Posts Tagged ‘second’

Myc inhibition an effective therapeutic strategy against most aggressive brain tumors

In a study published last year, the group succeded in eradicating lung tumors in transgenic mice by adopting the same strategy involving the expression of Omomyc, a Myc inhibitor designed by Soucek. They also confirmed that there were no side effects post-administration of repeated and long-term treatment. Importantly, there was no evidence of resistance to therapy — one of the greatest challenges in the treatment of cancer. These results therefore confirmed Myc inhibition as a sound and effective therapeutic strategy for the development of novel cancer drugs.

Soucek and her group were to raise the bar yet higher. Firstly, the focus on gene expression-based therapy under experimental study progressed and re-programed on the development of an administrable Omomyc-based drug. Second, the group continued to show the efficacy of Myc inhibition across different tumors and, above and beyond transgenic models, they showed the same success in human tumors using a technique that transfers human cancer cells to immunodeficient mice. “Upon reporting initial results at preclinical level, our main concern was how do demonstrate these findings in human tumors,” says Laura Soucek. “Firstly, we focused on how they could apply to other tissues and other more aggressive tumor types for which there are no effective treatments, whereby an ´Omomyc solution´ could make all the difference. We also aimed to reveal new insights into the mechanism of action of Omomyc in tumor cells.” It seems that Soucek’s group has now found answers to all these questions. “All our efforts must now concentrate on finding a means for its pharmacological administration. Based on our research currently underway, we have every reason to be optimistic” asserts Soucek.

A novel therapy for the most common and aggressive brain tumor

After four years´ exhaustive research, these latest results bring more good news and with them, preclinical Myc inhibition has also been validated as a therapeutic strategy against astrocytoma, a type of glioma, in vivo in mouse models and in vitro in stem cells of these tumors. In these models, which develop advanced brain tumors with clear neurological symptoms, treatment with the Omomyc transgene drastically reduces tumors and improves the associated symptoms until the mouse recovers and starts to act completely normally. Mice treated with Omomyc survived, whereas those without, did not. “We did not stop there,” explains Soucek, “we applied therapy with Omomyc to both human glioblastoma cell lines and mice with patient-derived tumor xenografts that faithfully recapitulate human tumors.” The therapeutic impact of Omomyc lies in its structure, which is similar to that of Myc, making it possible to block the transcription of genes controlled by this protein. Myc inhibition leads to “defects” in tumor cells and often results in their death by inducing mitotic aberrations, thus halting normal cell division.

“Our results undoubtedly show that Myc inhibition is effective in mouse tumors and, more notably, in human glioma.” she explains. The group has demonstrated the additional therapeutic potential of Omomyc thanks to their clinically orientated approach aimed against the most common and aggressive primary tumor to affect the adult central nervous system — glioblastoma, for which there is a critical call to improve current therapies which are largely ineffective. “This is the very first time that the use of Omomyc in human tumor specimens have been validated. We have also confirmed that Myc inhibition is effective against the tumor once it has developed, acts against tumor initiating cells, and prevents them from dividing, proliferating and forming the tumor again.” continues Dr. Soucek.

Mitotic catastrophe as the therapeutic mechanism of Myc inhibition

The Myc protein plays an important role in regulating gene transcription, controlling the expression of up to 15% of human genes. It is also implicated in cellular proliferation, differentiation and apoptosis (programmed cell death which is necessary for tissue regeneration and the elimination of damaged cells). However, alterations in this protein trigger uncontrolled cell proliferation, which can result in cancers developing in different tissues. Myc deregulation is actually found in most tumors including cancer of the cervix, breast, colon, lung, pancreas, and stomach.

Brain tumors can now be added to this list of potential tumors that can be targeted with Myc inhibition.

At the cellular level, we now know more about its mechanism of action. Regardless of the experimental system used, Myc inhibition reduces proliferation and increases cell death. “Importantly, the cells we treated with Omomyc went crazy. They showed problems with cell proliferation, with aberrant mitosis and the formation of cells with many nuclei that then died through mitotic catastrophe, that is, due to the inability to divide properly” explains Laura Soucek. “If we do not allow Myc to function normally, tumor cells cannot divide efficiently.” she affirms. Myc is not deregulated in healthy cells, hence, its inhibition does not generate any significant side effects that might limit the use of this therapy.

To conclude, Myc inhibition as a therapeutic strategy against brain tumors opens up new avenues signposting fresh hope and improved, more effective therapies for patients. Soucek and her team are consequently concentrating on translating their findings to the clinic. Preliminary results show promise.

source : http://www.sciencedaily.com/releases/2014/08/140818095023.htm

Mystery of brain cell growth unraveled by scientists

How a single protein can exert both a push and a pull force to nudge a neuron in the desired direction is a longstanding mystery that has now been solved by scientists from Dana-Farber Cancer Institute and collaborators in Europe and China.

