Researchers Discover New Target for Personalized Cancer Therapy

Captured by Case Western Reserve University

A common cancer pathway causing tumor growth is now being targeted by a number of new cancer drugs and shows promising results. A team of researchers at Case Western Reserve University School of Medicine have developed a novel method to disrupt this growth signaling pathway, with findings that suggest a new treatment for breast, colon, melanoma and other cancers.

The research team has pinpointed the cancer abnormality to a mutation in a gene called PIK3CA that results in a mutant protein, which may be an early cancer switch. By disrupting the mutated signaling pathway, the Case Western Reserve team, led by John Wang, PhD, inhibited the growth of cancer cells, opening the possibility to new cancer therapies.

Their findings, “Gain of interaction with IRS1 by p110α helical domain mutants is crucial for their oncogenic functions,” was published on May 2 in the journal Cancer Cell.

Cancer arises from a single cell, which has mutated in a small number of genes because of random errors in the DNA replication process. These mutations play key roles in carcinogenesis.

“This discovery has a broad impact on the treatment of human cancer patients because so many cancers are affected by this particular mutation in the p110α protein, which is encoded by the PIK3CA gene,” said Wang, an associate professor in the Department of Genetics and Case Comprehensive Cancer Center. “This is a significant advance because we can now disrupt this misdirected signaling pathway in cancer cells.”

“If you turn on a light, you have to turn on a switch. But in the case of the mutation of this protein, p110α turns on by itself,” Wang said. “The mutation rewires the circuit and is uncontrolled. This implies that if you break these wires, you can control the growth of cancer. Our current discovery may lead to finding less toxic drugs that can be used for personalized treatment for cancer patients in the future.”

“This research will impact the field by focusing us on new targets for treating and preventing metastasis in patients in a many different types of human cancers,” said Stanton Gerson, MD, Asa and Patricia Shiverick-Jane Shiverick (Tripp) Professor of Hematological Oncology, and director of Case Comprehensive Cancer Center and of Seidman Cancer Center at University Hospitals Case Medical Center.  Read more…

Tests to Predict Heart Problems and Stroke May Be More Useful Predictor of Memory Loss than Dementia Tests

Captured by the American Academy of Neurology

Risk prediction tools that estimate future risk of heart disease and stroke may be more useful predictors of future decline in cognitive abilities, or memory and thinking, than a dementia risk score, according to a new study published in the April 2, 2013, print issue of Neurology®, the medical journal of the American Academy of Neurology.

“This is the first study that compares these risk scores with a dementia risk score to study decline in cognitive abilities 10 years later,” said Sara Kaffashian, PhD, with the French National Institute of Health and Medical Research (INSERM) in Paris, France.

The study involved 7,830 men and women with an average age of 55. Risk of heart disease and stroke (cardiovascular disease) and risk of dementia were calculated for each participant at the beginning of the study. The heart disease risk score included the following risk factors: age, blood pressure, treatment for high blood pressure, high density lipoprotein (HDL) cholesterol, total cholesterol, smoking, and diabetes. The stroke risk score included age, blood pressure, treatment for high blood pressure, diabetes, smoking, history of heart disease, and presence of cardiac arrhythmia (irregular heart beat). Read more….

Transplanted Brain Cells in Monkeys Light Up Personalized Therapy

Captured by University of Wisconsin-Madison

For the first time, scientists have transplanted neural cells derived from a monkey’s skin into its brain and watched the cells develop into several types of mature brain cells, according to the authors of a new study in Cell Reports. After six months, the cells looked entirely normal, and were only detectable because they initially were tagged with a fluorescent protein.

Because the cells were derived from adult cells in each monkey’s skin, the experiment is a proof-of-principle for the concept of personalized medicine, where treatments are designed for each individual.

And since the skin cells were not “foreign” tissue, there were no signs of immune rejection — potentially a major problem with cell transplants. “When you look at the brain, you cannot tell that it is a graft,” says senior author Su-Chun Zhang, a professor of neuroscience at the University of Wisconsin-Madison. “Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope.”

