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Thursday, February 7, 2019
Breast cancer cells shifted into HER2 positive status with bold new strategy
When women or men receive the worrisome diagnosis of breast cancer, that news comes with an important piece of information, namely, whether their cancer is HER2-positive or HER2-negative. It can be especially difficult to hear that one’s cancer is HER2-negative, because it means an effective group of targeted anti-cancer drugs isn’t available.
A new study from the lab of Scripps Research chemist Matthew D. Disney, Ph.D., suggests that in the future, that might not be the final word on the matter. Writing in the Journal of the American Chemical Society, Disney’s group describes shifting three different cancer cell lines from HER2-negative status to HER2-positive status with the addition of a selective micro-RNA binding molecule they referred to as TGP-515.
It’s a revolutionary idea, that a cancer’s genotype might not have to be the limiting factor in its range of targeted treatment options. However, this is just a first step in a long series of work ahead to enable the technology to benefit cancer patients, Disney notes.
The team designed their compound by using a mathematical system Disney developed called Inforna. The compound rendered the cancer cells vulnerable to both Herceptin (trastuzumab) and Kadcyla (ado-trastuzumab emtansine), both targeted therapeutics. Meanwhile, it left healthy breast cells unaffected.
“It’s possible that precision medicines like Herceptin can be made available to a wider group of people by altering gene expression with therapeutics that bind not to the proteins but to noncoding RNA,” Disney says.
About 20 percent of people diagnosed with breast cancer have the HER2-positive mutation, which means the surface of their cancer cells have more of the HER2 protein on them. While that mutation is associated with faster growing, more aggressive cancers, since 1998 it has come with good options for effective treatment. Since the monoclonal antibody drug Herceptin was introduced, 10-year disease-free survival rates for the HER2-positive breast cancer subtype surged to 84 percent.
For breast cancer patients with dwindling options, switching on HER2 sensitivity might be life-changing, Disney says.
“This study is proof of concept for the strategy of creating sensitivity to a drug where one otherwise wouldn’t exist,” Disney says. “It also validates the notion that transcription of genes can be modulated via small molecule compounds engineered to bind to relevant noncoding RNA. This means that supposedly untreatable diseases may, one day, be readily treatable. There is a long way to go for this to get to patients, however.”
There were many challenges that had to be overcome to create the effective compound, says first author Matthew G. Costales, a Scripps Research graduate student. Unintended targets had to be identified and blocked, and selectivity engineered into the molecule. Disney’s computational system, Inforna, guided the efforts.
The first compound the Inforna database highlighted bound to two different micro RNAs, both 885 and 515. That could have posed problems. Further refinement made it clear that a compound could be designed to be selective for one micro RNA but not the other. Eventually they created a molecule that successfully selected only for the desired microRNA, 515. The result was that the cells produced increased HER2 levels, making them sensitive to the drugs.
“The demanding synthetic, biochemical, and cellular experiments described in this paper were three years in the making,” Costales says. “It required tremendous effort, but the work is by no means complete. I am looking forward to future work guided by the lessons we learned here.”
Disney credits his colleague, Scripps Research chemist Alexander Adibekian, Ph.D., with helping understand the mechanisms of action of their compound, TGP-515, and demonstrating its selectivity.
It’s important to note that this is a first step toward making drugs to boost HER2 sensitivity where there is none, Disney says. Significant additional research lies ahead, he says.
Successful tests in cultured cells must be followed with tests in mouse models of cancer, a process that will take several years. Financial support from the community, including Frenchman’s Creek Women for Cancer Research, Alan and Susan Fuirst, and the R. J. Scheller Graduate Student Fellowship, has helped made the work possible.
“These studies would not have been realized without the local support graciously provided by the community,” Disney says. “I am incredibly grateful for the community taking the time to invest in the future of biomedical research completed here at Scripps Research.”
