Project P13
Development of epigenetic-based therapies for PDAC
guenter.schneider@med.uni-goettingen.de
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gunnar.schotta@bmc.med.lmu.de(link sends e-mail)
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Aberrant changes of epigenetic landscapes in cancers contribute to the malignant phenotype. Thus, targeting epigenetic pathways are promising therapeutic concepts. In strong support, we have recently demonstrated that class I HDACs are overexpressed in significant fractions of PDAC patients and that therapies based on HDAC inhibitors (HDACi) revealed outstanding efficacy in pre-clinical models. Here we want to follow two leads in order to refine epigenetic therapies.
Firstly, we will define HDAC1, 2, 3 isoenzyme specific functions using novel genetic models. In combination with pharmacological screens we aim for developing novel HDACi-based combination therapies.
Secondly, we want to identify essential PDAC driver genes based on a specific epigenetic signature (super-enhancers). Mechanisms leading to forced expression of these driver genes will be identified through mapping of open chromatin regions within the super enhancers.
The ultimate goal is to translate key findings into therapeutic concepts to be tested in up-to-date human disease models.
Publications
Falcomata, C., Barthel, S., Schneider, G., Rad, R., Schmidt-Supprian, M., and Saur, D. (2023). Cancer Discov 13, 278-297. doi: 10.1158/2159-8290.CD-22-0876
Giansanti, P., Samaras, P., Bian, Y., Meng, C., Coluccio, A., Frejno, M., Jakubowsky, H., Dobiasch, S., Hazarika, R. R., Rechenberger, J., Calzada-Wack, J., Krumm, J., Mueller, S., Lee, C. Y., Wimberger, N., Lautenbacher, L., Hassan, Z., Chang, Y. C., Falcomata, C., Bayer, F. P., Barthel, S., Schmidt, T., Rad, R., Combs, S. E., The, M., Johannes, F., Saur, D., de Angelis, M. H., Wilhelm, M., Schneider, G., and Kuster, B. (2022). Nat Methods 19, 803-811. doi: 10.1038/s41592-022-01526-y
Orben, F., Lankes, K., Schneeweis, C., Hassan, Z., Jakubowsky, H., Krauss, L., Boniolo, F., Schneider, C., Schafer, A., Murr, J., Schlag, C., Kong, B., Ollinger, R., Wang, C., Beyer, G., Mahajan, U. M., Xue, Y., Mayerle, J., Schmid, R. M., Kuster, B., Rad, R., Braun, C. J., Wirth, M., Reichert, M., Saur, D., and Schneider, G. (2022). JCI Insight 7. doi: 10.1172/jci.insight.151353
Kramer, O. H., and Schneider, G. (2022). Clin Transl Med 12, e858. doi: 10.1002/ctm2.858
Peschke, K., Jakubowsky, H., Schafer, A., Maurer, C., Lange, S., Orben, F., Bernad, R., Harder, F. N., Eiber, M., Ollinger, R., Steiger, K., Schlitter, M., Weichert, W., Mayr, U., Phillip, V., Schlag, C., Schmid, R. M., Braren, R. F., Kong, B., Demir, I. E., Friess, H., Rad, R., Saur, D., Schneider, G., and Reichert, M. (2022). EMBO Mol Med 14, e14876. doi: 10.15252/emmm.202114876
Kaltenbacher, T., Loprich, J., Maresch, R., Weber, J., Muller, S., Oellinger, R., Gross, N., Griger, J., de Andrade Kratzig, N., Avramopoulos, P., Ramanujam, D., Brummer, S., Widholz, S. A., Barthel, S., Falcomata, C., Pfaus, A., Alnatsha, A., Mayerle, J., Schmidt-Supprian, M., Reichert, M., Schneider, G., Ehmer, U., Braun, C. J., Saur, D., Engelhardt, S., and Rad, R. (2022). Nat Protoc 17, 1142-1188. doi: 10.1038/s41596-021-00677-0
Schneeweis, C., Hassan, Z., Ascherl, K., Wirth, M., Koutsouli, S., Orben, F., Krauss, L., Schneider, C., Ollinger, R., Kramer, O. H., Rad, R., Reichert, M., Robles, M. S., Saur, D., and Schneider, G. (2022). Cancer Commun (Lond) 42, 360-364. doi: 10.1002/cac2.12280
Doffo, J., Bamopoulos, S. A., Kose, H., Orben, F., Zang, C., Pons, M., den Dekker, A. T., Brouwer, R. W. W., Baluapuri, A., Habringer, S., Reichert, M., Illendula, A., Kramer, O. H., Schick, M., Wolf, E., van, I. W. F. J., Esposito, I., Keller, U., Schneider, G., and Wirth, M. (2022). Proc Natl Acad Sci U S A 119. doi: 10.1073/pnas.2105691119
Falcomata, C., Barthel, S., Widholz, S. A., Schneeweis, C., Montero, J. J., Toska, A., Mir, J., Kaltenbacher, T., Heetmeyer, J., Swietlik, J. J., Cheng, J. Y., Teodorescu, B., Reichert, O., Schmitt, C., Grabichler, K., Coluccio, A., Boniolo, F., Veltkamp, C., Zukowska, M., Vargas, A. A., Paik, W. H., Jesinghaus, M., Steiger, K., Maresch, R., Ollinger, R., Ammon, T., Baranov, O., Robles, M. S., Rechenberger, J., Kuster, B., Meissner, F., Reichert, M., Flossdorf, M., Rad, R., Schmidt-Supprian, M., Schneider, G., and Saur, D. (2022). Nat Cancer 3, 318-336. doi: 10.1038/s43018-021-00326-1
Krauss, L., Urban, B. C., Hastreiter, S., Schneider, C., Wenzel, P., Hassan, Z., Wirth, M., Lankes, K., Terrasi, A., Klement, C., Cernilogar, F. M., Ollinger, R., de Andrade Kratzig, N., Engleitner, T., Schmid, R. M., Steiger, K., Rad, R., Kramer, O. H., Reichert, M., Schotta, G., Saur, D., and Schneider, G. (2022). Cancer Res 82, 695-707. doi: 10.1158/0008-5472.CAN-20-3209