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Comprehensive Cancer Center Freiburg - CCCF

DKTK-Freiburg Priority Area 1

Oncogenic Signaling and Medical Epigenetics

Oncogenic Signalling and Medical Epigenetics are key research areas aimed at understanding intra- and extracellular signalling pathways disturbed by mutations in liquid as well as solid cancer. At the DKTK partner site Freiburg the principle research strategy in this field is to enhance the molecular understanding of epigenetics and kinase signalling and to devise novel intervention strategies based upon these new insights. These novel therapeutic approaches will rely on (the combination of) identification, development and pre-clinical testing of innovative drug candidates. Subsequently, first in man and phase I/II IITs will be conducted. Specific topics include, but are not restricted to: DNA and histone modifications, readers of chromatin modifications, epigenetic control of transcription, intracellular kinase pathways, immunomodulation and stem-cell based therapies.

Chair of the priority area 1:

DKTK Professor for Medical Epigenetics Marc Timmers

Scientific committee members:

DKTK principal investigators and projects in priority area 1:

The therapeutic aim in juvenile myelomonocytic leukemia (JMML) is disease eradication rather than mitigation or palliation. Allogeneic hematopoietic stem cell transplant (HSCT) is a curative treatment option, achieving 5-year event-free survival (EFS) in the order of 55%. The response to chemotherapy, if any, is transient, and the duration of survival is not influenced.

Targeting the epigenome may be a useful alternative strategy. We previously reported recurrent DNA hypermethylation at specific genetic regions as a characteristic attribute of JMML cases with poor prognosis and high probability of relapse after HSCT. We followed this up with a comprehensive study investigating genome-wide DNA methylation profiles in 167 children with JMML, defining three JMML subgroups with unique molecular and clinical features and validated and harmonized these results in an intercontinental meta-analysis involving study groups in Europe, USA, and Japan.

Given the strong association between hypermethylation and treatment failure in JMML, the therapeutic potential of inhibiting DNA methylation appears particularly attractive. We were the first to report a pilot case where treatment with the DNA methyltransferase inhibitor azacitidine led to a complete hematologic and molecular remission before HSCT. We later documented 3 complete remissions and 2 partial remissions in 9 children receiving azacitidine prior to HSCT. These favorable results distinguished azacitidine as the most active pharmaceutical in JMML known so far and led to the industry-sponsored, multicenter, international phase 2 study AZA-JMML-001 (EudraCT 2014-002388-13), which recruited from 2015 to 2017 and documented a 61% response rate. Our institution provided central medical coordination, reference diagnostics, and pharmacodynamic studies for this trial.

To meet clinical needs particularly for JMML patients with high-risk profile, it is important to quickly transfer innovative therapy concepts for myeloid neoplasms to JMML. The availability of ex vivo models for preclinical testing is crucial for this process. We have therefore started the generation of JMML-derived induced pluripotent stem cell lines as important tools for drug development and future clinical study design.

We will also take the previous results to the clinic by implementing prospective DNA methylation classification for all children with JMML diagnosed in the European Working Group of Myelodysplastic Syndromes (EWOG-MDS) network, which is coordinated out of our institution. These investigations will pave the way for diversified prospective therapy studies for children with JMML. It is meanwhile accepted in the community that previous recommendations will have to be differentiated. When allocating therapy arms (including rapid HSCT, azacitidine with subsequent HSCT, azacitidine alone, or watch-and-wait) in a future study, the methylation classes will take a primary position.

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We identified the novel lysine methyltransferase KMT9 writing the chromatin mark histone H4 monomethylated at lysine 12 (H4K12me1). Depletion or enzymatic inactivation of KMT9 blocks not only proliferation of castration and enzalutamide-resistant prostate cancer cells and 3D organoids in vitro but also in xenograft and genetically engineered prostate tumours in vivo. Of note, KMT9 loss does not impair growth of non-transformed cells. The molecular mode of KMT9 action is independent of androgen receptor (AR) function thus, providing a promising, novel therapeutic paradigm for the treatment of castration-resistant prostate cancer (CRPC) exceeding the current gold standard of care. We developed high-potency drug-like KMT9 lead inhibitors displaying unprecedented specificity for KMT9.Here, we aim to develop our lead inhibitors to clinical candidates for phase I clinical testing.

