CP1: Translational platform for PDAC models and drug response validation

Central Project 1 (CP1) aims at providing complementary and molecularly characterized preclinical PDAC models, which can be chosen and accessed for translational studies by all members of the consortium. To this end, we are setting up a platform for Patient-Derived Xenograft (PDX)-models, organoids and primary cells which are univocally derived from PDAC patients enrolled in the Molecular Pancreas Program (MolPAC) of the UMG. Subtype analyses in translational PDAC models and primary PDAC material from MolPAC patients comprise RNA-seq-based transcriptome analyses, multigene panel sequencing and immunohistochemical stainings.

Moreover, and as a structural measure for treatment studies performed in SP1-7as well as for future investigator-initiated clinical trials, CP1 establishes an in vitro therapy validation platform. This pre-clinical drug platform evaluates the subtype-specificity of therapeutic strategies targeting genome dynamics as identified in SP1-7 in a highly standardized and comparable manner and elucidates the most promising drug combinations for subtype-driven treatment strategies in PDAC.

PIs:
Elisabeth Heßmann, Klinik für Gastroenterologie, gastrointestinale Onkologie und Endokrinologie
Matthias Dobbelstein, Institut für Molekulare Onkologie
Jochen Gaedcke, Klinik für Allgemein-, Viszeral- und Kinderchirurgie
Silke Kaulfuß & Prof. Dr. Bernd Wollnik, Institut für Humangenetik
Philipp Ströbel, Institut für Pathologie

Team:
Jennifer Appelhans (Institut für Pathologie)
Christin Kellner (AG Heßmann)
Waltraut Kopp (AG Heßmann)
Sercan Mercan (AG Ellenrieder)

Further information on the AG Heßmann, the Institut für Molekulare Onkologie and the Institut für Humangenetik is available on their respective websites.

SP1: Characterizing genome dynamics in ARID1A-deficient PDAC subtypes

38% of PDAC are characterized by alterations in genes encoding chromatin regulatory proteins, particularly members of the SWItch/Sucrose Non-Fermentable (SWI/SNF) family. Given the widespread loss-of-function mutations of different subunits of the SWI/SNF complex in a plethora of malignancies, members of this chromatin remodeling complex are referred to as pivotal tumor suppressors. AT-rich Interactive Domain-containing protein 1A (ARID1A) isthe most frequently altered subunit of the SWI/SNF complex in PDAC and has been associated with an aggressive PDAC phenotype and a bad disease outcome. Importantly, in other tumor entities, ARID1A-deficiency is connected to increased sensitivity towards PI3K/AKT-, ATR-, PARP- HDAC- and EZH2-inhibition, thus suggesting assessment of the ARID1A status as a promising therapy-predictive strategy in cancer treatment. However, whether ARID1A deficiency also predicts for certain therapeutic vulnerabilities in PDAC remains mainly elusive. SP1 aids at filling this gap and utilizes the structural and material-based resources as well as the diverse scientific expertise of the CRU 5002 to explore the mechanistic background and the functional implications of genome dynamic alterations that particularly characterize ARID1A-deficient PDAC subtypes. Moreover, we investigate the therapeutic potential of interfering with these genome dynamic alterations and hence sought to elucidate whether and how the ARID1A status can be considered for stratification-based therapy inPDAC treatment.

PI: Elisabeth Heßmann, Klinik für Gastroenterologie, gastrointestinale Onkologie und Endokrinologie, UMG

Team: 

Elisabeth Klingberg (AG Heßmann)
Marie Knak (AG Heßmann)
Charlotte Sigg (AG Heßmann)
Maria Ulisse (AG Heßmann)
Theresa Waßmann (AG Heßmann)
Zhe Zhang (AG Heßmann)

Further information on the AG Heßmann is available on their website.

SP3: Epigenetic regulation and therapeutic targeting of PDAC subtypes with aberrant drug metabolism

