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Barakat T.S.,Erasmus University Medical Center | Gribnau J.,Erasmus Medical Center
Journal of visualized experiments : JoVE | Year: 2014

Fluorescent in situ hybridization (FISH) is a molecular technique which enables the detection of nucleic acids in cells. DNA FISH is often used in cytogenetics and cancer diagnostics, and can detect aberrations of the genome, which often has important clinical implications. RNA FISH can be used to detect RNA molecules in cells and has provided important insights in regulation of gene expression. Combining DNA and RNA FISH within the same cell is technically challenging, as conditions suitable for DNA FISH might be too harsh for fragile, single stranded RNA molecules. We here present an easily applicable protocol which enables the combined, simultaneous detection of Xist RNA and DNA encoded by the X chromosomes. This combined DNA-RNA FISH protocol can likely be applied to other systems where both RNA and DNA need to be detected. Source

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For some adults, Zika virus is a rashy, flulike nuisance. But in a handful of people, the virus may trigger a severe neurological disease. About one in 4,000 people infected by Zika in French Polynesia in 2013 and 2014 got a rare autoimmune disease called Guillain-Barré syndrome, researchers estimate in a study published online February 29 in the Lancet. Of 42 people diagnosed with Guillain-Barré in that outbreak, all had antibodies that signaled a Zika infection. Most also had recent symptoms of the infection. In a control group of hospital patients who did not have Guillain-Barré, researchers saw signs of Zika less frequently: Just 54 out of 98 patients tested showed signs of the virus. Here's what we know about Zika How Zika became the prime suspect in microcephaly mystery Efforts to control mosquitoes take on new urgency The message from this earlier Zika outbreak is that countries in the throes of Zika today “need to be prepared to have adequate intensive care beds capacity to manage patients with Guillain-Barré syndrome,” writes study coauthor Arnaud Fontanet of the Pasteur Institute in Paris and colleagues, some of whom are from French Polynesia. The study, says public health researcher Ernesto Marques of the University of Pittsburgh, “tells us what I think a lot of people already thought: that Zika can cause Guillain-Barré syndrome.”  As with Zika and the birth defect microcephaly (SN: 2/20/16, p. 16), though, more work needs to be done to definitively prove the link. Several countries currently hard-hit by Zika have reported upticks in Guillain-Barré syndrome. Colombia, for instance, usually sees about 220 cases of the syndrome a year. But in just five weeks between mid-December 2015 to late January 2016, doctors diagnosed 86 cases, the World Health Organization reports. Other Zika-affected countries, including Brazil, El Salvador and Venezuela, have also reported unusually high numbers of cases. Despite the seemingly strong link between Zika and Guillain-Barré, Marques stresses that the risk of getting the syndrome after a Zika infection is quite low. “It’s important that people don’t think that if you get Zika, you are going to get Guillain-Barré.” The chance is much less than 1 percent, he says. And it’s too early to say whether the rate of Guillain-Barré estimated in the paper will be the same in ongoing Zika outbreaks, says Anna Durbin, a vaccine researcher at Johns Hopkins University. “We have a number now, but it’s not perfect,” she says. Ongoing studies in Brazil and other countries affected by Zika will help refine the rate. As suspected and confirmed Zika infections climbed in Colombia (black lines), cases of Guillain-Barré syndrome rose, too (blue bars). New cases of Guillain-Barré may be added retrospectively as they are confirmed. The syndrome begins as the body’s immune system attacks peripheral nerves, causing weakness or tingling sensations in the lower extremities. In severe cases, total paralysis can result, leaving people dependent on ventilators in intensive care units while they recover. Three to 5 percent of people with Guillain-Barré die from complications, scientists estimate. Other viruses, including HIV, influenza and dengue (like Zika, a flavivirus), are known to spark Guillain-Barré, possibly through their interactions with the body’s immune system, though the details remain mysterious. The timing of Guillain-Barré’s onset may make it easier for scientists to pin the disorder on Zika. Because the syndrome shows up days or weeks after an infection subsides, Guillain-Barré may offer a quicker readout of Zika’s effects than waiting months to see if microcephaly in babies are born to infected mothers, the WHO’s Bruce Aylward said in a news briefing February 19. Scientists conducting a multinational Guillain-Barré study may soon expand their study, called the International Guillain-Barre Syndrome Outcome Study, into Brazil and Colombia to look for signs of Zika infection in people with the syndrome. “We are developing a new version of the IGOS protocol that is more focused on Zika and other flaviviruses, to support the research in those countries,” says Bart Jacobs, an immunologist at Erasmus University Medical Center in Rotterdam, the Netherlands, who’s helping supervise the study. Further studies could also help explain why some people are susceptible to Guillain-Barré. Genetics, previous viral infections or toxins may all play a role.