Jia-huai Wang, PhD, who led the work at Dana-Farber and Peking University in Beijing, is a corresponding author of a report published in the August 7 online edition of Neuron that explains how one guidance protein, netrin-1, can either attract or repel a brain cell to steer it along its course. Wang and co-authors at the European Molecular Biology Laboratory (EMBL) in Hamburg, Germany, used X-ray crystallography to reveal the three-dimensional atomic structure of netrin-1 as it bound to a docking molecule, called DCC, on the axon of a neuron. The axon is the long, thin extension of a neuron that connects to other neurons or to muscle cells.

As connections between neurons are established — in the developing brain and throughout life — axons grow out from a neuron and extend through the brain until they reach the neuron they are connecting to. To choose its path, a growing axon senses and reacts to different molecules it encounters along the way. One of these molecules, netrin-1, posed an interesting puzzle: an axon can be both attracted to and repelled from this cue. The axon’s behavior is determined by two types of receptors on its tip: DCC drives attraction, while UNC5 in combination with DCC drives repulsion.

“How netrin works at the molecular level has long been a puzzle in neuroscience field,” said Wang, “We now provide structure evidences that reveal a novel mechanism of this important guidance cue molecule.” The structure showed that netrin-1 binds not to one, but to two DCC molecules. And most surprisingly, it binds those two molecules in different ways.

“Normally a receptor and a signal are like lock-and-key, they have evolved to bind each other and are highly specific — and that’s what we see in one netrin site,” said Meijers. “But the second binding site is a very unusual one, which is not specific for DCC.”

Not all of the second binding site connects directly to a receptor. Instead, in a large portion of the binding interface, it requires small molecules that act as middle-men. These intermediary molecules seem to have a preference for UNC5, so if the axon has both UNC5 and DCC receptors, netrin-1 will bind to one copy of UNC5 via those molecules and the other copy of DCC at the DCC-specific site. This triggers a cascade of events inside the cell that ultimately drives the axon away from the source of netrin-1, author Yan Zhang’s lab at Peking University found. The researchers surmised that, if an axon has only DCC receptors, each netrin-1 molecule binds two DCC molecules, which results in the axon being attracted to netrin-1. “By controlling whether or not UNC5 is present on its tip, an axon can switch from moving toward netrin to moving away from it, weaving through the brain to establish the right connection,” said Zhang.

Knowing how neurons switch from being attracted to netrin to being repelled opens the door to devise ways of activating that switch in other cells that respond to netrin cues, too. For instance, many cancer cells produce netrin to attract growing blood vessels that bring them nourishment and allow the tumor to grow, so switching off that attraction could starve the tumor, or at least prevent it from growing.

On the other hand, when cancers metastasize they often stop being responsive to netrin. In fact, the DCC receptor was first identified as a marker for an aggressive form of colon cancer, and DCC stands for “deleted in colorectal cancer.” Since colorectal cancer cells have no DCC, they are ‘immune’ to the programmed cell death that would normally follow once they move away from the lining of the gut and no longer have access to netrin. As a result, these tumor cells continue to move into the bloodstream, and metastasize to other tissues. “Therefore, to understand the molecular mechanism of how netrin works should also have a good impact in cancer biology,” said Wang.

The guidance issue is a very complicated cell biology problem. Meijers, Zhang, Wang and their colleagues are now investigating how other receptors bind to netrin-1, exactly how the intermediary molecules ‘choose’ their preferred receptor, how other guidance molecule binds to DCC, and how the system is regulated. The answers could one day enable researchers to steer a cell’s response to netrin and other guidance cues, ultimately changing its fate.

source : http://www.sciencedaily.com/releases/2014/08/140808111927.htm

Total darkness at night key to success of breast cancer therapy, study shows — ScienceDaily


Principal investigators and co-leaders of Tulane’s Circadian Cancer Biology Group, Steven Hill and David Blask, along with team members Robert Dauchy and Shulin Xiang, investigated the role of melatonin on the effectiveness of tamoxifen in combating human breast cancer cells implanted in rats.

“In the first phase of the study, we kept animals in a daily light/dark cycle of 12 hours of light followed by 12 hours of total darkness (melatonin is elevated during the dark phase) for several weeks,” says Hill. “In the second study, we exposed them to the same daily light/dark cycle; however, during the 12 hour dark phase, animals were exposed to extremely dim light at night (melatonin levels are suppressed), roughly equivalent to faint light coming under a door.”

Melatonin by itself delayed the formation of tumors and significantly slowed their growth but tamoxifen caused a dramatic regression of tumors in animals with either high nighttime levels of melatonin during complete darkness or those receiving melatonin supplementation during dim light at night exposure.

These findings have potentially enormous implications for women being treated with tamoxifen and also regularly exposed to light at night due to sleep problems, working night shifts or exposed to light from computer and TV screens.




“High melatonin levels at night put breast cancer cells to ‘sleep’ by turning off key growth mechanisms. These cells are vulnerable to tamoxifen. But when the lights are on and melatonin is suppressed, breast cancer cells ‘wake up’ and ignore tamoxifen,” Blask says.

The study could make light at night a new and serious risk factor for developing resistance to tamoxifen and other anticancer drugs and make the use of melatonin in combination with tamoxifen, administered at the optimal time of day or night, standard treatment for breast cancer patients.

source : http://www.sciencedaily.com/releases/2014/07/140725080408.htm