Targeting transcription-replication conflicts in MYCN-driven neuroblastoma
MYC proteins are transcription factors that bind to active promoters and promote transcriptional elongation. In neuroblastoma, a solid tumor in childhood, expression of MYCN is deregulated in high risk patients. Despite multimodal therapies the outcome of those patients is very poor showing the urgent need for new therapy options.
We could show already that MYC-driven tumors are dependent on Aurora-A and a sensitive to Aurora-A inhibitors. Those inhibitors entered already clinical trials but they have a lot of side effects and patients eventually relapse. We want to exploit combination therapies with Aurora-A inhibitors. Understanding the mechanisms how combination therapy is affecting the tumor will show new and specific vulnerabilities for improving therapy of neuroblastoma.
Identification of Resistance Mechanisms to CAR-T Cell Therapy in Hematologic and Solid Neoplasias
The clinical use of targeted cellular therapies, especially chimeric antigen receptor-modified T cells (CAR-T) has raised hopes for the treatment of advanced hematologic malignancies. However, relapses occur frequently and CAR-T therapy of solid malignancies is still in its infancy.
Here, we are evaluating relevant resistance mechanisms like immune escape of the malignant cells and insufficient effector function of the CAR-T product, exemplary in multiple myeloma and pancreatic cancer models. Based on our mechanistic insights, we are armoring the CAR-T specifically to improve their anti-tumor efficacy. Methods include next-generation T-cell engineering, high-resolution microscopy and single cell RNA sequencing.