Marina Emborg, an associate professor of medical physics at UW-Madison and the lead co-author of the study, says, “This is the first time I saw, in a nonhuman primate, that the transplanted cells were so well integrated, with such a minimal reaction. And after six months, to see no scar, that was the best part.”

The cells were implanted in the monkeys “using a state-of-the-art surgical procedure” guided by an MRI image, says Emborg. The three rhesus monkeys used in the study at the Wisconsin National Primate Research Center had a lesion in a brain region that causes the movement disorder Parkinson’s disease, which afflicts up to 1 million Americans. Parkinson’s is caused by the death of a small number of neurons that make dopamine, a signaling chemical used in the brain. Read more…

Still Some Unsettled Issues in Gestational Diabetes, But One Thing’s For Sure: Follow-up With Moms is Vital

An estimated 6 or 7 percent of pregnant women in the United States will develop gestational diabetes during pregnancy. That might not sound like much, but with 4 million births each year, that means about 250,000 annual cases of gestational diabetes – and these women have a seven-fold risk for developing Type 2 diabetes within a decade of delivery.

And yet, controversy still clouds gestational diabetes and how best to manage it, said Mark Landon, chair of the Department of Obstetrics and Gynecology at Ohio State University Wexner Medical Center.

Two large clinical trials, including one on which Landon was first author, have suggested that treating women with gestational diabetes – using dietary lifestyle interventions designed to keep blood sugar at normal levels for the vast majority of patients – significantly reduced the frequency of preeclampsia when compared to no treatment. Preeclampsia is a condition characterized by high blood pressure and protein in the urine after the 20th week of pregnancy. The only cure is delivery of the baby, but mild cases can be managed to delay delivery.

In spite of that, a meta-analysis published in 2010 stated that only modest evidence existed to show that treatment of gestational diabetes resulted in a benefit – but this analysis did not take preeclampsia into consideration.

Because gestational diabetes typically leads to larger babies, birth injuries also are a major concern – especially the possibility that a baby’s shoulder can get stuck in the birth canal, slowing delivery and creating conditions that could lead to shoulder nerve damage that lasts a lifetime.

Keeping the baby’s size in mind, practitioners must strike a balance between allowing a baby to develop safely to full term without letting it get so large that vaginal delivery becomes a dangerous prospect for mother and child. Waiting too long can lead to cesarean section, which carries its own complications.

A major analysis of 10 years of births appeared to suggest that 39 weeks gestation functioned as a good cutoff point to reduce risk of stillbirth or injury to the baby in mothers with gestational diabetes, though Landon said that seasoned physicians who have treated thousands of women with mild cases of gestational diabetes may not buy the argument that delivery is needed as early as 39 weeks.

Perhaps more useful to determine the optimal delivery time in the name of safety to mom and baby is estimating the baby’s weight. One national recommendation warned against prophylactic C-section in gestational diabetes pregnancies until a baby reached 4,500 grams, or just shy of 10 pounds, while a study suggested 4,250 grams, or 9.4 pounds, might be a more appropriate cutoff.

“Our approach continues to be for women who have never given birth vaginally is that we need to evaluate each woman carefully and individually … and consider a C-section even at a cutoff of 4,000 grams (8.8 pounds). This may seem like an aggressive approach, but given the flaws in the literature, it’s reasonable in clinical practice to do so,” Landon said.

Care for women with gestational diabetes does not stop in the delivery room, he noted, because of the elevated risk these women have of developing Type 2 diabetes and the need to plan these patients’ future pregnancies.

“We don’t do very well in this mission, and it is primarily a mission of those who provide obstetric care,” Landon noted, adding there are additional unknowns: “No one really knows what the appropriate time interval is for follow-up testing in women who screen normal for glucose in the immediate postpartum period but have a previous history of gestational diabetes.”

Landon co-authored a publication earlier this year calling on obstetricians to better promote women’s health after a diagnosis of gestational diabetes, including employing strategies that might reduce the frequency of diabetes and improve their overall general health.

