Tumorzentrum Freiburg - CCCF

Dpt. of Urology
Prof. Roland Schüle
Institute of Pharmaceutical Sciences
Prof. Manfred Jung
Dpt. Hematology, Oncology and Stem Cell Transplantation
Prof. Michael Lübbert
Center for Clinical Research
Prof. Dr. Marc Timmers

Partner Sites: Essen/Düsseldorf, Frankfurt/Mainz, Heidelberg, Tübingen

The overall aim of the project is to investigate the role of epigenetic alterations in tumorigenesis and treatment response of cancer. One of the specific objectives is to evaluate LSD1 (lysine-specifi c demethylase 1) as novel therapeutic target. On the other hand epigentically inactivated target genes should be molecularely characterized and methylom responses and resistance mechanisms should be investigated.

Evaluation of LSD1 as novel therapeutic target:

Histone modifications epigenetically constitute aberrant gene expression patterns that go along with the process of oncogenesis. Increased activity of the histone demethylase LSD1 is associated with progression of prostate cancer, lung cancer, sarcomas and neuroblastoma. The investigators hypothesize that silencing of LSD1 will result in reprogramming of the tumor cell epigenome towards a more benign phenotype and that LSD1 inhibitory therapy will be an effective novel therapeutic option for several malignancies. The aims of this project are:

• To demonstrate and explore the efficacy of three novel LSD1 inhibitors (developed by the lead discovery center Freiburg) in prostate cancer, lung cancer, sarcoma and neuroblastoma.
• To substantiate the mechanism of action in all tumor types by identification of the relevant LSD1 interaction partners and LSD1 regulated genes.
• To identify surrogate markers of LSD1 activity/LSD1 addiction of tumor cells to improve selection of suitable patient subsets for LSD1 inhibitory therapy.

LACID: LSD1 as anticancer target in the clinic (TRANSATRA) and in drug discovery

(Principal Investigator Prof. Lübbert)

Selective inhibitors of the lysine specific demethylase 1 (LSD1) where compounds from pharmaceutical companies are in phase I, interconnect with the clinical trial TRANSATRA which involves the LSD1 inhibitor tranylcypromine. 

LSD1 Inhibitors as New Anticancer Agents

Prof. Manfred Jung (overall coordination), Prof. Roland Schüle, Prof. Michael Lübbert

(Partner sites: Berlin, Essen/Düsseldorf, Frankfurt/Mainz, Heidelberg, Tübingen)

This research topic aims to design, synthesize and evaluate optimized inhibitors of the histone demethylase LSD1 as new anticancer agents. Lysine (K)-specific demethylase 1 (LSD1) is a validated anticancer target but existing inhibitors lack potency or suffer from poor pharmacokinetics. Therefore an optimization of inhibitors with good in vivo bio-distribution would result in highly valuable tools for identifying the role of epigenetic pathways and is promising new drugs for various tumor entities. Novel drugs based on LSD1 would be interesting candidates for for brain cancer, AML and prostate cancer – all tumor entities of general major interest in DKTK research. As LSD1 was found to have a potential general impact on cancer development and genesis it might be possible that the Topic “LSD1 Inhibitors as New Anticancer Agents” might generate bridges to several other projects or topics of further DKTK research groups. LSD1 has been shown to drive tumor cell growth and proliferation in vitro and in vivo in various tumor entities (prostate, neuroblastoma, colon cancer, AML). Inhibition of LSD1 by small molecules leads to inhibition of cancer cell proliferation in cell culture and in mouse models. Existing inhibitors need to be improved in terms of potency and bioavailability. At the same time, specific cellular models need to be established that allow a detailed mode of-action analysis of LSD1 inhibitors in the context of three main DKTK entities (colon cancer, gliomas, AML).

Institute of Molecular Medicine and Cell Research
Prof. Christoph Peters
Junior Research Group Dr. Dr. Melanie Börries

(Partner Sites: Berlin, Frankfurt/Mainz, Heidelberg, München, Tübingen)

1. Delineating the genetic heterogeneity in the Tumor-Stroma Interaction in Pancreatic  Adenocarcinoma

Pancreatic cancer is one oft he deadliest cancers with a mean five year survival of less than 5%. Pancreatic tumors are characterized by a high variability on the stroma content. Hence, tumor-stroma interactions and the support by pancreatic stellate cells and fibroblasts must play an important role. However, the determinants and causes of the tumor-stroma interactions and support remain yet unknown. Therefore, the project investigates transcriptome, proteome and secretome specificity as well as proliferation, migration and invasiveness in various Xenograft derived pancreatic tumor cell lines with respect to varying stroma content and the original pancreatic tumor. Using machine learning techniques as well as multivariate linear models we aim to detect processes and genes that both correlate and are causal to this tumor heterogeneity.

2. Mutation Analysis and functional characterization of juvenile myelomonocytic leukemia

Linked to the research program Molecular Diagnostic, Topic Molecular diagnostics of pediatric malignancies, Prof. Charlotte Niemeyer

JMML is a rare childhood cancer that leads most often to an early death of the patient, if untreated. The current cure is bone marrow transplantation, which, however can still lead to recurrent relapse. Albeit several mutations within the RAS pathway are known to be strongly associated with JMML, a thorough unbiased investigation on the driver mutations have not been undertaken so far. Based on the Whole Exome sequencing data of 75 patient tumors we will propose new mutations, experiments and functional associations that lead to the onset this disease for a better patient stratification, risk assessment and germline mutations driving JMML.

