Researchers have identified the neurons in monkeys that are dampened by scratching, a finding that could lead to new ways of alleviating itching in humans.

In people, a variety of stimuli, including chemicals like histamine, prompt sensory neurons to fire, sending a signal via the spinothalamic tract (STT) to the brain, prompting an itchy feeling.

To find out which of these neurons are suppressed by scratching, at the University of Minnesota in Minneapolis and colleagues implanted electrodes into the spinal tract of anaesthetised macaques before injecting histamine into their legs. STT neurons fired in response, but scratching the skin caused the frequency of the firing to drop in some of the neurons, indicating that these are the ones targeted by scratching.

The hope is to find the equivalent neurons in people, and then to work out how to suppress them, via drugs or electrical pulses, in order to relieve itchiness caused by skin problems such as scabies, eczema and psoriasis.

Anti-itch medications rarely offer sufficient relief, and scratching can damage skin and cause infections.

Journal reference: Nature Neuroscience, DOI: 10.1038/nn.2292

Success in mice is far from a guarantee of success in people, but human trials have now begun on one component of the therapy.

The research, by scientists in Australia and Japan, is “an exciting advance”, according to cancer biologist Carl June of the University of Pennsylvania, US: “This novel form of therapeutic vaccination would not only enable potent tumour eradication but also protect from recurrence.”

The idea of using the body’s immune system to kill cancerous cells is already routinely deployed. Our immune system contains killer white blood cells called cytotoxic T lymphocytes (CTLs), which single out and destroy tumours. But the body’s natural response to cancerous cells is often not strong enough to wipe out the tumour.

Calling reinforcements

The new therapy, called TrimAb (triple monoclonal antibody) therapy, may solve that problem. Mark Smyth, at the Peter MacCallum Cancer Centre in Australia, Kazuyoshi Takeda, at the Juntendo University School of Medicine in Japan, and colleagues used a cocktail of three different antibodies.

The first attacks the tumour directly, by stimulating the receptor for a death-inducing protein on tumour cells, called TRAIL. The boost that strengthens the response comes from the other two antibodies which activate killer T-cells that pitch in to kill the tumour.

TrimAb cleared large breast tumours in 80% of the mice that received the treatment, while the tumour disappeared in less than 30% of mice that got either single antibodies or double antibody combinations. And furthermore, the therapy induced a complete cure in 60% of the mice in which the breast cancer had spread to the lungs, liver, and brain.

Key to destruction

TrimAb causes T-cells to produce an immune molecule named interferon gamma. “This molecule is key to tumour destruction”, Smyth told New ĐÓ°ÉÔ­´´. While TrimAb elicited the killer molecule in the lymph nodes of treated mice, treatments with a single or a pair of antibodies did not. “TrimAb also recruits a higher frequency of CTLs to attack the tumour,” he adds.

Many cancers express TRAIL, so TrimAb is not just specific for breast cancers. In particular, says Smyth, it works for renal cancer and sarcomas, and colon cancer is a promising target.

TrimAb prevents the recurrence of cancer because destroying the tumours presents the immune system with antigens, priming it for the future. A specific advantage of this is that the immune system is then primed against that particular tumour.

Three antibody combinations have never been used in patients to treat cancers, says Smyth. Although the combination was non-toxic to mice, careful pilot testing of each component and combination needs to be done in human trials, he cautions. The team is now awaiting results of Phase I trials involving humanised anti-TRAIL antibodies.

Journal reference: Nature Medicine (DOI: 10.1038/nm1405)

The spread of cancer cells, or “metastasis”, is a major problem and the principal cause of mortality among cancer patients. Now researchers at Stanford University School of Medicine, California, US, headed by Amato Giaccia have discovered the enzyme that mediates metastasis.

The potentially rampant spread of cancer through the body depends on a number of factors. But low oxygen conditions are typically associated with the human cancer cells capable of spreading. The researchers uncovered the enzyme responsible for the spread of oxygen-starved cancer cells in human breast, head and neck cancers.

Dubbed LOX (lysyl oxidase), the enzyme is produced in cancer cells under low oxygen conditions. The team found that human breast cancer cells lacking oxygen produced more LOX. They also found that patients whose tumour cells made high amounts of LOX were more likely to suffer metastasis and had a lower chance of survival.

Lungs and liver

The team grew human breast cancer cells on artificial gels created to mimic the natural environment in which these cells move in the body. Normal cancer cells showed a branched appearance, typical of spreading cells. But cancer cells in which the production of LOX was blocked using an inhibitor, failed to spread on the gels. They remained in spherical clusters showing little branching and were completely immobile.

“LOX is implicated in the invasiveness of tumours”, says Giaccia. But it also does another thing. As well as causing cells to spread, he believes LOX also creates a “permissive niche” or environment which also boosts the cells’ growth so they multiply.

To test the therapeutic potential of LOX, the team engineered human breast cancer cells to produce less LOX than normal cancer cells. They then implanted these cells in the form of tumours into mice.

Hot target

In mice that received the normal tumours, the cancer cells spread to the lungs and liver. But those that received the tinkered tumours producing less LOX had fewer cancer cells in the lungs and none in the liver. Furthermore, when a chemical inhibitor of LOX was given to mice harbouring the normal tumours, metastasis was completely blocked. The team achieved the same effect using an antibody that blocked the function of LOX.

“The findings are highly interesting since they create an entirely new set of insights into the mechanisms of invasion and spread of cancer,” says Robert Weinberg, a cancer biologist at the Whitehead Institute for Biomedical Research, Massachusetts, US.

