A team at The Scripps Research Institute has developed a compound that reduced and even reversed fatty liver disease in animals, and had the added bonus of reducing plasma cholesterol levels. The details of the study were published in ACS Chemical Biology.

Fatty liver disease doesn't sound too good--and it isn't. Fats accumulate in the liver and can lead to cirrhosis and liver cancer. It affects up to a quarter of the general population worldwide, and is linked with being overweight and with Type 2 diabetes. There are currently very few effective treatments.

"We've been working on a pair of natural proteins called LXRα and LXRβ that stimulate fat production in the liver, and we thought our compound might be able to successfully suppress this process," said Thomas Burris, a professor at The Scripps Research Institute.

The researchers created and tested SR9238, a type of drug known as a synthetic LXR inverse agonist and thought to be the first drug effectively to suppress fat production in the liver. In mice fed with a high-fat diet, treatment with SR9238 cut fat production in the liver 90% and reversed the disease within a month even while the animals still ate fatty foods. It also cut levels of blood cholesterol by targeting the same enzyme as statins. There were no major side effects.

This is in preclinical studies and is at the very early stage of development, but if similar results can be replicated in humans, it could have potential in both nonalcoholic and alcoholic fatty liver disease.

- read the press release
- see the abstract

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Adding in a small molecule enzyme inhibitor to cancer chemotherapy could improve treatment of glioblastoma, a deadly brain cancer, according to U.S. preclinical research published in Molecular Cancer Therapeutics.

Glioblastomas are aggressive brain tumors and people may only have an average survival rate of 15 to 18 months. One of the standard treatments is Temodar (Merck and Bayer's temozolomide), but the tumors often develop resistance. Combination therapies that could reverse this would have a huge impact on outcomes and quality of life for patients and could cut costs for healthcare providers.

CFAK-Y15, developed by U.S.-based CureFAKtor Pharmaceuticals, inhibits focal adhesion kinase (FAK), an enzyme that is overexpressed in cancer cells. Mice with glioblastoma that were treated with CFAK-Y15 lived longer than the control animals, and in some cases their tumors shrank, especially when given in combination with temozolomide.

"We're eager to see this research move to the clinical phase because of the great need for more effective treatments for glioblastoma," says senior author William G. Cance of Roswell Park Cancer Institute and interim CEO at CureFAKtor. "The potential impact is great because glioblastomas are such an aggressive tumor, and because we know they produce FAK in especially high quantities."

- read the press release
- see the abstract

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A team of Australian and U.K.-based researchers has found a new transcription factor in preclinical studies and this could change how common breast cancer drugs such as tamoxifen and aromatase inhibitors are used.

Transcription factors regulate how genes are expressed--in other words, they switch genes on and off. This specific transcription factor, known (perhaps rather aptly for the tail end of the Christmas season) as ELF5, can change how a breast cancer cell reacts to the common drug tamoxifen. ELF5 can switch off the cell's sensitivity to estrogen early in its life cycle, transforming the tumor into a more aggressive type of cancer that is no longer sensitive to tamoxifen and other aromatase inhibitors. The results are published in PLoS Biology.

The researchers found that by targeting ELF5 and changing its levels in breast cancer cells, they could change the subtype of the cancer. This opens up the possibility of overcoming drug resistance by changing a hard-to-treat cancer to one that responds to well-known and easily available drugs once more through new small molecule or small interfering RNA (siRNA) agents.

This could also be a useful biomarker that could pick out the cancers that won't respond to tamoxifen and other linked drugs, helping to improve existing diagnostic, predictive and prognostic tests and supporting doctors in choosing the best drugs for each patient.

- read the press release
- see the paper

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New research could pave the way for treating malaria, among other serious diseases, by using a method that inhibits a particular calcium-regulated enzyme called calpain.

While the enzyme is essential to many cellular processes, one downside of calpain is that it eases the ability of parasites like Plasmodium falciparum, which causes malaria, to exit their host cells and invade other cells. Calpain is also thought to be a factor in some of the most debilitating diseases, including muscular dystrophy, AIDS, Alzheimer's disease, multiple sclerosis and cancer.

A study published in the latest issue of the Journal of the American Chemical Society highlights a new approach to calpain inhibition, which mimics a natural reaction with a synthesized molecule, stopping this destructive process. A U.S. team led by researchers at the Perelman School of Medicine at the University of Pennsylvania developed the new technique.

The UPenn study is significant because it's thought to be the first to use this kind of inhibitor.

"We found out that parasites like the one that causes malaria use human calpain to allow themselves to get out of the host cell," said study researcher Doron Greenbaum, an assistant professor of pharmacology at UPenn, in an interview with FierceBiotechResearch.

When the malaria parasite enters a cell, calpain essentially chews out the scaffolding of the cell, and once that is dissolved or broken down, the red blood cell falls apart, Greenbaum explained. But if the enzyme is blocked, the parasite becomes trapped within the red blood cell host and dies.

"So that's what led us to become interested in human calpain as a target for therapy for malaria," Greenbaum said.

Malaria, which causes flu-like symptoms and can progress to coma or death, is a major health concern around the world, especially in poor countries. An estimated 655,000 people worldwide died of malaria in 2010, according to the World Health Organization.

- here's UPenn's release

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A consortium of researchers from across the U.S. has taken a step forward in the treatment of amyotrophic lateral sclerosis (ALS) by transplanting neural stem cells into mice and slowing the paralysis caused by this lethal and incurable neurodegenerative disease.

ALS, also known as Lou Gehrig's disease, gradually takes away the ability to move by damaging nerve cells in the spinal cord. There is only one approved treatment, Sanofi-Aventis' Rilutek (riluzole), which does slow the progress of the disease.

Looking at the results of 11 separate and independent studies in which nerve stem cells were transplanted into the spinal column of mice with ALS, the researchers found that the stem cells cut the symptoms and slowed the course of the disease. They prolonged the survival of the mice to three or four times the life span of the untreated mice with ALS, and the animals also had better motor function (ability to control movement) and were able to breathe more easily.

However, there was more happening here than just replacing dud cells with working cells. The transplanted cells produced factors that supported the existing cells and protected them against damage, and reduced inflammation. The transplanted stem cells also reduced the number of diseased neural stem cells.

These findings could lead to potential treatments for ALS and for other neurodegenerative disorders, and the researchers are confident about the outcomes of the study. Senior author Evan Snyder of Sanford-Burnham Medical Research Institute's stem cell and regenerative biology program said in a press release: "While not a cure for human ALS, we believe that the careful transplantation of neural stem cells, particularly into areas that can best sustain life--respiratory control centers, for example--may be ready for clinical trials."

- read the press release
- see the abstract

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