3. Morphologisch kontrollierte, quantitative RNA und DNA Analysen von gematchten Kryo-und FFPE Geweben: epitheliale Tumoren und assoziiertes Normalepithel, inklusive Primärtumore und Metastasen

Linked to the research program Molecular Diagnostics, to topics from Prof. Silke Laßmann

Fresh-Frozen paraffin embedded tissue samples are commonly used in clinical routine to conserve patient material. The benefit is the low cost and robustness of the method. However, while FFPE samples conserve the tissue structure, it impacts the molecular structure of the RNA and DNA. This project aims to assess the quality and quantity of RNA and DNA from FFPE samples of epithelial tumors and associated metastasis. Using known cases and clinical outcomes as well as comparison with fresh frozen samples will assess the possibilities and limitations quantifying mutations and gene expression in such samples.  Additionally, we include in this study not only the original tumor but also the adjacent metastases.

4. Mutational Analysis from Ewing Sarcomas

Co-Work with Prof. Dr. med. Udo Kontny, former participating Investigator Freiburg, now RWTH Aachen, research topic Molecular Diagnostics of Pediatric Malignancies, Research Program Molecular Diagnostics

Ewing Sarkomas are a rare childhood malignancy whose generic origins still remain largely unknown. Using whole Exome sequencing we investigate mutations in a cohort of 13 ES patients. In particular we focus on SNVs in patients that have suffered a relapse to detect novel driver genes for this disease.

5. Targeting the Kinome to induce differentiation in human breast cancer stem cells

Linked to the research program Stem Cells in Oncology, linked to the work of Dr. Jochen Maurer

Triple negative breast cancers is once oft he most aggressive breast cancer subtypes, which are characterized by a more stem cell like identity oft he tumor cells. One putative approach to treat this cancer is to induce cancer stem cell differentiation. Based on a large-scale kinome knock-down study, we investigate on the transcriptome level the effect of several kinases that lead to cancer stem cell differentiation.

6. Detection of mutated, free circulating tumor DNA and noncoding RNA in plasma of patients with resectable, stage I-IIIA non-small cell lung cancer

Exosomes are free circulating vesicles containing tumor DNA and noncoding RNA that allow inferring the tumor status of a patient. Here we investigate the correlation between exosome content and tumor stage in various patients with the aim to derive plasma based biomarkers and predictors. For this we will correlate RNA sequencing data from blood and exosomes with clinical data and outcome. Moreover, we will characterize the tumor state by WES.

7. Identification of genetic drivers in childhood MDS using WES and RNA Sequencing

Linked to the research program Molecular Diagnostics, to a specific DKTK project by Prof. Nikolas von Bubnoff

The overall aim of this project is to identify and confirm novel somatic and constitutional genetic alterations that occur in childhood myelodysplastic syndromes (MDS) by combining genomics with transcriptomes from families with MDS history. The information about mutations might have prognostic significance or future therapeutic implications (i.e. activating mutations in “druggable” pathways”).

8.    Multivariate modeling tumor progression of colorectal cancer

Linked to the joint funding project Novel Tools for Dissection of Oncogenic Pathways, partner site München, Prof. Roland Rad.

Based on the transcriptome data from colorectal cancer in mice of different tumor stages and different colon parts we will infer multivariate models that elucidate spatiotemporal markers for cancer progression.
 

Institute for Molecular Medicine and Cell Research
Prof. Dr. Thomas Reinheckel - In Vivo Functions of Proteases
Dr. Tilman Brummer - Intracellular signalling pathways
Prof. Christoph Peters - Cancer Invasion and Metastasis

Department Pediatric Hematology and Oncology - Medical Center University of Freiburg
Dr. Miriam Erlacher - Apoptosis in Haematopoesis and Leukaemogenesis

Phosphorylation and proteolytic processes are involved in virtually all post‐transcriptional pathways that determine cell fate decisions. The “kinase” and “protease” worlds are highly interconnected (“The regulatory crosstalk between kinases and proteases in cancer” Nat Rev Cancer. 2010 10(4):278‐ 92). Proteases can be regulated by phosphorylation, while kinases can be activated or inactivated by proteolytic processing. There is an overwhelming amount of data establishing numerous kinases or proteases as prognostic markers and/or therapeutic targets in many cancer entities. However, there is surprisingly little knowledge on the combined prognostic value of specific proteases and kinases and whether the combined targeting of protease and kinase pathways would yield synergistic and sustained effects in cancer treatments. This project is aimed at comprehensive mutational and expression profiling of kinases and proteases in human breast, colon, and pancreatic carcinomas, as well as in juvenile myelomonocytic leukemia. Functional genetic shRNA screens for kinases and proteases involved in tumor cell invasion, metastasis, and survival will be done by testing combinations of already existing inhibitors for proteases and kinases in vitro and in vivo. Functional validation of individual and combined protease and kinase hits in vitro and in vivo as well as validation of the results in clinical samples will be performed.

Department of Thoracic Surgery, Division of Cancer Research
Prof. Sven Diederichs, Website: Division of Cancer Research

The forthcoming research topic(s) of the working group of Prof. Diederichs will be planned to investigate the role of long non-coding RNAs (lncRNAs) in cancer biology. Cellular and molecular functions of differentially regulated ncRNAs, specifically lung cancer associated ones will be in the focus to clarify their role related to cancer cell viability, mitosis and migration.