Targeted cancer treatments take centre stage

Until recently, when faced with inoperable cancer, clinicians had a fairly limited set of options: either blitz the patient with highly aggressive chemotherapy, or radiotherapy, or a combination of both.

Fortunately, largely thanks to a range of new cancer drugs that are tailored to attack specific targets on cancer cells, things are changing. And in tandem with the pharmaceutical industry’s efforts to develop more effective ’targeted treatments’, technology is increasingly playing a role in the development of therapies that are more comfortable and effective.

One of the most vigorous areas of development is improved targeting of radiotherapy. The science of using radiation to destroy cancer cells has developed fast in recent years.

The emergence of advanced 3D imaging techniques has enabled clinicians to incorporate ever greater levels of complexity into treatment plans. There has been a corresponding evolution in the types of technology used, with techniques such as intensity modulated radiation therapy (IMRT) enabling clinicians to shape radiation beams to closely approximate the shape of the tumour and spare more adjoining normal tissue than during conventional radiotherapy.

Now a technique that takes this ability to a new level is about to make its debut in the UK. The Cyberknife, which will begin treating patients next month at the private Harley Street Clinicin London, is a robot radiosurgery machine designed to treat tumours anywhere in the body with pinpoint precision.

While conventional radiotherapy devices are attached to a fixed gantry, the linear accelerator at the heart of the Cyberknife system is mounted on an agile, robotic arm. This enables it to deliver high-energy beams of radiation from hundreds of different angles around the patient’s body.

A sophisticated image guidance system that compensates for the most subtle patient movements helps ensure that throughout the treatment the beams are directed at the tumours.

Californian firm Accuray, Cyberknife’s developer, claims this system enables clinicians to use a smaller number of treatments to blast tumours with far higher doses of radiation than previously possible.

Vilim Simcik, the company’s senior vice-president, told The Engineer that it provides an option for patients diagnosed with previously inoperable tumours: ’We are becoming the tool of choice in treatments where other methods are simply not possible and where the patient simply cannot tolerate surgery,’ he said. ’We can deliver large doses of radiation in a very short period of time and treat things that no one else can treat: for instance, unstable tumours that are extremely close to the spinal cord.’

During a single treatment, which typically lasts up to 90 minutes, between 100 and 200 15-second pulses of radiation are beamed at the patient from more than 1,600 directions.

During this process, a suite of advanced image guidance techniques ensure the high-energy beams stay locked on their targets. Stereoscopic imagers mounted in the floor and ceiling track the anatomy, compare it with the pre-treatment scan data and trigger miniscule adjustments to the robotic manipulator and the treatment couch. ’No other systems are able to track and correct for target motion in near real time,’ claimed Simcik.

This process is complemented by a number of X-ray imaging techniques that are optimised for particular procedures. For instance, for abdominal and thoracic treatments, in order to minimise damage to healthy tissue, an arrangement of X-ray cameras and a vest equipped with LEDs is used to monitor the patient’s breathing and re-position the radiotherapy beam.

’We take a handful of x-ray images and correlate those with external markers,’ said Calvin Maurer, senior director of research. ’Through that correlation model we can predict the internal position in real time and use that information to drive the robot so as the tumour moves, the robot moves to keep the beam on target during respiration.’

In addition to the UK system there are 150 Cyberknife systems installed worldwide and, according to Maurer, there is growing evidence that the sophisticated device is shaping up to be a valuable tool in the radiotherapist’s arsenal.

In chemotherapy too, the trend is for improved targeting. And while many of the big advances take the form of new drugs able to hone in on the molecular characteristics of cancer cells, technology also looks set to play a role.

Of particular promise is the use of tiny nanoparticles that can move through the blood stream and cross cell walls to deliver drugs directly to tumours.

Although nanoparticles have been studied and talked about since the 1970s, new methods that enable the precise tailoring of their properties have led some to believe that the age of nanomedicine is just around the corner.

One person particularly excited by this field is Dr Eugen Barbu, a Portsmouth Universitybiomedic, who has just begun a three-year project to develop nanoparticles that could potentially be used to treat brain tumours, one of the most problematic forms of cancer.

Prof Darek Gorecki is working with Barbu on the project, funded by the Biotechnology and Biological Sciences Research Council. He said the brain is a particularly difficult organ to treat. To maintain the delicate balance of chemicals essential to its operation, its blood vessels are quite different to those found elsewhere in the body and limit the passage of numerous potentially harmful molecules.

Unfortunately, while protecting the brain, this so-called “blood-brain barrier” also acts as an obstacle to the effective delivery of targeted drugs. ’Other blood vessels are in a sense leaky — most drugs will quite easily penetrate out of the blood-stream into the tissue but not in the brain,’ he said. ’Over 90 per cent of drugs will not cross the blood brain barrier. People have come up with beautiful drugs that could really stop a brain-tumour in its tracks but it can’t penetrate into the brain.’

The aim of the Portsmouth project is to develop nanoparticles that will trick this barrier into opening briefly enough to allow the drug payload to be delivered.

The group has already demonstrated that it is possible to load nanoparticles with model drugs. The primary focus now, said Gorecki, is to get them to an acceptable size for use in the brain.

’If they are smaller than 20nm they will be excreted through kidney filtration and if they are bigger than 150nm they will activate macrophages [the white blood cells at the heart of our immune response]. We want to have nanoparticles that will stay in the blood stream, will not be excreted and we don’t want them too big; we are interested in nanoparticles smaller than about 100nm.’

In addition to the size constraints, Gorecki said the nanoparticles must also be made from a material that is biocompatible and biodegradable. ’Imagine that the nanoparticles are the crates in which you deliver the drug. If they are not biodegradable they will build up in the brain, with unforseen and highly unpredictable outcomes.’

The substance of choice is Chitosan, a biocompatible material produced from chitin, a biological polymer found in, among other places, the exoskeletons of crustaceans. The next step is develop optimised Chitason nanoparticles and test the material in laboratory-grown cell cultures that mimic the blood brain barrier.

In order to determine whether the particles are capable of opening the barrier, Gorecki said cells will be grown on a chip and measured changes in electrical impedance will be used to indicate the opening of these pathways.

The Portsmouth team hopes to have a nanoparticle that will be capable of targeting the brain with a drug within three years. Although Gorecki is unwilling to speculate on when the technology might be used to treat patients, he believes the approach has great promise for a range of targeted therapies. ’We’re not just interested in brain tumours: brain targeting via nanoparticles could be used for delivery of therapy for a broad spectrum of brain disorders ranging from Alzheimer’s, to Parkinson’s, to motor neurone disease,’ he said.