Revolutionary ultrasonic nanotechnology that could allow scientists to see inside a patient’s individual cells to help diagnose serious illnesses is being developed by researchers at The University of Nottingham.

The new technique would utilise ultrasound technology - more commonly used to look at whole bodies such as fetal scanners - to look inside cells. The components of the new technology would be many thousand times smaller than current systems.

The technology would be tiny enough to allow scientists to see inside and image individual cells in the human body, which would further our understanding of the structure and function of cells and could help to detect abnormalities to diagnose serious illnesses such as some cancers.

The work by the Ultrasonics Group in the Division of Electrical Systems and Optics has been deemed so potentially innovative it has recently been awarded a £850,000 five-year Platform Grant by the Engineering and Physical Sciences Research Council (EPSRC).

Ultrasound refers to sound waves that are at a frequency too high to be detected by the human ear, typically 20 kHz and above. Medical ultrasound uses an electrical transducer the size of a matchbox to produce sound waves at much higher frequencies, typically around 100-1000 times higher to probe bodies.

The Nottingham researchers are aiming to produce a miniaturised version of this technology, with transducers so tiny that you could fit 500 across the width of one human hair which would produce sound waves at frequencies a thousand times higher again, in the GHz range.

Dr Matt Clark of the Ultrasonics Group, said: “By examining the mechanical properties inside a cell there is a huge amount that we can learn about its structure and the way it functions. But it’s very much a leap into the unknown as this has never been achieved before.

“One of the reasons for this is that it presents an enormous technical challenge. To produce nano-ultrasonics you have to produce a nano-transducers, which essentially means taking a device that is currently the size of a matchbox and scaling it down to the nanoscale. How do you attach a wire to something so small?

“Our answer to some of these challenges is to create a device that works optically - using pulses of laser light to produce ultrasound rather than an electrical current. This allows us to talk to these tiny devices.”

The new technology may also allow scientists to see objects even smaller than optical microscopes and be so sensitive they may be able to measure single molecules.

In addition to medical applications, the new technology would have important uses as a testing facility for industry to assess the integrity and quality of materials and to detect tiny defects which could have an impact on performance or safety.

Ultrasonics is currently used in applications such as testing landing gear components in the aero industry for cracks and damage which may not be immediately visible or may develop with use.

The group is also looking at developing new inspection techniques for inspecting engineering metamaterials - advanced composites that are currently impossible to inspect with ultrasound. These materials offer huge performance advantages allowing radical new engineering but can’t be widely used because of the difficulty of inspection.

Dr Clark added: “We are also applying our technology to nanoengineering because we have to match the enormous growth in nanotechnology with techniques to inspect the nanoworld. As products and their components become ever tinier, the testing facilities for those also need to be scaled down accordingly.

In NEMS (nanoelectromechanical) and MEMS (microelectromechanical) based machines there is an increasing demand for testing facilities which offer the same capabilities as those for real-world sized devices.”

Source:
Lindsay Brooke

University of Nottingham

Roche and Plexxikon announced interim results from a phase I study with PLX4032 (R7204) a new, highly selective and potentially promising oral treatment for patients with advanced melanoma whose cancer harbours the BRAF mutation (known as mutation-positive). Patients treated with PLX4032 lived for a median of six months without their disease getting worse and more than half experienced significant shrinkage of their tumours; this included patients where the cancer had spread to the liver, lung and bone.1 Historically, less than 5% of metastatic melanoma patients are still alive five years after diagnosis.2

PLX4032 works in a highly innovative way by selectively targeting and destroying tumour cells carrying the BRAF mutation. BRAF is an important mediator of cell growth and division, but when mutated is known to cause 60% of melanomas, the most deadly form of skin cancer, and approximately eight percent of all solid tumours.

This was a phase I study involving 16 patients with BRAF positive melanoma and over half saw the extent of their cancer reduce by at least 30%.1 This experimental treatment will now be prioritised for phase II and III studies.

‘PLX4032 has shown both tumour shrinkage and delay in tumour progression in patients whose tumours harbour a BRAF mutation, as well as improved quality of life for symptomatic patients,’ stated Keith T. Flaherty, M.D., assistant professor at the Abramson Cancer Center of the University of Pennsylvania and principal investigator for the PLX4032 phase I clinical trial.

‘Seven years after BRAF mutations were first identified we have validation that this mutation is a cancer driver and therapeutic target. In addition to a new and important chapter in the story of targeted therapy development in cancer, we are especially excited for our melanoma patients for whom there are few treatment options.’

Following these initial positive findings, Roche and its partner Plexxikon will evaluate the activity of PLX4032 in larger trials to support a potential registration program beginning later this year. If successful, it is expected to launch with a tissue based companion diagnostic test, representing another step forward in personalising cancer treatment. The two companies in their strong partnership are co-developing PLX4032 for potential use in a number of cancers harbouring the BRAF mutation. They are also co-developing the diagnostic test to select mutation-positive patients for clinical trials, and ultimately, for treatment with PLX4032.

