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.
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.
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.
Impact of DNA damage signaling and elongation perturbation on MYC-driven transcription
MYC oncoproteins are essential transcription factors which integrate growth-promoting signals into transcription. Overexpression of MYC proteins gives rise to a multitude of cancers, however the exact mechanisms underlying MYC-driven oncogenesis remain controversial.
Recent works, including our own, have shown that MYC-driven transcription adapts to a variety of stimuli thus allowing cancer cells to proliferate rapidly under suboptimal conditions. We will seek to understand these adaptive mechanisms with a particular emphasis on DNA damage signaling pathways and specific transcription elongation factors.
Improvement of diagnosis and identification of potential new therapeutic targets in pediatric adrenocortical carcinoma (ACC) by panel sequencing
Adrenocortical carcinoma (ACC) are highly malignant tumors originating from the adrenal cortex. In both adults and children, this tumor entity is rare, with an incidence of 0.2-0.3 per 1 million/year in patients younger than 20 years. Adrenocortical carcinoma in children occur both sporadically and as part of hereditary syndromes.
In contrast to adult patients, nearly all pediatric ACCs are hormonally active with related clinical manifestations in the form of virilization, Cushing's syndrome, or precocious pubertas. Disorders occur with two age peaks: infancy and postpubertal (approximately 30%). The main therapeutic approach is surgical resection of the tumor, with additional systemic chemotherapy and mitotane therapy in advanced stages. Prognosis is poor with a 5-year survival rate of less than 40%. Only in infants the prognosis seems more favorable with an overall survival of about 80% in those under 4 years of age. An effective, established therapy for advanced and metastatic (high risk) ACCs does not yet exist.
Molecular studies in pediatric ACCs have identified mutations in the TP53, CTNNB1, ZNRF3 genes as well as overexpression of proteins of the IGF system. These are considered as key factors in tumorigenesis and progression. The improved molecular understanding of prognosis and tumor biology is therefore a necessary step to refine risk stratification and establish targeted therapy options for pediatric ACC patients in the future.
In order to expand the currently limited clinical knowledge on the treatment of pediatric ACCs, this project aims to identify potential drugable mutations by panel sequencing of more than 50 pediatric ACCs using the PSO-500 panel with additional specific genes of interest and methylation assays and to correlate identified mutations/methylation patterns with the clinical outcome (risk stratification). This will provide answers to the questions if there is a mutation spectrum comparable to adult ACCs, if there are "common mutations", if there are mutations/methylation patterns that correlate with clinical characteristics and a better or worse prognosis and if there are differences between pre- and postpubertal/adult ACCs.
Understanding and targeting the mechanisms of malignant transformation and tumor progression may lead to the development of better diagnostic tools/protocols and to novel therapeutic interventions in ACCs.