Given the likelihood that children of women with gestational diabetes in some ethnic populations have increased risk for childhood obesity and metabolic syndrome, obstetricians have an opportunity to help break the cycle of diabetes, Landon suggested.

“Our responsibility doesn’t end in the delivery room. It extends to ensure the future health of that mother and her baby.”

-Emily Caldwell

What Can WHI Tell Us About Diabetes in Postmenopausal Women?

Diabetes was not a focus of the Women’s Health Initiative, but the massive amounts of data collected on 161,000 postmenopausal participants will probably be answering questions about women’s health for years to come.

WHI consisted of randomized trials to test the effects of hormone therapy, low-fat diet and calcium + vitamin D on heart disease, cancer and fractures, as well as an observational study examining the relationship between lifestyle, health and risk factors and specific disease outcomes. Participants ranged in age from 50 to 79 years.

This being the largest, most comprehensive examination of women’s health ever in the United States, researchers did gather information on diabetes diagnoses in the participants, providing data that could be examined in later analyses.

Among the diabetes-related findings:

Looking at diabetes prevalence and incidence by ethnicity, WHI measures were similar to those seen in the broader adult population – lowest in whites and a tad higher in Asians, even higher in Hispanics and most prevalent among African Americans.

Researchers found a somewhat lower rate of diabetes among women who took estrogen plus progestin hormone therapy compared to placebo. In the estrogen-alone trial, there was also a decrease in diabetes, but it was not statistically significant.

“No one would tell you to take hormones or prescribe them to prevent diabetes because this minimal effect is far overshadowed by adverse effects,” said Barbara Howard, senior scientist at the MedStar Health Research Institute and professor of medicine at Georgetown University School of Medicine. “But this gives us clues … and could lead to research on viable approaches to preventing diabetes.”

About those adverse effects: The WHI was famous for its findings that combination hormone therapy was associated with increased risk of heart attack, stroke, blood clots and breast cancer as well as reduced risk of colorectal cancer and fewer fractures compared to placebo. Estrogen-only therapy, meanwhile, was associated with increased risk of stroke and blood clots, uncertain effects on breast cancer and no effect on colorectal cancer risk, and reduced risk of fracture.

Among the 49,000 women randomized to a low-fat diet or comparison group and followed for about eight years, there was no impact found on the diabetes rate. At the time of the study design, the aim was to reduce all kinds of fat to 20 percent of the diet to test effects of this diet on cancer prevention. The intervention led to more weight loss than did the control condition. “Our conclusion was that low-fat dietary patterns can be a useful approach for weight loss in lifestyle programs designed to prevent diabetes,” Howard said.

The calcium and vitamin D trial provided no hints that vitamin D, even measured in blood samples, had any effect on the incidence of diabetes.

In looking at relationships between diabetes risk and physical activity and body mass index, researchers found that in all women, no matter their race, higher BMI and lower physical activity were strong predictors of risk for diabetes, and the combination was an especially strong predictor. And the evidence suggested that in this area, different racial groups will respond roughly the same to lifestyle interventions emphasizing more physical activity and lower weight.

When scientists adjusted the data, they saw a 28 percent increase in risk for developing diabetes in current smokers compared to never smokers. New quitters retained a relatively high risk, primarily because they tended to gain weight. Once the cessation period passed, the risk lowered dramatically.

Howard’s take on this: It’s never too late to obtain health benefits from quitting smoking.

-Emily Caldwell

Getting Teens Thinking Healthy, Helping Them COPE

In a crowd-favorite presentation during the Global Diabetes Summit, Bernadette Melnyk said, we all know people don’t change behavior easily, which is why she has focused much of her career on helping teens making healthy behavior changes to help them live healthier with a focus on mental health.

17 percent of teens are obese or overweight, but one in four adolescents has a mental health problem and less than 25 percent receive any treatment. According to Melnyk, substantial studies that shows that in overweight teens, the more likely they are to have a mental health disorder. These mental health conditions make it hard for teens to picture themselves even living healthy lifestyles. And in many studies when behaviors have been modified in studies and short-term gains have been achieved in high-risk populations, teens gained the weight back.

