Research Program “Molecularly Targeted Therapy” (MTT)
The aim of the Program Molecularly Targeted Therapy (MTT) is to produce the data packages that are required to plan and conduct molecularly informed clinical studies based on the best possible evidence from preclinical research and on reverse translation of insights derived from studying patients treated with molecularly targeted therapies.
Being closely interlinked with the discovery of novel mechanisms and model development in the Programs Exploitation of Oncogenic Mechanisms (EOM) and Molecular Diagnostics, Early Detection and Biomarker Development (MDEB), specific expertise and preclinical datasets are contributed by MTT in preparation of clinical proof-of-concept (POC) trials. Within the DKTK translational circle, MTT therefore focuses on later stage development, validation and application of therapeutic and diagnostic strategies. MTT integrates internationally leading study groups, a portfolio of molecularly stratified clinical trials and established precision oncology programs within the DKTK. In MTT, the following main lines of research are being pursued:
- Rational combination therapy strategies focusing on pediatric and hematologic malignancies (leukemias and lymphomas)
- Targeting functional cell states and tumor-host interactions
- Targeting transcription and epigenetics
- Integrative clinical and biomarker analyses of “informative patients” treated in precision oncology programs and studies
In summary, the MTT Program provides the essential link between the discovery and clinical application of novel pharmacotherapeutic intervention strategies. It supports the later-stage development of leads derived from the EOM and MDEB Programs, and adds important aspects from the reverse translation of clinical findings to develop preclinical data packages which are a prerequisite to design and successfully negotiate sound concepts for clinical POC trials.
Selected major translational highlights
1. The precision oncology programs for advanced-stage childhood (INFORM/INFORM2) and adult (MASTER) provided the basis for genomics-guided phase I/II clinical trials of rational drug combinations based on rigorous preclinical efficacy testing within MTT (HD in collaboration with all other DKTK sites) as well as reverse translational approaches in MTT (liquid biopsies, generation of patient-avatar models, etc.). 102 patients with tumors harboring non-canonical BRAF mutations were identified within the DKTK network (MASTER program, so far) demonstrating that recruitment of patients for the DKTK-funded SORATRAM trial is feasible (EudraCT: 2018-003237-16). Thirty-five percent of these patients, harboring non-V600E BRAF mutants, were classified (cloned, functionally and pharmacologically analyzed) by the T. Brummer laboratory (FR) as clearly kinase-inactivating, thus fulfilling the major criterion for inclusion into the trial.
2. Multiple DKTK researchers (HD and DD) contributed first results of proteomic profiling of patient material, in addition to genomic data, within MASTER (Wahjudi et al., Int J Cancer 2020). Their research showed that integrative analysis of DNA, RNA and protein data might refine therapeutic stratification of individual patients and, thus, increase the success rate of precision cancer therapy. This approach is now also being explored for the INFORM platform.
3. Led by H. Farin (F/MZ) as a senior author, collaborative efforts of DKTK scientists from Frankfurt reported on the first “3D model for CAR-mediated cytotoxicity” using patient-derived colorectal cancer organoids” (Schnalzger et al., EMBO 2019).
4. Under the lead of S. Pfister, M. Zapatka, M. Kool, D. Jones and P. Lichter (HD), DKTK researchers from B, E/D, F/MZ, HD and M contributed to international efforts to define the landscape of genomic alterations across childhood cancers (Gröbner et al., Nature 2018; Brabetz et al., Nat Med 2018).
5. Under the lead of O. Witt (HD), recruitment started for an international, biomarker-driven phase I/II basket trial treating children with relapsed cancers with a combination of nivolumab plus entinostat in four different molecular strata (INFORM2-NivEnt; NCT03838042; van Tilburg et al., BMC Cancer 2020). The trial is funded by NCT Heidelberg and is a pioneering example of DKTK as enabler of the translation of discoveries and preclinical developments through DKTK funding into early-phase academic trials within the NCT framework.
6. N. von Bubnoff (FR) led the national efforts to launch a prospective trial in gastrointestinal stromal tumor (GIST) patients, validating plasma ctDNA sequencing for treatment monitoring and disease activity (Jilg et al., Int J Cancer 2019).
7. The ImbruVeRCHOP trial (NCT03129828), enabled by translational research funded by the DKTK, for patients 61-80 years of age with newly diagnosed CD20+ diffuse large B cell lymphoma, led by C. Schmidt and M. Hummel (B), highlights the strong clinical collaboration with partners in the DKTK consortium and beyond (Denker et al., Int J Hematol Oncol 2019).
8. The SEPION/AIO-PAK-0118 phase I/II trial (NCT04257448, led by J.T. Siveke (E/D)), enabled by basic research funded by the DKTK, investigates the feasibility and efficacy of combined epigenetic and chemotherapeutic targeting followed by an immunomodulating consolidation concept in untreated metastatic pancreatic cancer.