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Florida police are searching for a man who lurks in the shadows. For more than two years, he has terrorized at least a dozen women, peeping into windows and slipping into bedrooms to watch them sleep. He has touched several women’s feet or hair — some, he has sexually assaulted. The media dubbed him the “Serial Creeper,” and police are desperate to find him. In September, they released a sketch of a dark-haired, dark-eyed Latino man with smooth skin, high cheekbones and a pointed chin. But the sketch wasn’t drawn by a police artist based on eyewitness accounts. The Creeper has kept his face covered in every assault, says Kelly Denham, a police officer in Coral Gables, Fla. “He’s never been seen.” So local police had to pursue a less-conventional route: They bought a computer-generated image based on the Creeper’s DNA. For $4,500, a company based in Reston, Va., called Parabon NanoLabs analyzed DNA that the Creeper left behind at crime scenes. The analysis zeroed in on genetic clues linked to hair color, eye color, facial features and ancestry. Then, Parabon crafted a digital mash-up of the Creeper’s face. The images Parabon creates don’t offer an exact picture of a suspect, says Ellen Greytak, Parabon’s bioinformatics director. “We work with law enforcement to give them an idea of who they should be looking for,” she says — or which people to cross off the suspect list. In the last few years, several scientists and companies have ventured into the new world of appearance prediction. It’s a hazy place, where the roots of a person’s looks hide out in their genetic instruction books. Scientists dig up these roots by linking people’s physical features with tiny landmarks in their DNA. If investigators could use DNA to predict nose width, say, or eye size, they might have an easier time tracking down criminals. Proponents say the technology can do more than give investigators a lead in a case. It could also help put a face to ancient people — long-lost ancestors, or perhaps even Neandertals. Some even imagine giving parents-to-be a glimpse at their unborn child’s visage, though that’s still a far-off dream. In truth, the science for conjuring a person’s appearance from DNA remains a little skimpy. Facial features may be shaped by hundreds or thousands of genes — each with very tiny effects. And scientists have only just begun to sort it all out. Hair, eye and skin color, as well as ethnic background, are relatively easy to pin down. But the genetic roots of other traits, such as height and face shape, are scattered throughout people’s DNA like dandelion seeds in the wind. It’s hard to track down every wispy speck. That’s why some researchers think current prediction attempts aren’t ready for prime time. Some attempts rely mostly on genetic information about sex and ancestry (whether a person is male and of European descent, for example) to construct an image of someone’s face, says Manfred Kayser, a geneticist at Erasmus University Medical Center in Rotterdam, the Netherlands. And that, he says, “is not much more accurate than using your imagination.” Until recently, the face of one of England’s most notorious kings was left to artists’ imaginations. Known for his twisted spine and villainous ways, King Richard III probably had brown hair and dark eyes. Or maybe light hair and blue eyes — portraits painted after his death varied. But now, DNA has given scientists a better picture. In 2012, more than 500 years after Richard was cut down in battle, archaeologists dug up the monarch’s yellowed skeleton under a parking lot in England (SN: 3/9/13, p. 14). Analyses of dozens of genetic clues from the DNA in his ancient bones finally offered solid details about Richard’s appearance, Kayser and colleagues reported last year in Nature Communications (SN Online: 12/2/14). “Quite certainly he had blue eyes,” Kayser says. “And it’s very likely that he was blond as a kid and either blond or light brown as an adult.” Kayser and colleagues knew what to look for because they and other scientists have tracked down genes controlling hair and eye color. The researchers first had to scan the genetic instruction books of thousands of people. Each person’s instruction book, or genome, holds 3 billion chemical base pairs, DNA “letters” that spell out the plans for everything from sex to skin color. Most of those letters don’t vary much from person to person. But scientists can use slight changes in the text, one-letter differences called single nucleotide polymorphisms, to predict certain physical features. Kayser’s team can, for example, deduce