Ex vivo Drug Response Profiling

Treatment response in cancer is influenced by multiple biological factors including genetic alterations of tumor cells and the tumor microenvironment. While many of these factors can be characterized in tumor biopsies and used for diagnosis, treatment stratification and prediction of prognosis, the interplay and direct effects on drug response are often incompletely understood.

To investigate modulators of therapy response in patients, we can model drug response ex vivo. For this, we isolate primary tumor cells from peripheral blood or diagnostic biopsies and treat them with a large library of clinically available and experimental drugs.

This Drug Response Profiling (DRP) has helped us understand genetic modulators of drug response (Dietrich et al. 2012; Dietrich et al. 2018; Janssen et al. 2022), uncovered the microenvironmental impact on drug response (Herbst et al. 2022; Bruch et al. 2022) and identified mechanisms of drug resistance (Roider et al. 2020; Lu et al. 2021).

Additionally to important biological findings, ex vivo DRP can be used to predict the response of individual patients beyond known markers of therapy resistance. We previously performed the non-interventional prospective SMARTrial in which we directly correlated in vivo treatment response of patients with hematologic malignancies to ex vivo DRP. Based on this readout, we were able to treat patients who lacked any further standard treatment options. In one such case, we identified a surprising sensitivity to folate inhibitors which showed great clinical efficacy and enabled a subsequent allogeneic stem cell transplantation. (Liebers et al. 2019) This particular patient remains free of relapse multiple years after the stem cell transplantation.

Thereby, ex vivo DRP profiling has the potential to optimize treatment selection for cancer patients and in individual cases opens up new treatment options when standard-of-care treatment has failed.

  • Bruch, P. M., H. A. Giles, C. Kolb, S. A. Herbst, T. Becirovic, T. Roider, J. Lu, S. Scheinost, L. Wagner, J. Huellein, I. Berest, M. Kriegsmann, K. Kriegsmann, C. Zgorzelski, P. Dreger, J. B. Zaugg, C. Muller-Tidow, T. Zenz, W. Huber, and S. Dietrich. 2022. 'Drug-microenvironment perturbations reveal resistance mechanisms and prognostic subgroups in CLL', Mol Syst Biol, 18: e10855.
  • Dietrich, S., H. Glimm, M. Andrulis, C. von Kalle, A. D. Ho, and T. Zenz. 2012. 'BRAF inhibition in refractory hairy-cell leukemia', N Engl J Med, 366: 2038-40.
  • Dietrich, S., M. Oles, J. Lu, L. Sellner, S. Anders, B. Velten, B. Wu, J. Hullein, M. da Silva Liberio, T. Walther, L. Wagner, S. Rabe, S. Ghidelli-Disse, M. Bantscheff, A. K. Oles, M. Slabicki, A. Mock, C. C. Oakes, S. Wang, S. Oppermann, M. Lukas, V. Kim, M. Sill, A. Benner, A. Jauch, L. A. Sutton, E. Young, R. Rosenquist, X. Liu, A. Jethwa, K. S. Lee, J. Lewis, K. Putzker, C. Lutz, D. Rossi, A. Mokhir, T. Oellerich, K. Zirlik, M. Herling, F. Nguyen-Khac, C. Plass, E. Andersson, S. Mustjoki, C. von Kalle, A. D. Ho, M. Hensel, J. Durig, I. Ringshausen, M. Zapatka, W. Huber, and T. Zenz. 2018. 'Drug-perturbation-based stratification of blood cancer', J Clin Invest, 128: 427-45.
  • Herbst, Sophie A., Vladislav Kim, Eva C. Schitter, Peter-Martin Bruch, Tobias Roider, Nora Liebers, Carolin Kolb, Mareike Knoll, Junyan Lu, Peter Dreger, Carsten Müller-Tidow, Thorsten Zenz, Wolfgang Huber, and Sascha Dietrich. 2022. 'Imaging-based coculture model for high-throughput compound screening in hematological cancers', bioRxiv: 2022.02.18.481065.
  • Janssen, M., C. Schmidt, P. M. Bruch, M. F. Blank, C. Rohde, A. Waclawiczek, D. Heid, S. Renders, S. Gollner, L. Vierbaum, B. Besenbeck, S. A. Herbst, M. Knoll, C. Kolb, A. Przybylla, K. Weidenauer, A. K. Ludwig, M. A. Fabre, M. Gu, R. F. Schlenk, F. Stolzel, M. Bornhauser, C. Rollig, U. Platzbecker, C. D. Baldus, H. Serve, T. Sauer, S. Raffel, C. Pabst, G. S. Vassiliou, B. Vick, I. Jeremias, A. Trumpp, J. Krijgsveld, C. Muller-Tidow, and S. Dietrich. 2022. 'Venetoclax synergizes with Gilteritinib in FLT3 wildtype high-risk Acute Myeloid Leukemia by suppressing MCL-1', Blood.
  • Liebers, Nora, Peter-Martin Bruch, Agnes Gambietz, Holly Giles, Junyan Lu, Mareike Knoll, Carolin Kolb, Peter Dreger, Carsten Mueller-Tidow, Wolfgang Huber, Axel Benner, Thorsten Zenz, and Sascha Dietrich. 2019. 'Ex-Vivo Drug Response Profiling for Tailoring Treatment in Hematologic Malignancies: The Prospective Non-Interventional SMART-Trial', Blood, 134: 376-76.
  • Lu, J., E. Cannizzaro, F. Meier-Abt, S. Scheinost, P. M. Bruch, H. A. Giles, A. Lutge, J. Hullein, L. Wagner, B. Giacopelli, F. Nadeu, J. Delgado, E. Campo, M. Mangolini, I. Ringshausen, M. Bottcher, D. Mougiakakos, A. Jacobs, B. Bodenmiller, S. Dietrich, C. C. Oakes, T. Zenz, and W. Huber. 2021. 'Multi-omics reveals clinically relevant proliferative drive associated with mTOR-MYC-OXPHOS activity in chronic lymphocytic leukemia', Nat Cancer, 2: 853-64.
  • Roider, Tobias, Julian Seufert, Alexey Uvarovskii, Felix Frauhammer, Marie Bordas, Nima Abedpour, Marta Stolarczyk, Jan-Philipp Mallm, Sophie A. Herbst, Peter-Martin Bruch, Hyatt Balke-Want, Michael Hundemer, Karsten Rippe, Benjamin Goeppert, Martina Seiffert, Benedikt Brors, Gunhild Mechtersheimer, Thorsten Zenz, Martin Peifer, Björn Chapuy, Matthias Schlesner, Carsten Müller-Tidow, Stefan Fröhling, Wolfgang Huber, Simon Anders, and Sascha Dietrich. 2020. 'Dissecting intratumour heterogeneity of nodal B-cell lymphomas at the transcriptional, genetic and drug-response levels', Nature Cell Biology, 22: 896-906.
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