Summary

“Precision oncology” describes the ability to prevent and diagnose tumor diseases and predict response to specific cancer therapies, based on increasingly accurate, high-resolution molecular profiling as well as the functional understanding of individual tumors.

Such a stratification of patients is achieved through “next-generation” sequencing of tumor DNA and RNA within the MASTER (Molecularly-aided stratification for tumor eradication research) program, which can reveal genomic alterations that have immediate clinical implications.  Based on these we evaluate new therapeutic options within investigator-initiated molecularly-guided clinical trials and N-of-One studies.

Since most of the mutations identified in human cancers have unknown functional consequences and can therefore not directly be interpreted regarding their suitability as therapeutic targets, separating “driver” mutations from biologically neutral “passenger” alterations is critical for the translation of genetic information into the clinic. To address these challenges, we investigate the functional role of genetic alterations predicted to be damaging in appropriate experimental and patient-derived model systems, followed by analysis of the phenotypic consequences. The intermediate-term goal of these studies is to establish a versatile platform for rapid functional testing of mutations identified in individual cancers and implement a continuously evolving, “learning” system to support mechanism-based treatment decisions at NCT and help develop novel concepts for the systematic translation of molecular information into clinical action.

Selected Publications

Wünsche P, Eckert ESP, Holland-Letz T, Paruzynski A, Hotz-Wagenblatt A, Fronza R, Rath T, Gil‑Farina I, Schmidt M, von Kalle C, Klein C, Ball CR, Herbst F, Glimm H: Mapping Active Gene regulatory Regions in Human Repopulating Long-term HSCs. Cell Stem Cell, in press.

Heining C, Horak P, Uhrig S, Codo PL, Klink B, Hutter B, Fröhlich M, Bonekamp D, Richter D, Steiger K, Penzel R, Endris V, Ehrenberg KR, Frank S, Kleinheinz K, Toprak UH, Schlesner M, Mandal R, Schulz L, Lambertz H, Fetscher S, Bitzer M, Malek NP, Horger MS, Giese NA, Strobel O, Hackert T, Springfeld C, Feuerbach L, Bergmann F, Schröck E, von Kalle C, Weichert W, Scholl C, Ball CR, Stenzinger A, Brors B, Fröhling S, Glimm H. NRG1 Fusions in KRAS Wild-type Pancreatic Cancer. Cancer discovery, 2018: CD-18.

Giessler KM, Kleinheinz K, Huebschmann D, Balasubramanian GP, Dubash TD, Dieter SM, Siegl C, Herbst F, Weber S, Hoffmann CM, Fronza R, Buchhalter I, Paramasivam N, Eils R, Schmidt M, von Kalle C, Schneider M, Ulrich A, Scholl C, Fröhling S, Weichert W, Brors B, Schlesner M, Ball CR, Glimm H.: Genetic subclone architecture of tumor clone-initiating cells in colorectal cancer. J Exp Med. 2017 Jul 3;214(7):2073-2088.

Ball CR, Oppel F, Ehrenberg KR, Dubash TD, Dieter SM, Hoffmann CM, Abel U, Herbst F, Koch M, Werner J, Bergmann F, Ishaque N, Schmidt M, von Kalle C, Scholl C, Fröhling S, Brors B, Weichert W, Weitz J, Glimm H.: Succession of transiently active tumor-initiating cell clones in human pancreatic cancer xenografts. EMBO Mol Med. 2017 Jul;9(7):918-932.