a person’s eye color by looking at just six letters spread out over six genes. To figure out hair color, the researchers focus on 22 letters. For blue or brown eyes, the team’s predictions are more than 90 percent accurate. Hair color is almost as good, with accuracies ranging from about 80 to more than 90 percent — pointing out a redhead is the easiest. The team has used its system, called HIrisPlex, on DNA from King Richard’s bones. The system has crime-fighting appeal as well. It can pick out a person’s hair and eye color from blood, semen and saliva — even when DNA in the samples has broken down, the researchers reported last year in Forensic Science International: Genetics. That’s a big deal because forensic DNA can get shabby. If samples sit around too long at crime scenes, DNA can fall to pieces, becoming hard to analyze. With hair and eye color in hand, Kayser’s team has now added skin color to its system, the team reported in September at the International Society for Forensic Genetics meeting in Krakow, Poland. Preliminary results suggest that the skin-color test is about as accurate as the tests for eye and hair color. Clues about coloring are a good start for estimating appearance, but prediction tools are still rough around the edges. Eye colors other than blue and brown are difficult to predict, and DNA can’t distinguish between blond adults and brunet adults who were blond as children, for example. This person’s red hair and blue eyes were predicted using the HIrisPlex DNA testing system, which offers probabilities (see numbers) about a person’s likely coloring. Still, those traits, along with ancestry, are the easy ones, the low-hanging fruit, says geneticist Peter Visscher of the University of Queensland in Australia. Other features can be much harder for scientists to grab onto. Height and face shape, for example, are still mostly out of reach. If not for a scoliosis-curved spine, King Richard would have stood about 5 feet, 8 inches tall. Scientists calculated this number from the length of his thighbone. Using his DNA probably would have gotten them only somewhere in the ballpark. “For any individual, your best guess might be correct — but it might be off by two or three inches,” Visscher says. When it comes to predicting traits from DNA, two main factors come into play, he says. The first is how much genes, versus environment, influence a certain trait. (For some traits, like body weight, environment plays a big role.) The second is how many genes are involved. If lots of genes affect nose shape, for example, each gene’s individual contribution may be tiny and hard to suss out. The number of genes influencing height could be huge — probably in the thousands, Visscher says. For height more than any other complex trait, scientists have made a Herculean effort. Last year, Visscher and more than 400 colleagues pulled together data from 79 studies that scanned the genomes of more than 250,000 people. The analysis uncovered about 10,000 DNA letters linked to height sprinkled throughout the genome, the researchers reported in Nature Genetics. But even all that information isn’t enough for researchers to pin down a person’s height using  just his or her DNA. And if scientists can’t predict a well-studied trait like height, there’s even less hope for other, more obscure traits, like mouth size or distance between the eyes. In five to 10 years, Visscher says, with more data from more people, scientists might be able to say whether a person is much taller or shorter than average. But now, predicting height from DNA “is not good enough to be particularly helpful,” he says. “My guess is that it’s probably even worse for facial features.” A person can change the look of his or her face with a little makeup or a new haircut. But the underlying architecture — the length of the nose, the size of the ears — comes mostly from mom and dad. Scientists know that the blueprints for people’s features lie in their genes, Kayser says, but they have “an embryonic understanding of where in the genes.” He has been part of recent attempts to flesh out the links between DNA and appearance. In 2012, Kayser and colleagues used DNA and 2-D or 3-D images of nearly 10,000 participants to pick out five genes that influence face shape. One of those genes, PAX3, seems to tweak the bridge of the nose; that gene was also identified by other researchers earlier that year. Those findings are a great start, says Benedikt Hallgrimsson, an evolutionary biologist at the University of Calgary in Canada. But overall, “we still don’t know very much about the genetics of the shape of the face.” Tiny