Chemoresistance constitutes a major cause for the dismal prognosis of PDAC. Despite significant preclinical and clinical efforts to maximize therapeutic efficacy in PDAC treatment, the detailed mechanisms underlying therapy resistance remain largely elusive. Strikingly, there is a huge discrepancy between the antineoplastic effects of anti-cancer drugs in established cell lines in vitro and in patients. For instance, the antimetabolite gemcitabine is usually well tolerated in PDAC patients, but has very limited effectiveness to shrink pancreatic tumors and prolong survival. Drug metabolizing enzymes such as cytosolic 5'-nucleotidase 1A (NT5C1A) and cytidine deaminase (CDA) might define a clinically highly relevant molecular subgroup of PDAC patients that could be exploited for tailored treatment approaches. Based on previous data from our group, we hypothesize that chromatin dynamics define novel therapeutic PDAC subgroups that may correlate or partially overlap with existing molecular subtypes. In addition, we propose that patient subgroups can benefit from targeted therapeutic interventions in combination with selected cytotoxic compounds. SP3 analyses chromatin regulatory networks of subtype-specific drug metabolism pathways in human and murine PDAC in collaboration with other KFO5002 projects and test whether epigenetic targeting has therapeutic potential to disrupt these pathways in PDAC using a variety of different genetically engineered model systems and state of the art pharmacokinetic and pharmacodynamics assays.

PI: Albrecht Neeße, Klinik für Gastroentreologie, gastrointestinale Onkologie und Endokrinologie, UMG

Team:

Christoph Ammer-Herrmenau (AG Neeße)
Cathleen Heuer (AG Neeße)
Catharina Lingens (AG Neeße)
Nina Pfisterer (AG Neeße)
Charlotte Ratei (AG Neeße)
Areej Sahbaz  (AG Neeße)

Further information on the AG Neeße is available on their website.

SP5: Metabolic impact on chromatin topology in subpopulation-derived PDAC organoids

A hallmark of both tumorigenesis and cancer progression is the metabolic reprogramming of cancer cells, and an interest in targeting metabolic cancer traits has resurged. Specifically, as regards pancreatic cancer, the TCGA (The Cancer Genome Atlas) classification of PDACs was recently found to align well with distinct metabolic states. Classical PDAC tumors mostly rely on lipogenic metabolism, while the more aggressive squamous/ mesenchymal PDACs predominantly rely on glycolysis, with the two subtypes also displaying striking differences in glucose and glutamine utilization, as well as in mitochondrial function. These differences suggest differential sensitivity of PDACs to inhibitors targeting glycolysis, glutamine metabolism, lipid synthesis or redox balance. This coincidence between PDAC subtypes and metabolic states becomes even more relevant once one considers that specific metabolic pathways directly affect global chromatin methylation and acetylation levels and may, thus, contribute to the dramatic dysregulation of epigenetic profiles in tumours. It is exactly this link that our project will investigate: by combining studies of spatial genome organization, cis-element mapping, and single-cell transcriptomes in patient-derived PDAC organoids we aim at uncovering regulatory circuits that can be targeted for therapeutic intervention.

PIs:
Lena Conradi, Klinik für Allgemein, Viszeral- und Kinderchirurgie, UMG
Argyris Papantonis,  Institut für Pathologie, UMG

Team:

Kaida Hasanovic (AG Conradi)
Adi Mackay (AG Papantonis)
Teona Midelashvili (AG Conradi)
Anne Mittlmeier (AG Conradi)
Tiago De Oliveira (AG Conradi)
Theon Robin Tesch (AG Conradi)
Olaf Schultz (AG Conradi)
Kelvin Lai (AG Conradi)

Further information on the AG Papantonis and the AG Conradi is available on their respective websites.

SP7: Exploiting subtype-specific HSP90 targeting for sensitization of PDAC cells towards platinum-based therapy

The chemotherapy of pancreatic carcinoma often involves cisplatin, a drug that crosslinks DNA. If cancer cells fail to repair such crosslinks, they often die, resulting in a favorable tumor response. However, efficient repair of cisplatin-mediated DNA lesions result in cancer cell resistance and further tumor growth. To improve the efficacy of cisplatin, we are combining it with additional drugs that target heat shock proteins. Such heat shock proteins help to shape proteins shortly after their synthesis in the cell. A class of proteins that depends on heat shock proteins to a particularly high extent comprises the repair machinery for DNA crosslinks, called the Fanconi anemia pathway. Thus, targeting heat shock proteins with HSP90 antagonists results in the degradation of Fanconi anemia proteins, and thus renders the cell unable to repair cisplatin-induced DNA lesions. As a result, cancer cells respond to cisplatin with greater efficacy. However, the response to such drug combinations varies between individual tumor cells, and we are currently trying to find out the genetic features that determine their sensitivity. On the long run, we hope to improve such therapeutic combinations for patient care, and to find additional targets for enhanced therapeutic efficacy.

PI: Matthias Dobbelstein, Institut für Molekulare Onkologie 

Team:

Maj-Britt Paulsohn (AG Dobbelstein)

Further information on the Institute of Molecular Oncology is available on their website.