August 2022

Discovering a prognostic biomarker for early-stage non-ulcerated melanomas (Fellowship)

Ioana Cosgarea is a clinician scientist and specialty doctor in dermato-oncology at the Royal Victoria Infirmary and Freeman Hospital in Newcastle upon Tyne. Her interest is in cellular signaling in melanoma, its deregulation and how it can be harnessed for therapeutic benefit, either in the context of novel drug targets or as a prognostic or companion biomarker.

Ioana has recently completed a research fellowship in Professor Lovat's laboratory at Newcastle University, culminating in the discovery of the mechanisms that lead to the loss of epidermal AMBRA1 and Loricrin expression (AMLo), a novel prognostic biomarker recently discovered (with the support of the BSF) for early-stage non-ulcerated melanomas.

Above image: Dr Ioana Cosgarea

Mr Aidan Rose (PhD) and Professor Penny Lovat are co-investigators in this project. Mr Aidan Rose is a plastic surgeon at the Royal Victoria Infirmary who has significant experience in TGFβ signaling in cutaneous malignancy. Professor Penny Lovat, Newcastle University, is internationally acclaimed for expertise in cellular signaling in melanoma and the development and translation of prognostic biomarkers as well as novel drug targets.

The impact of melanoma

Melanoma is the most deadly form of skin cancer with a world-wide incidence that has increased by 119% since the 1990’s. It is the 5^th most common cancer in the UK. While the majority of melanomas diagnoses are early stage I and II tumours with an overall favourable prognosis, up to 15% of these patients develop disease recurrence or progression. This highlights the urgent need for credible prognostic biomarkers able to stratify patient follow up as well as treatment based on personalised risk.

Background work of our research group

We have recently described the loss of 2 proteins, AMBRA1 and Loricrin (AMBLor), in the skin overlying early stage melanomas as a prognostic biomarker. Our pilot data shows loss of AMBRA1 in the skin overlying primary melanomas is also associated with its loss in the surrounding tumour vessels, suggesting that AMBLor expression is a surrogate marker of melanoma progression (metastasis).

We found that the melanomas that have a higher risk of progression, secrete a growth factor called TGF-β2 that facilitates the loss of AMBRA1 in the skin. The loss of AMBRA1 in the surrounding vessels however is not mediated by tumour secretion of TGF-β2, but rather likely by other super family members i.e Bone Morphogenetic Protein ligands (BMPs). Secretion of BMP ligands has been linked to an aggressive melanoma subgroup and their effect on endothelial blood vessel integrity may reveal novel drug targets.

Future work

The BSF Research Award will enable our group through the present study to interrogate the hypothesis that targeting BMP signaling in melanoma may represent a novel therapeutic strategy to prevent tumour metastasis for which AMLo expression may be a companion biomarker.

The impact of our research

The results from this project will aid the identification of potentially high-risk early stage I/II melanomas and novel targets to drive the selection of precision-based therapeutics through the strategic application of the loss of endothelial AMBRA1 expression as a novel companion biomarker.

Ultimately, we aim to benefit patients by translating these findings into personalised therapeutics that improve survival.

Dr Ioana Cosgarea, Royal Victoria Infirmary and Freeman Hospital in Newcastle upon Tyne.

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