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.
Regulation of melanoma differentiation and immunogenicity through targeted inhibition of p90 ribosomal S6 kinases
In malignant melanoma, the MAPK pathway is frequently hyperactivated and plays a central role in tumour cell biology. The members of the p90 ribosomal S6 kinase (RSK) family represent important effectors of activated MAPK signalling. We have previously shown that melanoma cells of various genomic subgroups exhibit marked RSK activation and can be effectively targeted by RSK-specific small molecule inhibitors.
Based on the multi-facetted association of hyperactivated MAPK signalling with an immune evasive tumour state, we now aim to characterize the influence of the individual RSK family members on melanoma cell differentiation and immunogenicity, and thus to identify potential therapeutic targets to boost anti-cancer immunity and to improve immunotherapy responsiveness of melanoma patients.
Disruption of transcription-replication coordination as a therapeutical option for colorectal liver metastases
Today, the occurrence of metastases is still determining the prognosis of colorectal cancer (CRC). In the situation of colorectal liver metastases (CRLM) surgical resection is the only curative option but the approach is limited by postoperatively remaining functional liver tissue.
Here, we evaluate therapeutical targets of CRC in general and CRLM in particular as well as their effects on regenerative capacity of the liver. We focus on factors essential for transcription control (by either Polymerase I or II) to avoid conflicts with the replication machinery. Mechanistic findings are validated in organoid systems and transferred into immunocompetent mouse models for CRC liver metastases and liver regeneration.