More information: Matthew G. Costales et al, A Designed Small Molecule Inhibitor of a Non-Coding RNA Sensitizes HER2 Negative Cancers to Herceptin, Journal of the American Chemical Society (2019). DOI: 10.1021/jacs.8b10558
Cancer-causing HPV also tied to heart disease
Certain strains of HPV are known to cause cervical cancer and other types of tumors. Now, a new study raises the possibility that they might also contribute to heart disease.
Researchers found that among over 63,000 women, those infected with “high-risk” strains of human papillomavirus (HPV) were somewhat more likely to develop heart disease or suffer a stroke over the next several years.
The connection was seen mainly among women who were obese or had metabolic syndrome—a collection of risk factors for heart disease and stroke that includes high blood pressure and elevated blood sugar.
The findings do not prove that high-risk HPV directly contributes to cardiovascular disease, said Dr. Ann Bolger, a cardiologist and professor at the University of California, San Francisco.
With studies like this, “there’s always a possibility” that some other factors could explain the connection, said Bolger, who was not involved in the research.
“But I think these are fascinating data,” she added. “This should be explored further.”
HPV is a group of over 200 related viruses. Some of them are sexually transmitted and can cause genital warts. In some people, the infection becomes persistent; and persistent infection with high-risk HPV strains can eventually trigger cancer.
Those infections are behind virtually all cases of cervical cancer, according to the U.S. National Cancer Institute. And they often cause some rarer cancers, including tumors of the vagina, penis, anus and throat.
Still, there is no proof that high-risk HPV strains can directly damage arteries and contribute to heart attacks and strokes.
What’s needed now is more lab research, said senior researcher Dr. Seungho Ryu.
One possibility is that HPV directly feeds artery-clogging plaques by infecting cells in the walls of the blood vessels, according to Ryu, a professor at Sungkyunkwan University School of Medicine, in Seoul, South Korea.
Or, Ryu said, the virus might have more “indirect” effects by spurring systemic, chronic inflammation in the body.
That, however, is speculation for now.
The findings, published Feb. 7 in Circulation Research, are based on 63,411 Korean women who were free of heart trouble at the start of the study. All underwent HPV testing, and just under 8 percent were found to carry a high-risk strain.
Over the next several years, just over 1,100 women developed heart disease or suffered a stroke. That risk was 22 percent higher among those who’d tested positive for high-risk HPV—even after factors such as age, education, and smoking and exercise habits were taken into account.
Ryu’s team then looked at the connection based on women’s weight. It turned out that the association was largely confined to women who were obese: Those with a high-risk HPV infection were 71 percent more likely to develop cardiovascular trouble, versus obese women without those infections.
A similar pattern emerged when the researchers compared women with metabolic syndrome against those without.
Ryu’s team speculates that the inflammation and other cardiovascular consequences of obesity and metabolic syndrome might be exacerbated by HPV infection.
Bolger stressed that the findings should not “alarm” women who’ve ever been infected with high-risk HPV.
Even if the virus does increase the risk of heart disease, there are many steps women can take to counter that.
“Look at the basic things,” Bolger said. “Do you smoke? Do you get up and move every day? Do you know what your blood pressure is? Do you have it under control?”
Ryu made the same point. These findings, he said, suggest that women with a history of high-risk HPV can protect themselves by maintaining a healthy weight and normal blood pressure, blood sugar and cholesterol.
Then there’s the fact that high-risk HPV infections are now preventable through vaccination.
According to Bolger, this study raises the question of whether HPV vaccination could ultimately have an impact on cardiovascular disease rates, too.
In the United States, experts recommend that all girls and boys receive the HPV vaccine starting at age 11 or 12. It’s also advised for young adults who did not get it when they were kids.
More information: Seungho Ryu, M.D., professor, Sungkyunkwan University School of Medicine, Seoul, South Korea; Ann Bolger, M.D., professor emeritus, medicine, University of California, San Francisco; Feb. 7, 2019, Circulation Research, online.The U.S. Centers for Disease Control and Prevention has more on HPV infection.
