Scientists at the University of Alabama at Birmingham have identified a molecular pathway that seems to contribute to the ability of malignant glioma cells in a brain tumor to spread and invade previously healthy brain tissue. Researchers said the findings, published Sept. 19, 2013, in the journal PLOS ONE, provide new drug-discovery targets to rein in the ability of these cells to move.
Gliomas account for about a third of brain tumors, and survival rates are poor; only about half of the 10,000 Americans diagnosed with malignant glioma survive the first year, and only about one quarter survive for two years.
“Malignant gliomas are notorious, not only because of their resistance to conventional chemotherapy and radiation therapy, but also for their ability to invade the surrounding brain, thus causing neurological impairment and death,” said Hassan Fathallah-Shaykh, M.D., Ph.D., associate professor in the UAB Department of Neurology. “Brain invasion, a hallmark of gliomas, also helps glioma cells evade therapeutic strategies.”
Fathallah-Shaykh said there is a great deal of interest among scientists in the idea that a low-oxygen environment induces glioma cells to react with aggressive movement, migration and brain invasion. A relatively new cancer strategy to shrink tumors is to cut off the tumor’s blood supply – and thus its oxygen source – through the use of anti-angiogenesis drugs. Angiogenesis is the process of making new blood vessels.
“Stop angiogenesis and you shut off a tumor’s blood and oxygen supply, denying it the components it needs to grow,” said Fathallah-Shaykh. “Drugs that stop angiogenesis are believed to create a kind of killing field. This study identified four glioma cell lines that dramatically increased their motility when subjected to a low-oxygen environment – in effect escaping the killing field to create a new colony elsewhere in the brain.”
Fathallah-Shaykh and his team then identified two proteins that form a pathway linking low oxygen, or hypoxia, to increased motility.
“We identified a signaling protein that is activated by hypoxia called Src,” said Fathallah-Shaykh. “We also identified a downstream protein called neural Wiskott-Aldrich syndrome protein (N-WASP), which is regulated by Src in the cell lines with increased motility.”
The researchers then used protein inhibitors to shut off Src and N-WASP. When either protein was inhibited, low oxygen lost its ability to augment cell movement.
“These findings indicate that Src, N-WASP and the linkage between them – which is something we don’t fully understand yet – are key targets for drugs that would interfere with the ability of a cell to move.” said Fathallah-Shaykh. “If we can stop them from moving, then techniques such as anti-angiogenesis should be much more effective. Anti-motility drugs could be a key component in treating gliomas in the years to come.”
Lifestyle modifications, weight-loss medications and bariatric surgery are the three major modalities that will have clinical implications on the prevention and treatment of obesity, according to data presented here.
“With effective options in all of these three treatment modalities, we can now evolve rational data-driven models of care that treat obesity as a medical illness,” W. TimothyGarvey, MD, professor and chair in the department of nutrition sciences at the University of Alabama at Birmingham, and senior scientist at the Nutrition Obesity Research Center, told Endocrine Today.
During a presentation on emerging obesity therapies, Garvey reported recent data on phentermine-topiramate (Qsymia, Vivus) and lorcaserin (Belviq, Eisai), both of which gained approval in adults with an initial BMI of at least 30 or in those with a BMI of at least 27 and at least one weight-related condition, such as hypertension, type 2 diabetes or dyslipidemia.
“We’re in an exciting phase of drug development for obesity, with two drugs approved in the summer of 2012 that appear to be safe and effective for the treatment of obesity,” Garvey said.
“In addition, we have two other drugs that have finished or will soon finish phase 3 trials.”
One of these is bupropion/naltrexone (Contrave, Orexigen), an experimental agent now finished with phase 3 clinical trials. According to Garvey, a cardiovascular outcomes study is currently ongoing as requested by the FDA before approval. “The BP did not increase with the drug, but it didn’t go down to the extent that you’d predict with the weight loss achieved,” he said. “This will be the first cardiovascular outcomes study with a weight-loss drug where the data will be available in, perhaps, 2014.”
About an 8% weight loss was demonstrated and sustained during 1 year compared with 2% with placebo, Garvey said.
Furthermore, he referenced recent data from a 56-week, double blind, phase 3a clinical trial investigating higher-dose liraglutide (Victoza, Novo Nordisk) as a potential treatment for maintained weight loss in overweight or obese patients with type 2 diabetes. The manufacturer recently released the second phase 3a trial results from the clinical development program for liraglutide 3 mg as an obesity treatment.
“About 4 kg were lost on lifestyle intervention alone, and up to 9 kg were lost with high-dose liraglutide. There are 2-year data indicating that its efficacy for sustaining this weight loss is evident,” Garvey said.
However, Garvey said medical and surgical interventions provide the best outcomes in obese patients with complications, and optimal benefit–risk occurs when weight loss is used as a tool to treat these complications of obesity.
As an adjunct to lifestyle modification, the aforementioned new medical therapies can result in a 10% loss of body weight, but if a patient begins with a BMI of 38, he will likely be obese when therapies are complete, Garvey said.
“However, that 10% loss of body weight is sufficient to improve insulin sensitivity, glucose homeostasis, lipid levels, BP, diabetes prevention, CVD risk factors and better control of both glucose and BP in patients with type 2 diabetes. We’re achieving an amount of weight loss here that’s in fact beneficial in terms of cardiometabolic disease,” he said.
Garvey concluded with the economic burden of diabetes and obesity on the United States health care system. He told Endocrine Today that for the clinical research community to address the diabetes and obesity epidemics, the progression from prediabetes to diabetes should first be considered.
“A rational and effective obesity treatment paradigm that targets resources to patients who are at highest risk will be cost-effective in preventing diabetes,” he said. “The numbers vary, but it costs much more per year to take care of a patient with diabetes than it does to take care of a patient without diabetes.”
Source: Endocrine today
The question of which oxygen-saturation level is best for very premature infants remains open after the publication of two studies over the weekend. Commentators suggest that levels under 90% should be avoided, however.
Researchers in the BOOST II study (published in the New England Journal of Medicine) report outcomes at hospital discharge for some 2400 infants randomized to lower (85 to 89%) or higher (91 to 95%) saturation levels. Interpretation is muddied somewhat by the fact that the oximeters had a measurement flaw that wasn’t discovered until halfway through the study. Among infants measured with corrected oximeters, mortality was higher for those receiving lower oxygen saturation (23% vs. 16%). Retinopathy was lower with lower saturation.
In JAMA, COT study researchers found no significant differences in the rates of mortality or retinopathy by 18 months in some 1200 infants similarly studied.
Commentators say the best interim course would be to target saturation levels between 90% and 95%, realizing the dangers of retinopathy.