Identifying novel targeted therapies for cancer using CRISPR/Cas9 dropout screens in PDX models in vivo

• Applicant: Professorin Dr. Irmela Jeremias, Ph.D.
• Subject Area: Hematology, Oncology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 537701335

Large numbers of poorly characterized compounds exist and there is a major unmet need to prioritize effective drugs for resource-intensive clinical development. Targeted therapies inhibit a specific protein to eliminate tumor cells and molecular approaches allow prioritizing targeted therapies. The underlying concept is that downregulation of a particular mRNA by a molecular approach has the same effect as inhibition of the corresponding protein by a targeted drug. While this concept has been widely exploited in cell lines in vitro, we recently transferred it to patient-derived xenograft (PDX) models that more faithfully mimic the patient's clinical situation. Importantly, genetically engineered PDX models studied in vivo allowed the discovery of new high potential tumor vulnerabilities that remained hidden for in vitro approaches and were restricted to the in vivo setting. In the present proposal, we will exploit acute myeloid leukemia (AML) as model disease and perform CRISPR/Cas9 screens in PDX mouse models in vivo with the aim to identify novel gene essentialities and corresponding targeted therapies. Once identified, drugs and compounds will be thoroughly tested in preclinical treatment trials in PDX models in vivo, focusing on cancer stem cells and relapse-inducing cells. Our work allows prioritizing novel targeted therapies for clinical development, for the benefit of patients with AML and presumably other tumors.

• DFG Programme: Reinhart Koselleck Projects