Projects and Programs

Heterogeneity, Evolution, and Resistance in Oncogenic Fusion Gene-Expressing Sarcomas Affecting Adolescents and Young Adults  |  HEROES-AYA

HEROES-AYA aims to address the challenge of tumor heterogeneity (ITH) in sarcomas, particularly those driven by chimeric fusion genes, which are key to tumor evolution and therapy resistance. By combining cutting-edge multi-omics, single-cell and spatial analyses, and preclinical models, the consortium will explore ITH at unprecedented resolution and identify vulnerabilities to overcome treatment resistance. Leveraging the established INFORM and MASTER precision oncology networks, HEROES-AYA will apply these insights to develop innovative clinical trials and therapeutic strategies, improving outcomes for young sarcoma patients.

Subprojects analyze intra-tumor heterogeneity and clonal evolution in adolescent and young adult cancers using advanced multi-omics, digital pathology, and imaging techniques, and integrate this data to identify key drivers of FDS diversification and make the data publicly accessible. It develops in vitro and in vivo models to identify treatment vulnerabilities in FDS, and establishes a framework for clinical trials in AYAs to address treatment resistance and improve outcomes using insights from earlier program stages.

MiHUBx: Use Case Digital Workflow Integration in Personalized Oncology

As part of the Medical Informatics Initiative (MII), the Federal Ministry of Education and Research (BMBF) is funding six new collaborative projects, the Digital Progress Hubs in Health. These projects aim to improve the availability of data and collaboration across various areas of healthcare, from inpatient to outpatient care, as well as rehabilitation and aftercare.

The close connection between research and clinical care is essential to treating cancer patients based on the latest scientific findings. Therefore, the use case of the Medical Informatics Hub in Saxony (MiHUBx) focuses on improving the digital networking of all partners in personalized medicine. In addition to enabling smooth data exchange, the digital integration of treating physicians and experts will be supported, and processes will be accelerated. Information from unstructured data formats, such as medical reports, will be made accessible through a shared portal and made available to all partners. Furthermore, patients will have the opportunity to access information tailored to their treatment context and actively participate in the program. This aims to enhance patient awareness and involvement.

Continuous data collection ensures that doctors have a comprehensive data and information base for treatment at all times. Researchers will also have new opportunities to further improve approaches and methods in personalized oncology.

Clinical Programs and Networks

DKFZ/NCT/DKTK MASTER-Program

Rare cancers account for nearly 25% of adult malignancies. They represent an underserved patient population whose outcome is unfavorable compared to more common entities due to incomplete biological understanding and inadequate representation in clinical trials.

In recent years, NCT and DKFZ have laid the groundwork to address this challenge by establishing the MASTER program. This prospective registry trial employs comprehensive molecular analysis, including whole-genome/exome (WGS/WES) and RNA sequencing (RNA-seq) and genome-wide DNA methylation profiling, in patients with advanced rare cancers across histologies to inform clinical-decision making. Whenever possible analyses also include mass spectrometry-based (phosphor)proteomics, ex vivo drug sensitivity profiling and spacial resolution of the immune environment. Based on the MASTER workflow, which includes a multicenter molecular tumor board (MTB), we provide clinically relevant management recommendations, comprising diagnostic reevaluation and molecularly informed treatment. Recommended therapies resulted in significantly improved outcome, illustrating the potential of molecularly guided treatment to improve the treatment of patients with rare cancers. Based on the MASTER program, more than 100 research projects have taken shape. Examples led by PIs from the department include: 

• Evaluation of the potential of comprehensive genomic and epigenomic analysis in cancer of unknown primary for guiding molecularly-informed therapies
• Investigating the therapeutic relevance of NRG1-Fusions in KRAS Wild-Type Pancreatic Cancer
• Developing machine learning-based clinical decision support for molecularly-informed early-line treatment in sarcoma and neuroendocrine neoplasia

RATIONALE

RATIONALE is a prospective, randomized multicenter trial investigating the clinical impact of comprehensive genomic, epigenomic and transcriptomic analysis, as established in the DKFZ/NCT/DKTK MASTER program, in patients with advanced rare cancers. Patients will be assigned to one of two arms in which molecular tumor profiles generated by WGS, RNA-seq, and DNA methylation profiling will either be provided to treating physicians immediately or upon progression on standard treatment. MTB recommendations will include matching molecularly stratified clinical trials and application for reimbursement of off-label use. As the primary endpoint we investigate progression free survival, secondary endpoints being overall survival, overall response rate, and disease control rate, as well as toxicity and patient reported outcomes. Furthermore, we aim to expand the range of multidimensional characterization of rare cancers for detecting clinically actionable profiles by integrating mass spectrometry-based (phosphor)proteomics, ex vivo drug sensitivity profiling, and spatially resolved proteomic analyses in a subset of patients.