The consortium of scientists and physicians at eight German sites is dedicated to fundamental questions of tumor heterogeneity with a particular focus on therapy-related changes. To this end, they are investigating the plasticity of tumors under selective pressure both temporally in the course of therapy and spatially with the help of analytical methods that take a high-resolution look at genomic, transcriptomic and proteomic mechanisms as well as the interaction with the tumor environment. In order to be able to study the heterogeneity and thus the differences in tumor cells with sufficient resolution, methods are primarily used that enable observation at the single cell level.
Focus on fusion-driven sarcomas
From a biological point of view, fusion-related sarcomas are particularly well suited for research into basic principles of tumor heterogeneity, as gene fusions are early, tumor-initiating events that are frequently used diagnostically due to their clonal and entity-defining character. On the one hand, this has the advantage that the presence of a specific gene fusion can be inferred during routine diagnostics. On the other hand, there is a characteristic genetic feature that is maintained throughout the development of these tumors and facilitates the investigation of divergent subclones and plasticity. Finally, fusion-related sarcomas are usually characterized by a comparatively low genetic complexity, which facilitates the differentiation between relevant and non-causative alterations and thus also the identification of events or patterns that promote tumor heterogeneity or represent a response to evolutionary pressure under therapy.
Precision oncology programs as an entry portal
Recruitment for the project is based on two large precision oncology programs at the NCT sites in Dresden and Heidelberg, within the German Consortium for Translational Cancer Research (DKTK) and at the DKFZ: MASTER and INFORM, and their respective patient bases. These are (inter)national registry studies in which children (INFORM) and young adults (MASTER) with advanced cancers are examined molecularly and treated more effectively using a standardized procedure. Their aim is to find starting points for targeted therapies and to lay the foundation for controlled clinical trials in molecularly defined patient groups. In both programs, the clinical evaluation of molecular profiles and therapeutic decision-making by cross-institutional molecular tumor boards is already established. At the time of application, 2,000 and 3,500 patients were enrolled in INFORM and MASTER respectively. The proportion of cases with fusion-related sarcomas is around 30% in both programs, which illustrates the clinical challenge associated with these diseases.
Translation into clinical trials in close interaction with patient representatives
From a clinical perspective, the aim of the consortium is therefore to ensure that the newly gained knowledge is quickly fed back into the clinic. There are significantly fewer effective therapies for sarcomas in particular than for many other types of cancer, and there is a considerable need for medical action due to the predominantly young age of the patients. For this reason, the consortium's findings are to be systematically implemented in clinical study concepts. In cooperation with European and German tumor registries for sarcomas and the structures of INFORM and MASTER, the clinical course of the examined patients is systematically tracked.
If the evaluation of this data shows clinical efficacy, a functional validation of the starting points will follow in a sub-project of HEROES-AYA, in which the mechanisms found will be tested and examined in more detail in patient-derived short-term cultures, organoids or other models. The aim is to gather information on drug intervention options that will support the design of a clinical trial.
New promising therapeutic approaches are transferred to clinical trials as quickly as possible with the help of the rolling phase II design. The rolling phase II design is characterized by sequential, adaptive phase II studies with short-term endpoints that are opened in rapid succession. By linking the program to the registries and interacting closely with patient representatives, the aim is to enable as many patients with fusion-driven sarcomas as possible to participate in the study. HEROES-AYA has set itself the task of pioneering work and developing joint protocols and care structures for the young patient group, which is often difficult to include in cross-age group studies. Here in particular, the involvement of patients and patient representatives is immensely helpful.
The HEROES-AYA project was launched in August 2022. The first clinical trials are expected in 2025.
