Posts Tagged ‘work’

Blood test for ‘nicked’ protein predicts prostate cancer treatment response

The study evaluated two groups of 31 men with prostate cancer that had spread and whose blood levels of prostate-specific antigen (PSA) were still rising despite low testosterone levels. Investigators gave each man either enzalutamide (Xtandi) or abiraterone (Zytiga) and tracked whether their PSA levels continued to rise, an indication that the drugs were not working. In the enzalutamide group, none of 12 patients whose blood samples tested positive for AR-V7 responded to the drug, compared with 10 responders among 19 men who had no AR-V7 detected. In the abiraterone group, none of six AR-V7-positive patients responded, compared with 17 responders among 25 patients lacking AR-V7.

Enzalutamide and abiraterone have been very successful in lengthening the lives of about 80 percent of patients with metastatic prostate cancer, says Emmanuel Antonarakis, M.D., assistant professor of oncology at Johns Hopkins, but the drugs do not work in the remaining 20 percent of patients.

“Until now, we haven’t been able to predict which patients will not respond to these therapies. If our results are confirmed by other researchers, a blood test could use AR-V7 as a biomarker to predict enzalutamide and abiraterone resistance, and let us direct patients who test positive for AR-V7 toward other types of therapy sooner, saving time and money while avoiding futile therapy,” says Antonarakis.

Prostate cancer thrives on male sex hormones (or “androgens”), including testosterone. Enzalutamide and abiraterone target proteins called androgen receptors and block the receptors’ ability to activate prostate cancer cells. AR-V7 is a shortened form of the androgen receptor that lacks a binding spot targeted by enzalutamide and abiraterone. With no binding spot for the two drugs, AR-V7 is free to manipulate prostate cancer cells’ genetic material, which makes the cancer cells grow and spread.

Antonarakis and his colleague Jun Luo, Ph.D., who first identified AR-V7 in 2008, also tracked patients’ progression-free survival (the length of time a patient lives with the disease but does not get worse) and overall survival. They found that, in men receiving enzalutamide, progression-free survival was 2.1 months in AR-V7-positive patients and 6.1 months in AR-V7-negative patients, while overall survival was 5.5 months in AR-V7-positive men and up to 9 months in AR-V7-negative men. Similarly, in men receiving abiraterone, progression-free survival was 2.3 months in AR-V7-positive patients and up to 6 months in AR-V7-negative patients, while overall survival was 10.6 months in AR-V7-positive men and up to 12 months in AR-V7-negative men. The investigators caution that most of the study patients had advanced disease and received multiple prior therapies, so their outcomes may not be generalizable to all men with prostate cancer.

“Patients whose blood samples contained AR-V7 got no benefit from either enzalutamide or abiraterone,” says Antonarakis. He adds that the shortened AR-V7 protein could appear in patients’ blood samples at the very start of therapy or acquired later, after therapy has begun. He says, “This test could be used before starting enzalutamide or abiraterone therapy, and if the test shows the presence of AR-V7, patients may opt for a different therapy. It could also be used to monitor patients receiving enzalutamide or abiraterone for AR-V7, providing an indication these drugs may not work for much longer.”

source : http://www.sciencedaily.com/releases/2014/09/140903203752.htm

Injected bacteria shrink tumors in rats, dogs and humans

In its natural form, C. novyi is found in the soil and, in certain cases, can cause tissue-damaging infection in cattle, sheep and humans. The microbe thrives only in oxygen-poor environments, which makes it a targeted means of destroying oxygen-starved cells in tumors that are difficult to treat with chemotherapy and radiation. The Johns Hopkins team removed one of the bacteria’s toxin-producing genes to make it safer for therapeutic use.

For the study, the researchers tested direct-tumor injection of the C. novyi-NT spores in 16 pet dogs that were being treated for naturally occurring tumors. Six of the dogs had an anti-tumor response 21 days after their first treatment. Three of the six showed complete eradication of their tumors, and the length of the longest diameter of the tumor shrunk by at least 30 percent in the three other dogs.

Most of the dogs experienced side effects typical of a bacterial infection, such as fever and tumor abscesses and inflammation, according to a report on the work published online Aug. 13 in Science Translational Medicine.

In a Phase I clinical trial of C. novyi-NT spores conducted at MD Anderson Cancer Center, a patient with an advanced soft tissue tumor in the abdomen received the spore injection directly into a metastatic tumor in her arm. The treatment significantly reduced the tumor in and around the bone. “She had a very vigorous inflammatory response and abscess formation,” according to Nicholas Roberts, Vet.M.B., Ph.D. “But at the moment, we haven’t treated enough people to be sure if the spectrum of responses that we see in dogs will truly recapitulate what we see in people.”

“One advantage of using bacteria to treat cancer is that you can modify these bacteria relatively easily, to equip them with other therapeutic agents, or make them less toxic as we have done here, ” said Shibin Zhou, M.D., Ph.D., associate professor of oncology at the Cancer Center. Zhou is also the director of experimental therapeutics at the Kimmel Cancer Center’s Ludwig Center for Cancer Genetics and Therapeutics. He and colleagues at Johns Hopkins began exploring C. novyi’s cancer-fighting potential more than a decade ago after studying hundred-year old accounts of an early immunotherapy called Coley toxins, which grew out of the observation that some cancer patients who contracted serious bacterial infections showed cancer remission.

