Exploiting drug-sensitivity- and surface-expression-signatures in Acute myeloid leukemia subpopulations to impede resistance development

• Applicant: Professor Dr. Sascha Dietrich
• Subject Area: Hematology, Oncology ; Toxicology, Laboratory Medicine
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563479976

There have been improvements in Acute myeloid leukemia (AML) survival, not least due to progress in standard treatments such as chemotherapy and transplant strategies but also due to new treatment modalities such as molecularly targeted drugs and/or immunotherapeutics. However, many patients who initially respond to treatment eventually develop leukemia recurrence. These relapsed leukemias often respond worse to salvage treatment than during first line therapy. They might occur because therapies almost inevitably leave residual cancer cells behind (minimal residual disease, MRD), a reservoir from which relapse can emerge. The chances for such residual leukemia cells to survive treatment are increased by intra-tumor heterogeneity (ITH). Traditionally, the focus has been on genetic ITH, which arises by accumulation of mutations in a proliferating population of tumour cells. There is, however, growing evidence that therapy resistance mediating ITH can also be caused by non-genetic factors. Such factors include chromatin-remodeling (reprogramming) and cell-extrinsic signaling (microenvironment). This can result in different cell states and differential therapy response phenotypes even when the genetic background is the same. Experimentally, differential response to cancer treatments by tumor subpopulations of the same patient has been shown by us and others. Importantly, we could show that the level of ex vivo drug response of bulk tumor samples supplemented and exceeded the predictive quality for patient outcome of genetic analyses alone,5 and we see an enormous potential to add ITH (i.e., the tumor-subpopulation-specific drug response) as an additional layer to further improve prediction efficacy of the in vivo response - and ultimately prevent resistance formation. Hence, we consider a predictive and actionable understanding of how ITH relates to drug sensitivity as a great leap towards better treatment outcomes. For instance, suitably personalized therapies would include combinations of drugs that target all coexisting subpopulations, preventing the outgrowth of a resistant tumor clone under the therapeutic pressure. To address this need we aim to establish an experimental setup which allows us 1) to robustly identify AML subpopulations and isolate them for in-depth molecular profiling (WGS, RNAseq, surface-proteomics) 2), to predict common and unique vulnerabilities via their drug response profiles (molecular and immunotherapeutic), 3) to design rational combination therapies targeting all coexisting subpopulations, and 4) to determine whether subpopulation specific drug responses (ex vivo) correlate with leukemia subpopulation survival in vivo. Therefore, we aim to develop an (immuno-)therapeutic repertoire which can be queried for tailored treatment of AML patients.

• DFG Programme: Research Grants
• Co-Investigator: Privatdozent Dr. Marc Seifert