differences in a person’s DNA, known as single nucleotide polymorphisms, or SNPs, can help predict physical features. Some traits are easier to predict than others. Last year, researchers tried to ferret out more clues. In a controversial paper published in PLOS Genetics, Penn State anthropologist Mark Shriver and colleagues crafted 3-D models of people’s faces by tapping into genetic information from 592 participants. That’s not nearly enough people to study something so complex, Hallgrimsson says. Some of the data Parabon uses in its analyses come from Shriver’s collection efforts, but even Shriver isn’t convinced that face-predicting technology is ready for the mainstream. Hallgrimsson agrees: “My worry is that they’re going into this too soon on too shaky a foundation of science.” Parabon hasn’t yet published a study that tests its predictions’ accuracy, but several law enforcement agencies have checked it out, says bioinformatics director Greytak. Sometimes agencies give the company a test drive, and send out a few DNA samples before buying the product. The agencies then compare photographs with Parabon’s predictions. “We’ve nailed every single one of those,” Greytak says, though the agencies haven’t made test results public. Parabon’s predictions consider genetic information about sex, ancestry and facial characteristics from databases that include about 15,000 people. Still, Greytak says, “we need a lot more data. That’s the big thing.” If you want to capture the variation of human faces, she says, you need to know what a wide variety of faces look like relative to their genetics. Greytak acknowledges that Parabon’s technology can’t identify individuals, like a photograph can. But the technology is “absolutely ready from the point of view of exclusion,” she says. Investigators can use the images to rule out suspects. So in the search for the Serial Creeper, for example, police could eliminate suspects with red hair and blue eyes. For the Creeper, who hasn’t been linked to a crime since August, the profile gave stumped investigators a new avenue to explore. “We’re at a standstill in the investigation — that’s why we turned to the Parabon DNA profile,” Denham says. “Let’s see what we can come up with to try and find this guy.” This article appears in the December 12, 2015, issue of Science News with the headline, "What's in a face?"

The research, which is published online Jan. 28, 2016 in the journal Molecular Cell, indicates XPG is essential to our health in ways far beyond it's been given credit for. "We discovered a new function for an "old" repair protein that shows the protein is key to genome stability, and is probably important for suppressing breast and ovarian cancer," says Priscilla Cooper of Berkeley Lab's Biological Systems and Engineering Division. She conducted the research with Kelly Trego and several other Berkeley Lab researchers, and scientists from Colorado State University, Yale University, and Erasmus University Medical Center in the Netherlands. Scientists have known for years that XPG helps carry out a DNA repair process that activates when only one of DNA's two strands is damaged. The process, called nucleotide excision repair, removes DNA lesions caused by sun exposure, chemotherapy, and other sources. Now, to their surprise, the Berkeley Lab scientists discovered XPG is also instrumental in a process called homologous recombination, which repairs breaks on both DNA strands in cells that are copying their genomes to get ready to divide. Double-strand breaks are especially perilous to an organism because they can lead to genome rearrangements in a cell. The scientists learned that XPG interacts with at least five other cellular proteins, including BRCA1 and BRCA2, to carry out homologous recombination. Defects in genes that express BRCA1 and BRCA2 are known causes of breast, ovarian, pancreatic, and prostate cancer. Their new study shows that cells with reduced levels of XPG have a much higher prevalence of genome instability in the form of cell cycle defects, DNA double-strand breaks, chromosomal abnormalities, and other problems. The first hint that XPG does something in addition to nucleotide excision repair came about two decades ago when scientists learned that particular mutations in the gene that codes for XPG cause an extremely rare and devastating premature aging disorder called Cockayne syndrome. Nucleotide excision repair is not implicated in Cockayne syndrome, so scientists knew XPG must play a role in another fundamental cellular process. What that function was, however, remained a big mystery. "We've spent the past several years