Although blocking LOX can block the spread of cancer, it does nothing to the primary tumour itself, cautions Giaccia. “But since LOX is involved in the early and late stages of the spread, it is a hot therapeutic target,” he adds. The team is now developing human-compatible antibodies to block LOX.

Journal reference: Nature (DOI: 10.1038/nature04695)

Cocaine triggers changes in the brain that lead to the development of drug sensitisation – a learning-associated process that underlies addiction. Like many addictive drugs, cocaine ups the concentration of the brain chemical dopamine, causing neurons that respond to dopamine to fire.

This process reorganises the brain circuitry and hardwires the addiction by disrupting the normal connections between two different brain regions. Those areas are the hippocampus and prefrontal cortex – associated with learning and memory – and the ventral tegmental area, involved with feelings of pleasure, reward and behavioural motivation (see “Cocaine use prevents adaptive behaviour“). But how cocaine drives this change in dopamine neurons was unclear until recently.

Switch blocker

Now, Christian Luescher and Camilla Bellone at the University of Geneva, Switzerland have shown that cocaine causes a switch in the components, or subunits, which make up the receptors on the surface of neurons in the ventral tegmental area, the brain’s “pleasure centre”. This leads to excitatory wiring – or strong stimulation of these cells. Brain slices from mice given cocaine, showed the receptors in their brains had undergone a subunit switch.

“The subunit switch allows for the increase in [neuron stimulation] and the wiring associated with the [cocaine] sensitisation. So we blocked the switch to see if we could reverse the effect,” says Luescher.

The team injected a chemical that selectively blocked the receptor switch in cocaine-treated mice. While mice that did not receive the chemical continued to show strong excitation in the brain to cocaine, the drug’s effect was reversed in treated mice.

Conditioned place

“These findings suggest possible mechanisms for reversing cocaine induced changes in the brain, and they begin to point the way for the development of novel therapeutic agents for human addiction,” says neuroscientist Robert Malenka at Stanford University Medical Center, California, US.

The Swiss team is now conducting behavioural tests on mice to study the effect of the chemical. When put in a cage containing two compartments, in one of which they receive cocaine, mice learn to prefer the compartment associated with cocaine-injection over time. The team hopes that injecting their chemical into cocaine-sensitised mice might abolish this preference.

The work provides important new insights on the effects of cocaine in the brain, says Mark Ungless, a neuroscientist at Oxford University, UK. Reversing the effects with a specific drug treatment opens an interesting future avenue for novel therapies for humans, he adds.

“Although their findings are exciting and the team has uncovered a potential target to interfere with early events in drug addiction, we are still a long way from translating these findings in humans”, warns Pablo Castillo, neurobiologist at the Albert Einstein College of Medicine in New York, US.

Journal Reference: Nature Neuroscience (DOI: 10.1038/nn1682)

The antibodies have helped rats with damaged spinal cords to walk again, by blocking the action of Nogo, a protein that stops nerve cells sprouting new connections. But there were concerns about whether blocking Nogo would lead to uncontrolled neuronal rewiring in the brain or spinal cord and it was also unclear how such a therapy could be given to humans.

Now Martin Schwab and his colleagues at the University of Zurich in Switzerland have infused two antibodies, 11C7 and 7B12, into the damaged spinal cords of rats. An osmotic mini-pump connected to a fine catheter was used to deliver the antibodies directly into the cerebrospinal fluid surrounding the injured part of the spinal cord – a method of delivery that could easily be applied to humans, they say. The antibodies triggered regeneration of axons, the fine thread-like extensions that connect neurons, and enabled injured rats to swim, cross the rungs of a ladder without slipping and traverse a narrow beam (Annals of Neurology, vol 58, p 706).

Moreover, the antibodies did not cause hyperalgesia, a condition in which even a simple touch is sensed as pain – a sign that would have indicated wrong neuronal connections had been made.

Schwab’s team has been developing antibodies that are suitable for humans in collaboration with pharmaceutical giant Novartis. He says they intend to begin clinical trials lasting two to three years in the very near future.

“There is sufficient experimental evidence to view these trials with some optimism,” says Robin Franklin, a neuroscientist at the University of Cambridge.

“The antibodies enabled rats with damaged spinal cords to walk, swim and cross the rungs of a ladder without slipping”

But blocking Nogo alone might not lead to complete recovery, says team member Lisa Schnell. More likely, it could become part of a combined approach to treating spinal injuries. “What we still need is a bridge that links the lesioned nerve to the rest of the spinal cord,” she says. The nerves also need growth factors in order to keep sprouting and stay functional.

Towards this end, Geoffrey Raisman at University College London is working on supplying the necessary stimulants for nerve regrowth by transplanting sheath cells from the back of the nose onto the spinal cord of patients. These cells are renowned for their ability to foster regeneration of injured nerve fibres. Such treatments have shown promise in paralysed dogs, which regained some movement in their legs after the transplant (New ĐÓ°ÉÔ­´´, 16 April 2005, p 14). Clinical trials in humans are expected to begin this year.

Nick Jeffery, a veterinary surgeon at the University of Cambridge who carried out the experiments in dogs, cautions against translating the results of animal experiments directly into humans. While there is reason to be optimistic about the prospects of using antibodies to block Nogo, there could be differences in the extent of functional recovery between rats and humans, he says. Blocking Nogo in humans could also have other, as yet unknown, effects on the body.