Prior dengue infection protects against Zika
The higher a person’s immunity to dengue virus, the lower their risk of Zika infection, an international team of scientists led by the University of Pittsburgh Graduate School of Public Health, Yale School of Public Health and University of Florida report today in the journal Science.
The study—which followed nearly 1,500 people living in a poor neighborhood at the heart of the 2015 Zika outbreak in Brazil—also provides evidence that Brazil’s Zika epidemic has largely petered out because enough people acquired immunity to reduce the efficiency of transmission.
“Take that with a grain of salt, though,” said co-senior author Ernesto T.A. Marques, M.D., Ph.D., associate professor in Pitt Public Health’s Department of Infectious Diseases and Microbiology and public health researcher at Fundação Oswaldo Cruz in Brazil. “Our study was in a very small urban area, and it is likely that in other parts of Brazil, even different neighborhoods within the same city, people are still susceptible to Zika infection.”
The discovery relied on tests for dengue and Zika developed by Marques and his team and patented by Pitt. Marques is scientific director of Cura Zika, an international alliance to spur research into Zika, microcephaly and other congenital conditions it causes in babies.
The research team tapped into a long-running study of the health of people living in urban slums in Salvador, a city in northeast Brazil, led by co-senior author Albert Ko, M.D., chair of epidemiology at the Yale School of Public Health. Study participants gave multiple blood samples before, during and after the Zika epidemic. Samples collected in October 2014 and March 2015 were almost entirely negative for Zika, but by October 2015, 63 percent showed evidence of Zika infection.
Before the Zika outbreak, a subset of 642 participants also had been tested for previous dengue infection, and 86 percent were positive. Specifically, the test assessed the level of antibodies the participants had in their blood against dengue. The team found that each doubling of dengue antibody levels corresponded to a 9 percent reduction in risk of Zika.
“This means that there are some cross-protective antibodies that dengue provides against Zika,” said Marques. “Future study may be warranted to assess whether the new dengue vaccines could be useful in preventing Zika infection.”
Paradoxically, computational models by co-senior author Derek A.T. Cummings, Ph.D., professor of biology at the University of Florida, revealed that participants who had a very recent dengue infection were actually more susceptible to Zika.
The scientists suspect several possible explanations: It could be that protective antibodies haven’t developed yet or there’s something about these people’s immune systems that increases their risk of contracting Zika. And the mosquitoes that transmit dengue also transmit Zika, so a recent dengue infection could simply mean they are in a place where Zika transmission is active as well.
Additional study also is needed to determine how these findings could prove useful to clinicians, Marques said.
Developing reliable, commercially available tests for women of child-bearing age to assess their previous dengue and Zika exposure is of immediate concern, along with evaluating recommendations so clinicians know what to do with that information, noted Marques. Testing could help clinicians determine whether vaccinating women against dengue could help protect them from Zika during pregnancy. It also would give a baseline, so obstetricians would know how closely to monitor a pregnant woman’s fetus for microcephaly, based on her susceptibility to Zika.
Ongoing studies also are following babies born to women who contracted Zika during pregnancy to assess the effect of the mother’s immunity to dengue on the degree of Zika-related congenital conditions in the babies.
More information: I. Rodriguez-Barraquer at University of California, San Francisco in San Francisco, CA el al., “Impact of preexisting dengue immunity on Zika virus emergence in a dengue endemic region,” Science(2019). science.sciencemag.org/cgi/doi … 1126/science.aav6618
Weight-Loss Surgery Typically Pushes Type 2 Diabetes Into Remission
As many as 7 out of 10 people with type 2 diabetes can achieve long-term disease remission by having weight-loss surgery called gastric bypass, according to a new Danish study.
The surgery isn’t necessarily a cure for type 2 diabetes. Some people who go into remission and appear to no longer have the disease can relapse and start having symptoms again. In this study, 27 percent of people who were in remission relapsed during the five-year follow-up.
But the study also linked gastric bypass surgery to a nearly 50 percent reduction in microvascular complications. These complications include kidney disease, nerve damage and vision problems.
