Pancreatic cancer (PDAC) is one of the most aggressive cancers with a dismal prognosis; effective treatment options are desperately needed. In this Joint Funding Project, DKTK experts have joined forces to rationally develop effective combination therapies against pancreatic cancer by exploring the molecular mechanisms behind the development of therapy resistance in cancer cells. The consortium identified several new mechanisms responsible for the large heterogeneity observed in pancreatic cancer. This included e.g. the discovery of Ras gene dosage variation as a fundamental determinant of pancreatic cancer biology (Mueller et al., 2018 Nature) by human and mouse studies. Additionally, researchers from the team defined two differently aggressive molecular subtypes of PDAC providing the insight that in the more aggressive group of tumors a phenomenon known as "viral mimicry" leads to a cancer-promoting inflammatory reaction (Espinet et al., 2020 Cancer Discov). In another approach, members of the consortium have developed an innovative epigenetic targeting strategy based on dual BET/HDAC inhibitors and showed its potency as a novel chromatin‐targeting approach for future clinical development for treatment of PDAC (Zhang et al., 2020 Int J Cancer).

Publications:

(1)    Espinet, E., Gu, Z., Imbusch, C.D., Giese, N.A., Buscher, M., Safavi, M., Weisenburger, S., Klein, C., Vogel, V., Falcone, M., Insua-Rodriguez, J., Reitberger, M., Thiel, V., Kossi, S.O., Muckenhuber, A., Sarai, K., Lee, A.Y., Backx, E., Zarei, S., Gaida, M.M., Rodriguez-Paredes, M., Donato, E., Yen, H.Y., Eils, R., Schlesner, M., Pfarr, N., Hackert, T., Plass, C., Brors, B., Steiger, K., Weichenhan, D., Arda, H.E., Rooman, I., Kopp, J.L., Strobel, O., Weichert, W., Sprick, M.R., & Trumpp, A. (2020). Aggressive PDACs show hypomethylation of repetitive elements and the execution of an intrinsic IFN program linked to a ductal cell-of-origin. Cancer Discov. doi: http://dx.doi.org/10.1158/2159-8290.CD-20-1202

(2)    Zhang, X., Zegar, T., Weiser, T., Hamdan, F.H., Berger, B.T., Lucas, R., Balourdas, D.I., Ladigan, S., Cheung, P.F., Liffers, S.T., Trajkovic-Arsic, M., Scheffler, B., Joerger, A.C., Hahn, S.A., Johnsen, S.A., Knapp, S., & Siveke, J.T. (2020). Characterization of a dual BET/HDAC inhibitor for treatment of pancreatic ductal adenocarcinoma. Int J Cancer, 147(10), 2847-2861. doi: http://dx.doi.org/10.1002/ijc.33137

(3)    Mueller, S., Engleitner, T., Maresch, R., Zukowska, M., Lange, S., Kaltenbacher, T., Konukiewitz, B., Ollinger, R., Zwiebel, M., Strong, A., Yen, H.Y., Banerjee, R., Louzada, S., Fu, B., Seidler, B., Gotzfried, J., Schuck, K., Hassan, Z., Arbeiter, A., Schonhuber, N., Klein, S., Veltkamp, C., Friedrich, M., Rad, L., Barenboim, M., Ziegenhain, C., Hess, J., Dovey, O.M., Eser, S., Parekh, S., Constantino-Casas, F., de la Rosa, J., Sierra, M.I., Fraga, M., Mayerle, J., Kloppel, G., Cadinanos, J., Liu, P., Vassiliou, G., Weichert, W., Steiger, K., Enard, W., Schmid, R.M., Yang, F., Unger, K., Schneider, G., Varela, I., Bradley, A., Saur, D., & Rad, R. (2018). Evolutionary routes and KRAS dosage define pancreatic cancer phenotypes. Nature, 554(7690), 62-68. doi: http://dx.doi.org/10.1038/nature25459