Melnyk’s secret sauce to this problem is her COPE program, which focuses on thinking, emotion, exercise, nutrition in hopes of decreasing teen’s doubts and increasing their ability make changes. In other words, if you teach teens to think differently, they can act differently. 

In each session, after working on goal setting, emotional coping skills, behavior therapy and more, the teens get up and moving with a “wheel of fitness” where they learn various activities and movement, which are all designed to be done in the middle of the classroom. They also learn about nutrition like social eating, portion sizes and nutrition labels. In the final sessions of the after-school program, they integrate how to put all these together and help the teens make a lifestyle plan.

Melnyk’s study showed many positives results from a decrease in BMI to decreases in depressive and anxiety symptoms. The purpose of her current study is to evaluate the efficacy of COPE/Healthy Lifestyles TEEN (thinking, emotions, exercise and nutrition) program on the healthy lifestyle behaviors, BMI, mental health and academic outcomes of 779 high school 14-16 year old adolescents.   The key regarding many of these findings in implementation. So she said: why does this matter to schools and why should they enact the COPE program?

She is also measuring academic outcomes and found that because of the cognitive behavioral skills the teens learned, they can improve their academic skill level because of the confidence and coping skills they learn in the program.

The COPE program will be used as either a preventive or management intervention program for overweight/obesity in adolescents. The program is now being developed so that it can be implemented in schools across the country. Her work in also now ongoing to adapt the program for school-age child and college-age youth.

Has focusing on your mental health ever helped you through an illness? How can we get more teens to learn the importance of improving their mental health?

Future of Diabetes Diagnosis, with Help from Pharmacogenetics: Dozens of Type 2 Subtypes

Personalized health care in the context of diabetes, and especially Type 2, someday is likely to involve the diagnosis of patients with one of multiple diabetes subtypes based on an individual’s biological symptoms, physical characteristics and genetic profile, according to Ewan Pearson, a clinical senior lecturer at the University of Dundee in Scotland.

Speaking at a plenary session of the 2012 Global Diabetes Summit hosted by Ohio State’s Diabetes Research Center at Wexner Medical Center, Pearson outlined how stratifying diabetes patients by the origins of their disease and genetic predispositions that influence their response to drugs could dramatically change how patients are treated.

This practice could be a long way off, he said, or, “Who knows? This might not be too far away.”

Pearson, also honorary consultant in diabetes & endocrinology at Ninewells Hospital and Medical School, said the current approach to diabetes diagnosis is oversimplified, with the vast majority of cases defined as Type 2 diabetes. Only a tiny percentage are diagnosed as MODY – maturity onset diabetes of the young.

Detailing a number of case studies that make it abundantly clear how different Type 2 diabetes patients can be in terms of biological symptoms and sensitivity to drugs, Pearson suggested that MODY is not considered frequently enough as an alternative diagnosis to Type 2.

Personalized drug treatment could be much more effective in these stratified patients because their genes would offer clues about which medications, and at which doses, will work best for them. For example, studies have already uncovered gene variants that can affect how statins work at different doses – and roughly 90 percent of diabetes patients take these drugs to control cholesterol.

Similar pharmacogenetic research into genetic variants that influence sensitivity to blood sugar-lowering drugs are in their earliest stages. Pearson and colleagues have identified a likely target gene on chromosome 11 that influences the effects of metformin, an enormously popular drug for lowering blood sugar in Type 2 diabetes, but much more work is required to fully understand that gene’s role. Scientists also have some hints about variants that influence response to another class of glucose-control agents as well.

In cases where variants have been identified that affect patient response to drugs, however, the effects are too limited or affect too few people to justify incorporating genomic analysis into clinical care at this point, he noted.

Pearson asserted that pharmacogenetics will continue to advance discoveries that will have clear implications and lead to “good clinical medicine” that will avoid oversimplification.

“I do think this is the future of diabetes and I’m optimistic that we’ll start identifying some subtypes over the course of the next 5 years,” he said.

-Emily Caldwell