Funding tool: Basic research projects
Project-ID: LS14-007
Project start: 01. Februar 2016
Project end: will follow
Runtime: 35 months / finished
Funding amount: € 340.000,00

Brief summary:

Melanoma is one of the most frequent tumors in young adults and despite it only accounts for 4% of all cases of skin cancer, melanoma is responsible for 79% of all skin cancer related deaths. Despite progress has been achieved in treatment of Melanoma (e.g with B-raf inhibitors), finally patients succumb due to resistance mechanisms acquired by the tumor. Many lines of evidence have shown that especially metastatic melanoma exhibits a strong metabolic turnover, which is needed to fuel cell proliferation and anabolic pathways. This increased cellular turnover also results in an increased demand to maintain the redox homeostasis. Here we propose to analyze this high metabolic and therefore also ROS (Reactive Oxigen Species) generating stress as a possible Achilles heel of melanoma. One of the major regulators of stress response in cancer is NRF2. It plays a central role in protection of cells against oxidative and xenobiotic stresses. Therefore the inhibition of NRF2 or its target genes might re-establish the sensitivity of melanoma to apoptosis driven by ROS. Furthermore this mechanism could prevent resistance mechanisms frequently observed in metastatic melanoma and it might abolish the frequently observed activation of endothelial cells, which surround tumor cells. It is highly likely that a combination of state of the art melanoma treatment with compounds that inhibit the generation of ROS scavengers, potentiates the effectiveness of the current treatment regiments. He we will use CRISPR based methods as well as pharmacological inhibition to elucidate the mechanistic role of NRF2 in melanoma cells and on endothelial cells. Furthermore we will transfer knowledge gained from our model by closely cooperating with clinicians, who routinely care for melanoma patients. Concluding, we propose that abolishing the antioxidative response by suppressing NRF2 directly or its targets will be an effective contribution in the battle to fight metastatic melanoma.

Keywords:
Cancer Biology