorate histone lysines with one or more methyl groups, which silences gene expression by squeezing associated DNA into an impenetrable coil.

“Previously scientists knew that mutations in methylating enzymes like PRC2 occur in some cancers,” says Shilatifard. “What was surprising here was finding that mutation in one of the copies of the histone H3 gene, one of the proteins that PRC2 modifies, is associated with cancer. To figure out how that happened, we were interested in developing an in vivo model for the process in systems that we can study.”

The team first engineered a version of histone H3.3 that mimicked the K27-to-M mutation and then inserted that construct into embryonic fly tissues to produce the damaged protein in a living fruit fly. Using antibodies that recognize methylated lysines, they discovered that a dose of the mutant protein was sufficient to decrease global methylation of normal histone H3.3 proteins at K27, just as loss of the PRC2 repressor would. When the group engineered a similar K-to-M mutant at lysine 9 (K9), they saw similar results. This analysis of the H3K27 and H3K9 mutants confirmed in vivo that K-to-M mutations in histone H3.3 repress a key repressor, PRC2, but did not nail down how this happened.

“One question was whether a single amino acid change like this could alter the way histone H3.3 interacts with other proteins,” says Marc Morgan, Ph.D., a co-first author of the paper, “The mutant could be either losing or gaining something.” To determine which, the group collaborated with the Stowers Proteomics Center to compare factors binding to normal histone H3.3 versus the K-to-M mutants using mass spectrometry.

That analysis revealed that the presence of mutant histones globally dampens histone interactions with some of the usual repressor suspects. But in what Morgan calls an “Aha!” moment, they detected promiscuous association of a demethylase called KDM3B with the histone H3K9 mutant. “This suggests that these mutations inappropriately pull a demethylating enzyme onto chromatin, which then erases methylation marks in histones around it,” Morgan says.

Loss of methylation marks could allow expression of nearby genes. To confirm this, the group employed a Drosophila staining trick that allows experimenters to visualize how repressed genes are affected in entire tissues. The expression of KDM3B demethylase derepressed the gene expression in tissues such as salivary glands, just like the expression of the H3K9 mutant. This supports the idea that K-to-M mutations recruit a demethylase (like KDM3B) to demethylate chromatin on the K9 residue of H3.3 proteins in the neighborhood, where it likely uncoils chromatin to allow activation of genes that should be silenced.

This outcome could cause cancer in numerous ways. “One possibility might be that oncogenes that are usually silenced by methylation of residue 9 might be derepressed in the presence of the mutation,” says Hans-Martin Herz, Ph.D., a co-first author of the paper. But Herz is cautious in interpreting these findings, simply because, unlike the K27 mutations, mutations at residue K9 are not yet reported to be associated with cancer.

Intriguingly, other researchers recently reported a different K-to-M mutation (at residue 36 of histone H3.3) in chondroblastoma, a bone cancer sub-type. Why K-to-M mutations are so specific to a particular cancer is unknown, but Shilatifard says there can be little doubt that they play a central rather than a bystander role in tumorigenesis. “Uncharacterized K-to-M mutations may occur in other cancers,” he says. “Our work allows us to identify the molecular players involved in chromatin signaling in Drosophila and then apply those findings to human cells.”

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