by Simon Rodwell | 9 March 2013 11:04
Proposals were invited for a study to investigate an aspect of the early detection of melanoma or the prevention of misdiagnosis, involving primary or secondary care, or both. Submissions were sought for a project that would be deliverable within 18-24 months, with a maximum overall grant by Melanoma Focus of £100,000.
Six submissions were received from research groups throughout the UK. These were evaluated by the charity’s Scientific Committee, led by Professor Mark Middleton. It was decided that the award should go to a group from Newcastle University – details below. For a technical overview of the project click here.
Project: Validation of Ambra-1 and Loricrin as prognostic biomarkers for the early detection of high risk melanomas
There is a high rate of mortality if melanoma spreads (or ‘metastasises’) from the skin to other parts of the body. Thankfully, most patients can be cured if their melanomas are surgically removed from the skin before this happens. Analysing melanomas after their removal can help clinicians predict which patients remain likely to develop metastatic disease but at present the accuracy of using this method for prognosis is not exact.
Loss of the surface layer of the skin over a melanoma is known as ulceration. Patients whose melanomas become ulcerated have a worse outcome, but the exact reason for this is unclear. We have shown in an initial group of melanoma patients that the loss of two proteins, Ambra-1 and loricrin, in this skin layer is linked to the development of ulceration, hence a greater risk of the disease spreading.
This research project will look for changes in these two proteins in this skin layer in melanomas from a larger group of patients. We aim to find out how to predict which patients are at a higher risk of metastatic melanoma, and who will therefore need to be followed up more closely by clinicians after surgery.
We hope to gain a better understanding of the link between these proteins and skin ulceration, as well as their relationship with another protein, known as transforming growth factor beta-2 (TGFβ2), which is linked to cell proliferation and is found in melanomas. This, in turn, may help us develop new treatments for patients who are identified as being at higher risk of disease spread. Discovering earlier and more effective therapies would reduce the rate of metastasis and overall mortality from this most deadly form of skin cancer.
Comment by Dr Rob Ellis
‘We are extremely delighted to receive this award as we feel that the results we have seen in a previous cohort of patients, as well as multiple laboratory experiments, suggests that we may have begun to unravel the enigma of melanoma ulceration. In doing so, we have identified two proteins in the epidermis overlying melanomas that when lost in the early stages of melanoma development suggest that a patient is at high risk of disease spread and higher mortality.
‘By further understanding this process, we may be able to develop new drug treatments to prevent the spread of disease and so impact greatly on the mortality from the condition.
‘The support of the Melanoma Focus has enabled us to take this project forward, allowing potential patient benefit as soon as possible’.
The successful applications for funding under the first round of the charity’s Patient Impact Programme were announced in mid-2013. Of the 10 applications received, two were supported by grants of up to £100,000 each. To qualify, a project had to be capable of delivering tangible improvements and benefits for melanoma patients and have popular appeal, with a rationale that can be widely appreciated and a scientific basis that is accessible for the general public. The successful groups and their research projects were as follows:
Project A: Metformin and survival from melanoma
‘Melanoma patients often seek advice at diagnosis about lifestyle: what they should do to best look after their health in the future. Currently there is very little evidence on which to base such advice. One question that arises is whether any drugs taken for other medical conditions should be avoided; and whether drugs taken for common conditions such as diabetes might also have an effect on melanoma.
‘Scientists have published evidence that one drug, metformin, prescribed to diabetic melanoma patients could have harmful effects for some and yet beneficial effects for others, depending on the genetic profile of their cancer. Our project is designed to investigate this by identifying melanoma patients with diabetes and testing their tumours for mutations’.
Project B: Strategic biomarkers for aggressive melanoma
‘Melanoma in its advanced stages has a striking propensity to spread (metastasise) to distant organs including the liver, lungs and brain at which time it is incurable and frequently causes rapid death. There is increasing evidence that the early use of anti-melanoma drugs allows more effective treatment and better clinical outcomes. Development of simple, non-invasive tests (particularly blood tests) to detect metastatic disease before the patient develops symptoms is therefore a high priority for melanoma research. We have developed such tests in which we detect changes in the DNA profile present in blood that occur in patients with metastatic disease. The tests we are developing require only a blood sample taken at routine clinical follow up and are extremely sensitive and specific for detection of metastatic melanoma.
‘We now want to increase the utility of these tests by incorporating additional genes (identified in our laboratory) that may increase the effectiveness of the test and greatly increase the number of patients tested to refine our tests to a level that is compatible with implementation in the clinic. Achieving this would expedite the introduction to routine clinical practice of blood tests to detect sub-clinical metastasis and would inform a change in the treatment paradigm towards early use of anti-melanoma drugs. We believe that this would result in markedly improved clinical outcomes’.
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