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. For the next research period MTT will pursue four main lines of research

  1. Rational combination therapy strategies focusing on pediatric and hematologic malignancies (leukemias and lymphomas)
  2. Targeting functional cell states and tumor-host interactions
  3. Targeting transcription and epigenetics
  4. 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.

Highlight Achievements

  • Mutational dynamics between primary and relapse neuroblastomas. In neuroblastoma, a highly aggressive, often MYCN-driven embryonal tumor in children, the DKTK team was able to shed light on recurrent RAS mutations detectable in a relapse setting, but typically not at the time of primary disease (Schramm et al., Nat Genet 2015).
  • Whole-exome sequencing in adult early T cell precursor (ETP)-ALL reveals a high rate of DNMT3A mutations. The epigenetic regulator DNMT3A is frequently mutated in adult leukemia, thus indicating novel avenues for targeted therapy approaches (Neumann et al., Blood 2013).
  • Combined inhibition of bromodomain and extra-terminal proteins and histone deacetylases as a potential epigenetics-based therapy for pancreatic ductal adenocarcinoma (PDAC). A synergistic effect between the bromodomain inhibitor JQ1 and the HDAC inhibitor SAHA was identified in a faithful model of PDAC in vivo and shown to be dependent on intact CDKN1C function (Mazur et al., Nat Med 2015).
  • Identification in blood samples from breast cancer patients of a population of circulating tumor cells that initiate metastasis in a xenograft assay. The functional and phenotypic definition of metastasis-initiating cells provides novel targets for curative breast cancer therapies (Baccelli et al., Nat Biotechnol 2013).
  • Vemurafenib in multiple non-melanoma cancers with BRAF V600 mutations: This basket trial, in which patients were recruited based on the presence of a BRAF V600E mutation across different tumor entities, showed (i) that this approach is feasible and (ii) that different histologies are associated with variable responses to vemurafenib. Thus, lineage context and co-mutations play a crucial role in the response to targeted monotherapies (Hyman et al., NEJM 2015).