The researchers focused on soft tissue tumors because “these tumors are often locally advanced, and they have spread into normal tissue,” said Roberts, a Ludwig Center and Department of Pathology researcher. The bacteria cannot germinate in normal tissues and will only attack the oxygen-starved or hypoxic cells in the tumor and spare healthy tissue around the cancer.

Verena Staedtke, M.D., Ph.D., a Johns Hopkins neuro-oncology fellow, first tested the spore injection in rats with implanted brain tumors called gliomas. Microscopic evaluation of the tumors showed that the treatment killed tumor cells but spared healthy cells just a few micrometers away. The treatment also prolonged the rats’ survival, with treated rats surviving an average of 33 days after the tumor was implanted, compared with an average of 18 days in rats that did not receive the C. noyvi-NT spore injection.

The researchers then extended their tests of the injection to dogs. “One of the reasons that we treated dogs with C. novyi-NT before people is because dogs can be a good guide to what may happen in people,” Roberts said. The dog tumors share many genetic similarities with human tumors, he explained, and their tumors appeared spontaneously as they would in humans. Dogs are also treated with many of the same cancer drugs as humans and respond similarly.

The dogs showed a variety of anti-tumor responses and inflammatory side effects.

Zhou said that study of the C. novyi-NT spore injection in humans is ongoing, but the final results of their treatment are not yet available. “We expect that some patients will have a stronger response than others, but that’s true of other therapies as well. Now, we want to know how well the patients can tolerate this kind of therapy.”

It may be possible to combine traditional treatments like chemotherapy with the C. novyi-NT therapy, said Zhou, who added that the researchers have already studied these combinations in mice.

“Some of these traditional therapies are able to increase the hypoxic region in a tumor and would make the bacterial infection more potent and increase its anti-tumor efficiency,” Staedtke suggested. “C. novyi-NT is an agent that could be combined with a multitude of chemotherapy agents or radiation.”

“Another good thing about using bacteria as a therapeutic agent is that once they’re infecting the tumor, they can induce a strong immune response against tumor cells themselves,” Zhou said.

Previous studies in mice, he noted, suggest that C. novyi-NT may help create a lingering immune response that fights metastatic tumors long after the initial bacterial treatment, but this effect remains to be seen in the dog and human studies.

source : http://www.sciencedaily.com/releases/2014/08/140813173906.htm

Synthetic molecule makes cancer self-destruct

These synthetic ion transporters, described this week in the journal Nature Chemistry, confirm a two-decades-old hypothesis that could point the way to new anticancer drugs while also benefitting patients with cystic fibrosis.

Synthetic ion transporters have been created before, but this is the first time researchers have shown them working in a real biological system where transported ions demonstrably cause cells to self-destruct.

Cells in the human body work hard to maintain a stable concentration of ions inside their cell membranes. Disruption of this delicate balance can trigger cells to go through apoptosis, known as programmed cell death, a mechanism the body uses to rid itself of damaged or dangerous cells.

One way of destroying cancer cells would be to trigger this innate self-destruct sequence by skewing the ion balance in cells. Unfortunately, when a cell becomes cancerous, it changes the way it transports ions across its cell membrane in a way that blocks apoptosis.

Almost two decades ago, a natural substance called prodigiosin was discovered that acted as a natural ion transporter and has an anticancer effect.

Since then, it has been a “chemist’s dream,” said Jonathan Sessler, professor in The University of Texas at Austin’s College of Natural Sciences and co-author of the study, to find “synthetic transporters that might be able to do exactly the same job, but better, and also work for treating diseases such as cystic fibrosis where chloride channels don’t work.”

Sessler and his collaborators, led by professors Injae Shin of Yonsei University and Philip A. Gale of the University of Southampton and King Abdulaziz University, were able to bring this dream to fruition.

The University of Texas members of the team created a synthetic ion transporter that binds to chloride ions. The molecule works by essentially surrounding the chloride ion in an organic blanket, allowing the ion to dissolve in the cell’s membrane, which is composed largely of lipids, or fats. The researchers found that the transporter tends to use the sodium channels that naturally occur in the cell’s membrane, bringing sodium ions along for the ride.

Gale and his team found that the ion transporters were effective in a model system using artificial lipid membranes.

Shin and his working group were then able to show that these molecules promote cell death in cultured human cancer cells. One of the key findings was that the cancer cell’s ion concentrations changed before apoptosis was triggered, rather than as a side effect of the cell’s death.

“We have thus closed the loop and shown that this mechanism of chloride influx into the cell by a synthetic transporter does indeed trigger apoptosis,” said Sessler. “This is exciting because it points the way towards a new approach to anticancer drug development.”

Sessler noted that right now, their synthetic molecule triggers programmed cell death in both cancerous and healthy cells. To be useful in treating cancer, a version of a chloride anion transporter will have to be developed that binds only to cancerous cells. This could be done by linking the transporter in question to a site-directing molecule, such as the texaphyrin molecules that Sessler’s lab has previously synthesized.

The results were a culmination of many years of work across three continents and six universities.

“We have demonstrated that this mechanism is viable, that this idea that’s been around for over two decades is scientifically valid, and that’s exciting,” said Sessler. “We were able to show sodium is really going in, chloride is really going in. There is now, I think, very little ambiguity as to the validity of this two-decades-old hypothesis.”

The next step for the researchers will be to take the synthetic ion transporters and test them in animal models.

source : http://www.sciencedaily.com/releases/2014/08/140811151634.htm