searching for this unknown function of XPG," says Trego. To begin their search, the Berkeley Lab scientists reduced the expression of XPG in human cells and studied what happened. These "knockdown" cells had a slew of problems associated with cell growth and cell cycle, as well as an increase in DNA double-strand breaks. Next, the scientists set out to determine whether these problems are caused by a breakdown in the DNA replication process, in which two identical copies of DNA are made from one DNA molecule. They treated the cells with a chemical that causes replicative stress, and sure enough, the cells with reduced XPG levels were much more susceptible to the chemical. This narrowed the search to homologous recombination repair, which is the most prevalent way of fixing broken replication forks. More research all but confirmed XPG's importance in homologous recombination repair: the scientists found that cells with reduced levels of XPG had a 50 percent loss in the repair process. In a final step, the scientists mapped out mechanistically how XPG helps drive homologous recombination repair. Their results suggest that XPG swoops in during the initial stage of the process to clear chromatin of BRCA1, a protein that helps initiate repair. This step is thought to serve as a "reset button" for homologous recombination repair to allow the process to proceed. Almost nothing was known about this important step until now. The scientists also found that XPG interacts with BRCA2 during a later stage in the process to load a protein called RAD51 onto DNA in need of repair. RAD51 is the "recombinase" protein that is essential for carrying out homologous recombination repair, but it needs help loading onto damaged DNA to perform its function. "Until now, these direct interactions between XPG and BRCA1, BRCA2, and RAD51 during homologous recombination repair were unknown," says Cooper. "These interactions, and the greatly increased genome instability that occurs in XPG's absence, strongly suggest the protein is another important tumor-suppressor protein." Explore further: Enhanced DNA-repair mechanism can cause breast cancer

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When the patient entered a trial of an experimental prostate-cancer treatment, he was in bad shape. The disease had spread to at least ten different parts of his body, including his arm and leg bones, and his hip, spine and ribs. The tumours caused him so much discomfort that, despite heavy use of pain-relieving medication, he was unable to sit up. Chemotherapy had failed to halt the spread of the cancer. But now, nearly seven years after finishing the trial, the patient's tumours have disappeared, his pain has vanished and his blood levels of prostate-specific antigen (PSA; a protein biomarker used to monitor malignancy) give no indication of the disease. “We always are cautious using the word 'cure',” says Fred Saad, a prostate-cancer researcher at the University of Montreal in Canada, who ran the study. “There are diseases we have cured in a very advanced stage, like lymphoma, like testicular cancer,” he says. But despite individual successes, advanced prostate cancer is still considered to be incurable. Many men with the disease have tumours that grow so slowly that they never cause a problem. Others can be cured by treating the tumour within the prostate gland. But in some, the cancer spreads to elsewhere in the body, usually to the bones. The first line of treatment for these men is to suppress the male sex hormones (androgens), such as testosterone, that stimulate prostate tumours to grow — a form of chemical castration. Within a year or two, however, tumours become resistant to this treatment. Until the early 2000s, there were no available treatment options for castration-resistant prostate cancer (CRPC). Since 2010, a handful of therapeutic strategies for treating CRPC have emerged. But at best, they add a few months to patients' median survival time. So researchers are working to understand the mechanisms by which prostate cancer is able to resist efforts to overcome it, and to develop approaches that can permanently defeat the disease. Saad's study is one such attempt1. The phase II trial focused on men with metastatic CRPC whose condition had worsened despite undergoing chemotherapy with docetaxel, a drug from the taxane family. The researchers focused on clusterin, a protein that increases in concentration when cells are stressed and seems to protect the cells from damaging agents. Researchers suspect that clusterin helps various types of tumour to become resistant to drugs used in chemotherapy. By