“Patients with obesity and type 2 diabetes should be offered bariatric surgery early on in the course of their disease, while there is still a great chance of diabetes remission,” said study lead author Dr. Lene Ring Madsen, from Aarhus University Hospital in Denmark.
There are several types of weight-loss, or bariatric, surgery, including gastric bypass and gastric sleeve.
Gastric bypass, also called Roux-en-Y, involves making the stomach smaller and bypassing part of the small intestine, according to the U.S. National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). After this surgery, people get fuller on much less food, and the body doesn’t absorb as many calories.
Gastric sleeve surgery (or sleeve gastrectomy) involves removing a portion of your stomach so you get fuller faster, according to NIDDK. This type of surgery has been gaining in popularity, but Madsen said the procedure is newer, so researchers don’t yet have long-term data on it.
Although this study didn’t look at the reasons gastric bypass can lead to type 2 diabetes remission, Madsen said other studies have suggested that weight loss is one factor. She added that calorie restriction and hormone changes also likely play a role.
Dr. Mitchell Roslin, director of bariatric surgery at Northern Westchester Hospital in Mount Kisco, N.Y., reviewed the findings.
“Patients with the best weight loss have the best resolution of type 2 diabetes, but the mechanisms are much more complex than just weight loss,” he said.
Roslin said change in the types of foods a person eats, and in how well the body uses insulin, along with changes in glucose (sugar) production in the liver all likely contribute to the improvement in type 2 diabetes.
The current study included more than 1,100 people who had gastric bypass in hospitals in Northern Denmark. The surgeries took place between 2006 and 2015.
Researchers compared the patients who had surgery to nearly 1,100 type 2 diabetics who didn’t.
Sixty-five percent of the surgical patients went into diabetes remission within six months. A year after surgery, 74 percent had remission of their type 2 diabetes, the study found. During the first five years after surgery, the remission rate remained at 70 percent or higher.
However, people in the study who were on insulin before the surgery were less likely to go into remission. People who had less control of their blood sugar levels were also less likely to do so. People over 60 also had more trouble attaining remission compared to people under 40.
Those who had type 2 diabetes for a shorter time (fewer than 2.6 years) were more likely to achieve remission.
As time passed, some people’s diabetes returned. In the second year, 6 percent relapsed. During the third year, that figure drifted up to 12 percent and by five years, 27 percent had relapsed.
Still, the benefits from the surgery cannot be overlooked. “Bariatric surgery is a real treatment for type 2 diabetes, and it has been underutilized,” Roslin said.
He said one of the most important findings was how well the surgery reduced the risk of many diabetes complications.
“People are scared of diabetes,” Roslin noted. “They’re scared of the blindness and the amputations, and this study shows that bariatric surgery is a treatment that may reduce those complications by 50 percent.”
Findings were published Feb. 6 in Diabetologia.
More information
The U.S. National Institute of Diabetes and Digestive and Kidney Diseases offers more aboutweight-loss surgery.
SOURCES: Lene Ring Madsen, M.D., Ph.D., Aarhus University Hospital, Denmark; Mitchell Roslin, M.D., director, bariatric surgery, Northern Westchester Hospital, Mount Kisco, N.Y.; Feb. 6, 2019, Diabetologia
Johnson & Johnson will list drug prices in TV commercials
Johnson & Johnson says it will start giving the list price of its prescription drugs in television ads.
The company would be the first drugmaker to take that step.
J&J said Thursday it would start with its popular blood thinner, Xarelto. By late March, commercials will give the pill’s list price plus typical out-of-pocket costs. The information will appear on screen at the end of the commercial. It will include a link to a website where people can enter insurance information to get more specific costs.
Without insurance, Xarelto costs $450 to $540 per month, depending on the pharmacy.
The move follows a Trump administration proposal to require list prices in TV ads. The pharmaceutical industry opposed that, arguing that few people pay the high list prices.
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