Past projects

Validation of Ambra-1 and Loricrin as prognostic biomarkers for the early detection of high-risk melanomas

Principal Investigators:

Dr Rob Ellis, The James Cook University Hospital, Middlesbrough and Institute of Cellular Medicine, Newcastle University
Professor Penny Lovat, Institute of Cellular Medicine, Newcastle University

Co-Investigators

Dr Marie Labus, Business Development Manager, Research and Enterprise Services, Newcastle University

Summary

 If melanoma spreads (or ‘metastasises’) from the skin to other parts of the body, the prognosis or likelihood of recovery will be affected. 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. Currently 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. In an initial group of melanoma patients, it was shown that the loss of two proteins, Ambra-1 and loricrin, in this skin layer is linked to the development of ulceration, and a greater risk of the disease spreading.

This research project looked for changes in these two proteins in the ulcerated skin layer of melanomas from a large group of patients. The aim was 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.

The researchers gained 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). TGFβ2 is linked to how cells in the body grow and divide and is found in melanomas. Gaining understanding of these proteins may help to 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 serious form of skin cancer.

Comment from Principal Investigators

“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”

Next Steps

The project resulted in the first melanoma test to identify those at low risk of cancer spreading.
By applying the test – called AMBLor® – to the standard biopsy of the primary melanoma on its removal, patients who are at low risk of the disease reoccurring or spreading can be identified. Melanoma Focus are delighted to fund the initial research that developed this test – which may change the follow-up pathways for patients with stage 1a-2b melanomas.

The effectiveness of the AMLo test is yet to be fully evaluated by the NHS, BAD and NICE.  However, if endorsed, this test may be offered to early-stage melanoma patients to potentially reduce the need for some follow-up which will be great news for patients.

Strategic biomarkers for aggressive melanoma

Principal Investigators:

Professor Charlotte Proby, Medical Research Institute, University of Dundee

Co-Investigators

Dr Tim Crook
Dr Colin Fleming
Dr Mathieu Boniol
Professor Catherine Harwood
Dr Rubeta Matin

Summary

Melanoma in its advanced stages tends to spread (metastasise) to distant organs including the liver, lungs and brain. When this happens, it can become incurable and reduces the life expectancy of the patient significantly.
There is increasing evidence that the early and adjuvant use of systemic 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. Tests have been developed in which changes in the DNA profile can be detected in blood samples from patients with metastatic melanoma.
The tests that have been developed only require a blood sample to be taken at a routine clinical follow up and are extremely sensitive and specific for detection of metastatic melanoma.

This research project wants to increase how useful these tests are by including additional genes (identified in their laboratory) that may increase the effectiveness of the test and greatly increase the number of patients tested. This will mean the tests can be improved to a level that they will be useful for testing patients in melanoma clinics.
By achieving this it would mean that these blood tests can be introduced into routine clinical practice. This will increase the detection of metastasis that don’t show up on current standard tests and would help to initiate a change in the treatment of patients with metastatic melanoma, for example, being able to use drugs to treat the melanoma earlier rather than later.
The researchers believe that this would result in markedly improved clinical outcomes.

Comment from the Principal Investigator

“This Melanoma Focus funded research was very productive leading to 4 publications revealing epigenetic mechanisms involved in melanoma progression and metastasis (see below).
We made good progress in better understanding the epigenetic mechanisms that drive melanoma metastasis, but this work has not led to a commercially exploitable test for a variety of reasons, one being the introduction of adjuvant systemic therapy for high risk melanomas. In terms of defining melanoma ‘risk’ (i.e., risk of lymph node metastasis), it has been superseded by work on gene expression profiling (GEP) and we are currently validating a clinic-pathological-GEP algorithm that appears to robustly identify those low-risk melanomas with a less than 10% risk of a positive SLNB. Ultimately, we are hopeful that this test will identify those melanoma patients who will benefit from adjuvant systemic therapy without the need to perform SLNB, as SLNB is an imperfect and potentially morbid procedure.”

References and Publications relating to this project

• Wang H, Lee S, Nigro CL, Lattanzio L, Merlano M, Monteverde M, Matin R, Purdie K, Mladkova N, Bergamaschi D, Harwood C, Syed N, Szlosarek P, Briasoulis E, McHugh A, Thompson A, Evans A, Leigh I, Fleming C, Inman GJ, Hatzimichael E, Proby C, Crook T. NT5E (CD73) is epigenetically regulated in malignant melanoma and associated with metastatic site specificity. Br J Cancer. 2012;106(8):1446-52. doi: 10.1038/bjc.2012.95

• Lo Nigro C, Wang H, McHugh A, Lattanzio L, Matin R, Harwood C, Syed N, Hatzimichael E, Briasoulis E, Merlano M, Evans A, Thompson A, Leigh I, Fleming C, Inman GJ, Proby C, Crook T. Methylated tissue factor pathway inhibitor 2 (TFPI2) DNA in serum is a biomarker of metastatic melanoma. J Invest Dermatol. 2013;133(5):1278-85. doi: 10.1038/jid.2012. 493.

• Atkinson A, Renziehausen A, Wang H, Lo Nigro C, Lattanzio L, Merlano M, Rao B, Weir L, Evans A, Matin R, Harwood C, Szlosarek P, Pickering JG, Fleming C, Sim VR, Li S, Vasta JT, Raines RT, Boniol M, Thompson A, Proby C, Crook T, Syed N. The collagen prolyl hydroxylases are bifunctional growth regulators in melanoma. J Invest Dermatol. 2018; 139(5):1118-1126. doi: 10.1016/j.jid.2018.10.038.

• Renziehausen A, Wang H, Rao B, Weir L, Nigro CL, Lattanzio L, Merlano M, Vega-Rioja A, Del Carmen Fernandez-Carranco M, Hajji N, Matin R, Harwood C, Li S, Sim VR, O’Neill K, Evans A, Thompson A, Szlosarek P, Fleming C, Stebbing J, Proby C, Tzakos AG, Syed N, Crook T. The renin angiotensin system (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention. Oncogene 2019;38(13):2320-2336. doi: 10.1038/ s41388-018-0563-y