inhibiting clusterin with a drug known as custirsen, the team hoped to once again make CRPC tumours vulnerable to the effects of chemotherapy. The results of the trial were encouraging. Men who received custirsen together with docetaxel and the immunosuppressant drug prednisone showed a reduction in both pain and PSA levels. Saad's patient with the impressive results, who was 62 when he started the trial, had seen his PSA level shoot up from 74 to 115 nanograms per millilitre in the 3 weeks before treatment (a PSA level below 4 ng ml−1 is generally considered normal; a man who has had his prostate removed and is now cancer free should have a level of 0). Within 2 weeks of starting the trial, his PSA levels had dropped to around 70 ng ml−1, and after 24 weeks, they had plummeted to less than 0.03 ng ml−1. Seven years on, the patient's PSA level is undetectable. Although this particular case does not prove that custirsen can cure prostate cancer, Saad thinks that it is remarkable. The larger story of custirsen — an example of a DNA-based 'antisense' drug that binds to RNA and switches a gene off — is less clear. A phase III trial that used custirsen alongside docetaxel and prednisone showed no statistically significant improvement in the survival of participants with advanced prostate cancer compared with those who received the same treatment, but without custirsen. The results of another phase III trial, which combines custirsen and prednisone with a different anticancer drug, cabazitaxel, are expected by early 2016. Saad says that the key to finding effective treatments for advanced prostate cancer lies in identifying those men — like his star patient — who will respond to a given therapy, perhaps because of a particular mutation or variation in their tumour. That requires determining which molecular mechanisms help to confer resistance to drugs in certain people, and finding ways to test for them. Large studies that are unable to identify subgroups of patients who respond to a therapy can lead researchers to dismiss drugs that would work well in the right individuals. “The ones that are actually responding are drowned in a sea of non-responders,” says Saad. The resistance of prostate cancer to chemical castration develops by several routes. One biomarker of a particular mechanism of resistance has already been found — a receptor protein that binds androgens within the cell. Two new anti-androgen drugs, enzalutamide and abiraterone, can extend the lives of men with metastatic prostate cancer by up to three years. Eventually, those drugs stop working in almost all men — but 20–40% of patients never respond at all2. The reason for this initial resistance is a variation in the messenger RNA sequence that is used as a template for building the androgen-receptor protein itself. To make the receptor, the DNA of the androgen-receptor gene is first converted into a sequence of RNA that encodes all parts of the receptor protein. Any RNA that does not code for protein is cut out and the remaining pieces of RNA are joined or 'spliced' together to produce the receptor template. Occasionally, pieces of protein-coding RNA are also removed during splicing, which creates different versions — splice variants — of the receptor template. In one, androgen-receptor variant 7 (AR-V7), the receptor is missing its ligand-binding area, called the carboxyl terminal. This is what the androgen normally attaches to, but with no receptor mechanism to interfere with, the drugs are powerless. However, the area of the androgen receptor that triggers the cell to divide, found at the protein's opposite end, still works. “It can cause the cancer cell to grow and divide even without testosterone being present,” says Emmanuel Antonarakis, an oncologist at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, Maryland, who helped to identify the variant. Using a blood test, Antonarakis has compared men whose tumours contain AR-V7 with those whose tumours do not. Whereas men who tested negative for AR-V7 responded equally well to both anti-androgen drugs and chemotherapy with taxanes, those with AR-V7 did not respond to the anti-androgen drugs. But they did respond to chemotherapy with taxanes, which disrupt the microtubules that help cells to divide. Antonarakis's finding is supported by a study from the Erasmus University Medical Center Rotterdam in the Netherlands, in which investigators showed that AR-V7 does not diminish the effect of the taxane cabazitaxel3. A study from University Hospital Ulm in Germany confirmed the link between the variant and androgen resistance4. If these findings hold