Hippo Pathway to Better Cancer Treatment? Unusual Key to Regulating Cell Growth

July 11, 2013 — Researchers at the University of British Columbia have discovered a potential new pathway to treat cancer by asking some odd questions about the size of animals.

"Mammals display a huge range in size from the largest blue whale to the tiniest fruit bat," says Colby Zaph, assistant professor of Pathology and Laboratory Medicine at the Biomedical Research Centre, who co-authored the study published in Developmental Cell.

"So why don't we have miniature whales or gigantic bats? It turns out that there are specific pathways that tell cells when to grow and when to stop."

One of those pathways is called the Hippo pathway -- a key control in how our organs are perfectly suited to our bodies, despite differences in size. Zaph, along with postdoctoral research fellow Menno Oudhoff, uncovered that size differences could be manipulated after a specific chemical modification called methylation dramatically affected its function.

Using mice genetically lacking an enzyme called Set7, the results show that methylation of a protein called Yap is critical for the function of the Hippo pathway. Loss of the Set7 enzyme resulted in cell growth and larger organs.

"It's too early to tell how successful modifying this pathway could be in terms of helping with treatment of cancer. But based on our results, drugs that may activate the Set7 enzyme -- to stop cell growth -- may be invaluable to fighting cancers with Hippo pathway mutations" says Zaph.

The pathway has gone relatively unchanged despite evolution and could play a crucial role in regenerative medicine, including in skin growth and liver regeneration.

"Harnessing these results to treat diseases is now the next step."

http://www.sciencedaily.com/releases/2013/07/130711135308.htm

RNA Interference Cancer Treatment? Delivering RNA With Tiny Sponge-Like Spheres

ScienceDaily (Feb. 27, 2012) — For the past decade, scientists have been pursuing cancer treatments based on RNA interference -- a phenomenon that offers a way to shut off malfunctioning genes with short snippets of RNA. However, one huge challenge remains: finding a way to efficiently deliver the RNA.

Most of the time, short interfering RNA (siRNA) -- the type used for RNA interference -- is quickly broken down inside the body by enzymes that defend against infection by RNA viruses.

"It's been a real struggle to try to design a delivery system that allows us to administer siRNA, especially if you want to target it to a specific part of the body," says Paula Hammond, the David H. Koch Professor in Engineering at MIT.

Hammond and her colleagues have now come up with a novel delivery vehicle in which RNA is packed into microspheres so dense that they withstand degradation until they reach their destinations. The new system, described Feb. 26 in the journal Nature Materials, knocks down expression of specific genes as effectively as existing delivery methods, but with a much smaller dose of particles.

Read on:  http://www.sciencedaily.com/releases/2012/02/120227094331.htm

British flowers are the source of a new cancer drug

The search for more effective cancer treatments may soon harness the healing power of the Autumn crocus.

Researchers are poised to start clinical trials with a new "smart bomb" treatment, derived from the flower, targeted specifically at tumours.

The treatment, called colchicine, was able to slow the growth of and even completely "kill" a range of different cancers, in experiments with mice.

The research was highlighted at the British Science Festival in Bradford.

The team behind it, from the Institute for Cancer Therapeutics (ICT) at the University of Bradford, has published the work in the journal Cancer Research.

The native British Autumn crocus, otherwise known as "meadow saffron" or "naked lady", is recorded in early herbal guides as a treatment for inflammation.

This is because it contains the potent chemical colchicine, which is known to have medicinal properties, including anti-cancer effects.

But colchicine is toxic to other tissues in the body, as well as cancer, so until now its use has been limited.

The researchers at ICT have now altered the colchicine molecule so it is inactive in the body until it reaches the tumour.

Once there, the chemical becomes active and breaks up the blood vessels supplying the tumour, effectively starving it.

This effect is made possible because of enzymes that all tumours produce, whose usual function is to break down the normal cells nearby, allowing the tumour to spread.

The modified colchicine molecule has a protein attached to it that makes it harmless. But the tumour enzyme specifically targets the protein and removes it.

The colchicine is then activated, and the process of breaking down blood vessels and starving the cancerous cells begins.

Optimistic but cautious
One of the things that may make this drug so effective, Professor Patterson said, is that it will be "only active in the tumour, and not cause damage to normal tissue".

Because the enzyme necessary to activate the toxic colchicine is produced only by solid tumours, it may be possible to treat cancers effectively with virtually no side effects to the rest of the body.

Moreover, as the drug will be activated wherever the enzyme is produced, the delivery mechanism should allow treatment of particularly problematic cases of metastasis, where the cancer spreads from its initial site.

Pre-clinical tests in mice have shown startlingly successful results.

"What we're looking for is a delay in the growth of the tumour," said Professor Patterson.

"But sometimes the treatment is so effective that in half of the studies, the mice appeared to be cured of their cancer. All mice responded to the treatment."

Just one dose of the colchicine produced this remarkable effect. But if it passes clinical tests, the researchers believe it will be used alongside existing cancer treatments, as part of the complex process of tackling the disease.

The researchers hope that the treatment will enter the initial stage of clinical testing at St James's Hospital in Leeds within the next 18 months.

Professor Patterson said that he was "very optimistic about the opportunities of the treatment, but still cautious because everything done to date has been in the laboratory".

Paul Workman, head of cancer therapeutics at the Institute of Cancer Research, called the work an "interesting new approach".

"The project is still at quite an early stage but the results so far look promising in the laboratory models that have been studied," he said.

"If confirmed in more extensive laboratory studies, drugs based on this approach could be very useful as part of combination treatments for various cancers."
By Leila Battison Science reporter
http://www.bbc.co.uk/news/science-environment-14855666