Malignant melanoma is the most serious form of skin cancer. In the UK, more than 10,400 people are diagnosed with malignant melanoma each year3 and it is the most common kind of cancer for women in their 20’s.4 Worryingly, the number of people diagnosed in the UK has quadrupled since the 1970’s - making it the most rapidly increasing cancer3. Melanoma is treatable if caught early but patients who develop metastatic disease are rarely cured with available treatments. Only a small proportion of people (<5%) live more than two years once systemic metastases become evident.5

About the study

Promising preliminary findings reported in BRAF mutation-positive melanoma patients include:1

- PLX4032 has been well tolerated at therapeutic doses
- Partial responses (of at least 30% tumour volume reduction) in nine mutation-positive melanoma patients
- Regression of metastatic lesions in every site to which melanoma commonly spreads, including to the liver, lung and bone
- Disease control lasting up to 14 months with continuous therapy, with many patients still receiving treatment
- Interim median progression-free survival of approximately six months

By contrast, no treatment response was observed in a small group of patients without the BRAF mutation, and progression-free survival was less than two months, consistent with historical data.

Drug-related adverse events, including rash and photosensitivity, have been classified as mild in grade. Serious adverse events, including diagnosis of cutaneous squamous cell carcinoma, were observed in some patients after chronic treatment; however the safety profile has been warranted favourable for this population and the trial authorised to proceed to the next stage of investigation.

The PLX4032 data not only represent an important step forward in understanding and treating malignant melanoma, but also represent a significant advance in the use of biomarkers and diagnostic tools and the potential benefits of tailoring cancer treatment to individual patients.

References:

1 Flaherty K. Phase 1 study of PLX4032: Proof of concept for V600E BRAF mutation as a therapeutic target in human cancer. Oral presentation. Presented at ASCO 2009

2 The Healthcare Center, Facts About Metastatic Melanoma

3 Cancer Research UK Press Release 25 May 2009 See here
Last accessed May 2009

4 Cancer Research UK Press Release April 2009. See here
Last accessed May 2009

5 Boyle P, et al. World Cancer Report. IARC Press, Lyon, 2008

Source
Roche

The damage that our modern living and working environment could be doing to our health will be investigated by a new £5M MRC-HPA Centre for Environment and Health at Imperial College London and King’s College London.

The new Centre will analyse the health of people across the UK and how this is affected by aspects of the environment in which they live and work, from traffic fumes and noise from overhead aircraft, to chemicals in the environment such as the by-products of disinfection in the water supply.

The Centre will particularly focus on vulnerable people, including children and the elderly, and how environmental factors outside their control could be increasing their risk of respiratory problems, heart disease and cancer.

The Centre is core funded by the Medical Research Council (MRC) and the UK’s Health Protection Agency (HPA), with the two universities funding new posts and studentships. Its researchers will be working with the HPA so that if their work reveals a new health risk, the HPA can take account of the Centre’s findings in its advice to government.

Researchers estimate that air pollution alone could be causing several thousands of people to be admitted to hospital and die prematurely each year, because of the damage minute particles of pollutants could do to the heart and lungs.

However, there is currently limited evidence about the effects of most pollutants on people’s health, because much of the relevant data comes from animal studies. Humans are typically exposed to low doses of pollutants, often acting in combination, over long periods of time. This makes their effects difficult to measure.

The new Centre will conduct epidemiological studies of large numbers of people and analyse in detail which pollutants they are exposed to during their daily lives. Its researchers will use new tools in areas such as mapping, modelling, toxicology, genomics, proteomics and metabonomics to answer questions such as which pollutants people are being exposed to and when and how the levels of these change over time.

The researchers hope that the new work will help reveal where pollutants may be posing even small excess risks to health. Clusters of health problems may be visible in large groups that might not show up when looking at smaller groups of people.

Professor Paul Elliott from Imperial College London, the Director of the new MRC-HPA Centre for Environment and Health, said: “Your body has to deal with hundreds of different pollutants every day, the vast majority of which are probably harmless. However, we know that some pollutants can cause health problems - for example, some of the minute particles found in diesel fumes can make people’s asthma symptoms worse.

“It’s quite difficult to work out whether certain pollutants are affecting our health because we are exposed to so many, over such long periods of time. Our new Centre is developing methods to look at the exposure of many thousands of people. Through this research we will investigate the extent, for example, a particular chemical is contributing to a particular health problem.”

Professor Frank Kelly from King’s College London, the Deputy Director of the new Centre, said “We are very much looking forward to working with colleagues at Imperial College to address a range of challenging environmental issues which contribute to the chronic disease burden in the 21st century”.

Dr John Stephenson, the Director of Research and Development at the Health Protection Agency, added: “The establishment of the MRC-HPA Centre for Environment and Health provides the UK with a world-class research facility, capable of assessing the impact of environmental factors on human health, which will greatly enhance the HPA’s ability to provide accurate and timely advice to Government.”

Projects planned at the new Centre include:

• A study exploring whether land that is contaminated with chemicals from industrial and domestic pollution could have a negative impact on people’s health. The researchers will analyse data on a large group of people living near such land to see whether there are any unusual patterns of health problems. Some studies have suggested that living near contaminated land might be associated with an increased risk of reproductive problems.

• A study of people living near London’s Heathrow airport, exploring how air and noise pollution can affect people’s health. The research will analyse the effects of living near road traffic from airport uses as well as aeroplanes. Current evidence suggests that air pollution and noise affect the cardiovascular system in different ways. Building on existing work, the new study will look at the effects of exposure to both forms of pollution together.
• A study exploring whether London’s Low Emission Zone, which was introduced in 2008 to improve London’s air quality by reducing diesel fumes, has a beneficial effect on the health of people living and working in the Greater London area. The Low Emission Zone targets large diesel-engined vehicles, such as lorries. It requires the most individually polluting vehicles travelling in the Greater London area to either meet specific emissions standards or pay a daily charge.

Source:
Laura Gallagher

Imperial College London