up, Antonarakis says that men with AR-V7 could skip the anti-androgen treatment and go straight for chemotherapy. Men who test negative can choose between the two. Soon, there might also be more treatment options for men with AR-V7. The drug galeterone, for example, the subject of a phase III trial, works in three different ways. Like enzalutamide, it prevents androgens from binding to their receptors. And like abiraterone, it interferes with the production of testosterone. But galeterone also degrades the androgen receptor itself — an action that could prevent the cell from becoming resistant to the other two lines of attack. According to Antonarakis, galeterone is the first anti-androgen drug “that actually may be effective in men who have AR-V7”. So far, testing has shown that PSA levels dropped in men with CRPC who took galeterone during phase II trials. Initial results of a phase III trial, which focuses specifically on men with AR-V7, are expected by the end of 2016. Essa Pharma of Vancouver, Canada, is taking a different approach to the problem of resistance with its drug EPI-506, currently being prepared for phase I/II testing. Although most anti-androgen drugs target the end of the androgen receptor to which androgens bind, Essa's drug is the first to target the receptor's opposite end, which can interact with the DNA of the cell. By blocking this part of the receptor, the drug could prevent it from doing its job — stopping the cancer in its tracks. “If it can't bind to DNA, it can't switch on these genes to divide, multiply and spread,” Antonarakis says. Splice variants are not the only way that prostate cancer can become resistant to anti-androgen drugs. When hit with a therapy, the disease — like any other cancer — mutates and develops mechanisms to help it to survive and grow. And anti-androgen drugs such as enzalutamide and abiraterone can inadvertently switch on the cancer-promoting mechanisms that androgens normally suppress. “You activate a sort of replacement pathway,” says Timothy Thompson, an oncologist who is director of prostate-cancer research at the University of Texas MD Anderson Cancer Center in Houston. Anti-androgen drugs actually “unrepress” oncogenes such as c-MYB, switching on pathways that help to promote the growth of cancer. In fact, drugs such as enzalutamide seem to stimulate mechanisms that repair DNA damage5 — not enough to create normal cells, but sufficient to allow cancer cells to multiply and spread. Researchers are searching for specific steps in the c-MYB pathway that they could target with new or existing drugs. Of particular interest is a class of enzymes called poly(ADP-ribose) polymerases, known as PARPs, which play a part in repairing damaged DNA6. Drugs that inhibit PARPs might disrupt the repair process and make cells more vulnerable to other forms of chemotherapy. PARP inhibitors are already being tested for the treatment of patients with breast cancer who have mutations in the genes BRCA1 and BRCA2, and in December 2014, olaparib became the first such drug to be approved by the US Food and Drug Administration for treating ovarian cancers with the same BRCA mutations. In April 2015, researchers from the Institute of Cancer Research and the Royal Marsden NHS Foundation Trust in London presented the results of a phase II trial of olaparib for men with metastatic prostate cancer. Lead researcher Johann De Bono says that a handful of patients showed “spectacular responses” to treatment with olaparib — their tumours disappeared from imaging scans. Others saw their PSA level cut in half. And all of the seven trial participants who had mutations in the gene BRCA2 responded to the drug in some way. Such discoveries could open the door to multipronged approaches in the fight against a disease for which there was no effective therapy just over a decade ago. That could revolutionize the treatment of advanced prostate cancer, says Saad, by bringing approaches in line with those for other cancers. “Prostate cancer is still one of the few, or only, solid tumours treated with a mono-treatment approach,” he says. “Where we need to go in the future is combining therapies.” Although it might be a long time before the lives of most men with advanced prostate cancer can be significantly prolonged, Antonarakis agrees that combining therapies that block androgen receptors and destroy resistance mechanisms will soon stop the disease from being 100% fatal. “In the next five to ten years,” he predicts, “we will be able to cure a small percentage of metastatic castration-resistant prostate cancer.”

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