In recent years significant breakthroughs in the treatment of metastatic melanoma have been achieved. Small molecule signal transduction inhibitors (e.g. directed against mutated BRAF or MEK kinases) and immunotherapies (e.g. adoptive T cell therapies or antibody-mediated blockade of immune checkpoints) have been shown to prolong the survival of patients with advanced disease. However, primary or secondary resistance limits the long-term efficacy of these therapeutic approaches. In this project we investigate in appropriate preclinical mouse models for melanoma multimodal regimens that effectively combine signal transduction inhibitors with immunomodulatory agents for the treatment of melanoma and try to gain fundamental insights that help to rationally design such combination treatment protocols exploiting the Genentech/Roche drug portfolio.
1. Evaluate the impact of Genentech/Roche MAPK inhibitors (e.g. MEKi, ERKi alone and in combination) on the growth and phenotype of HGF-CDK4(R24C) mouse melanoma cells as well as their interaction with immune cells in vitro and in vivo.
2. Optimize protocols that are able to enhance the efficacy of our established immunotherapies (e.g. innate immune stimulation and adoptive T cell therapy) in the HGF-CDK4(R24C) mouse melanoma model with Genentech/Roche immunomodulatory agents (e.g. IFNa, aPDL1 mAb, IDOi alone and in combination).
3. Identify strategies that effectively combine Genentech/Roche MAPK inhibitors and immunomodulatory agents in the HGF-CDK4(R24C) mouse melanoma model.
The long-term goal of our work is to provide valuable information that can facilitate the clinical translation of effective combination therapies in ongoing and future trials in order to improve melanoma patient care. As MAPK pathway inhibition and novel immunotherapies also play a critical role in other tumor entities, the expected results of our experiments will likely also have implications beyond melanoma. In addition, we may delineate strategies to prevent unexpected interferences between the different treatment modalities regarding the mechanisms of therapy resistance.