Project-ID: LS15-007
Project start: 01. November 2016
Runtime: 36 months / finished
Funding amount: € 297.110,00

Brief summary

Malignant melanoma is the most frequent cause of skin cancer-related deaths. Despite the progress in understanding the biology of this disease, it still remains a significant clinical problem. Melanoma is often associated with activating mutations in the BRAF gene at the amino acid position 600, which results in an uncontrolled activation of the MAP-kinase pathway and - as a consequence - leads to increased cell proliferation and migration. Although several BRAF inhibitors, such as vemurafenib, have been proven to be highly effective in inhibiting BRAFV600 mutated melanomas, resistant-associated secondary mutations, which reactivate alternative survival pathways, often occur. We have recently reported on the response of chondroitin sulfate proteoglycan 4 (CSPG4)-specific Abs to enhance the anti-proliferative effects of vemurafenib. These data implied that the microenvironment is important in determining the effect of targeting CSPG4 on cell migration and invasion and suggest a role for CSPG4 in the phenotypic plasticity of melanoma cells and the emergence of a transient drug-resistant state. Central to the model of stress-induced drug tolerance resulting in multi-drug resistant cancer cells called induced-drug tolerant cells (IDTCs) is their propensity to develop colonies for which cell adhesion is crucial. Based on these findings of cell adhesion and cell motility being crucial for early drug resistance we propose that anti-CSPG4 antibodies, which have shown promising results in two different animal models, prevent or delay IDTC formation in mutant BRAF melanoma cells if combined with standard treatment modalities such as BRAF and MEK inhibitors. During this project we will validate this hypothesis with in vitro and in vivo models of melanoma, we will analyse changes on protein and gene expression levels induced by these treatment modalities and we will validate these experimental data on patients´-derived melanoma samples. Targeting IDTCs with anti-CSPG4 antibodies could be a crucial step for the prevention of acquired drug resistance.

Keywords:
tumor cell biology