Funding tool: Basic research projects
Project-ID: LS10-028
Project start: 01. September 2011
Project end: will follow
Runtime: 36 months / finished
Funding amount: € 273.000,00

Brief summary:

Amongst the different skin cancer types, malignant cutaneuous melanoma causes the highest death toll in Europe. Even though public awareness improved, both incidence and mortality is still increasing.
While the early detection and removal of the primary tumour is associated with a good patient prognosis, the occurrence of distant metastasis drops the median survival time to only 6 to 9 months. Therefore, the treatment and its outcome of affected patients have to be closely monitored to detect as early as possible recurrence and metastasis of the tumour. However, all current serological screening-methods lack the sensitivity and specificity to fulfil this requirement. Moreover, the heterogeneity of melanoma demands an individual patient management.
The focus of this study is the development of serological personalised DNA biomarkers for fast and reliable assessment of melanoma metastasis and response to treatment.
All cancers arise because of mutations that have occurred in the genome of previously normal cells. Due to the clonal expansion of these tumour-founder cells, all tumour-cells share a high number of identical mutations, which distinguishes them from all other cells of the body. DNA harbouring these mutations can be unambiguously identified and thus will be used as biomarker in this study. By sequencing and comparing selected “cancer genes” and DNA of both healthy and tumour tissue, tumour-specific mutations are detected in each patient.
Moreover, since all living cells and in addition necrotic as well as apoptotic tumour cells actively release DNA into the blood, the quantification of this tumour derived cell-free DNA in the plasma presents an ideal biomarker for the tumour burden. As consistently also metastasising cells harbour these mutations, they can be quantified in the cell-fraction of the blood. For this purpose, we have already developed an enhanced mutation-specific qPCR-method with a sufficient discrimination limit to detect mutated DNA from non-mutated DNA in the blood.
A unique feature of this method is its applicability to all solid tumours, regardless of tumour-type and species. This allows us to optimise several points of this method in a melanoma animal model, prior to applying it in a clinical study on melanoma patients with varying disease stages. Tumour-specific cell-free DNA and metastasising cells will be quantified in serial blood samples before and in periodic intervals after surgery, and compared to routine-diagnostics and clinical outcome. DNA as biomarker has the exceptional advantage that it cannot escape detection like protein or RNA markers by its changed expression. The resulting quantitative data will give important insights into tumour-dynamics. Besides the scientific value of the study, a resulting possibility to change an ineffective therapy earlier could considerably improve the therapy-management of melanoma patients.

Keywords:
melanoma, personalised medicine, serological biomarkers, therapy response