Colorectal cancer (CRC) is a heterogeneous disease at molecular level leading to heterogeneous outcomes, therapy, drug responses and primary or secondary resistance to targeted treatments. This heterogeneity represents a major challenge for precise interpretation of prognostic and predictive markers. Whereas primary colorectal cancer without metastasis is mostly curable by surgical resection and adjuvant systemic therapy, metastatic disease remains largely incurable and is still a major life-threatening situation. Preclinical studies so far rarely focus on the metastatic situation but focus on the primary tumor. Therefore, it is critical to expand these preclinical studies to the process of metastasis and to develop metastasis-specific therapeutic approaches. It is well known since Virchow that there is an association between cancer and the immune system and now it is well described that the tumor microenvironment plays a critical role in carcinogenesis. Dissemination and metastasis is only facilitated when tumors evade detection and destruction by the immune system and it is assumed that immune subversion by primary tumors plays an essential role in enabling metastatic spread to distant organs and spread of tumor-induced inflammation to become systemic plays a critical role in metastasis. Thus, there is an urgent need to deepen our fundamental understanding of immune cell crosstalk in cancer especially for metastatic cancer, how this crosstalk can be manipulated for direct therapeutic targeting or can be modulated that conservative therapeutic approaches are more efficient. Suggesting that treatment approaches for CRC metastasis should include considerations about the underlying tumor microenvironment in the specific metastasis location and possible adapted immunomodulation strategies. It is well described that the microbiome impacts colorectal carcinogenesis. As metastasis of colorectal cancer are not a sterile microenvironment either. We hypothesized that bacteria also regulate the process of metastasis. Therefore to understand the cellular and microbial landscape of the metastatic tumor microenvironment and the intercellular interactions in the metastasis of CRC is a critical prerequisite for the design of new immunotherapeutic treatment strategies.

In recent years, numerous insights have been gained into the development, metabolism and alterations of glioblastoma, however, the interactions within the immune compartment are poorly understood and require further research. Comprehension and modulation of the T cell response in gliomas is an important goal to overcome the “cold” immune environment and optimize T cell-based immunotherapies. T-cells that invade glioblastoma encounter a deeply immunosuppressive microenvironment which is challenging to improve. Immune therapeutical approaches in the future and recent trials investigating checkpoint inhibitions failed. A novel immunotherapy concept is required engaging other microenvironmental targets to boost T-cell activation.

Our project aims to explore the underlying mechanisms of T cell dysfunction in malignant brain tumors and to decipher the components of brain structural immunity that contribute to the nonproductive T cell response. Novel high-dimensional data acquisition with spatially resolved multi-omics will enable accurate reconstruction of cellular relationships and interactions. Further functional testing requires immunocompetent models that will utilize human brain tissue in a personalized slice model. In addition, we aim to manipulate identified components of the tumor microenvironment and test their potential impact in clinical settings to overcome the immunosuppressive environment and open new perspectives for successful immunotherapies.

Cancer-genome sequencing projects led to the realization that epigenetic pathways are often disturbed by gene mutations in solid cancers. The epigenetic control is exerted at the level of the structure and modification of chromatin and disturbances directly impacts tissue-specific programs of gene transcription and, hence, of cell identity and behaviour. An attractive aspect of epigenetic control for effective intervention strategies in solid cancers is the dynamic equilibrium of epigenetic states and the specificity and selectivity of the enzymes determining this equilibrium.

Epigenetic control of transcription complexes:
Our research focuses on the molecular pathways controlling methylation of lysine-4 of histone H3 (H3K4), which are frequently mutated in urothelial, lung, renal and endometrial cancers. Histone H3K4 methylation is antagonized by specific demethylases and by H3K27 methylases. All these entities are also vulnerable to mutation as shown for several solid cancers. However, the precise effects of mutational disturbances on epigenetic balances and on gene transcription are not well understood.

We investigate epigenetic balances from the viewpoints of: TGF-b/SMAD control of epigenetics in colorectal cancer, of the MLL3/4 complexes in urothelial carcinoma and of menin-MLL1/2 complexes in the MEN1 syndrome. In addition, we aim to understand the role of the KDM5 and KDM6 demethylases in setting the balances in H3K4 and H3K27 methylation and in enhancer/promoter function at a global level. Central in our research are methodologies for advanced (quantitative) proteomics, genomics and cancer cell models.

The basal transcription factor TFIID integrates both signal transduction, transcription factor activity and epigenetic signalling at the level of gene promoters to determine transcriptional frequencies. We are exploiting our knowledge of epigenetic control of gene transcription by TFIID through the development and application of small molecules targeting chromatin reader domains. These epigenetic drugs will be examined for transcriptional and cellular effects in different solid cancer models.