Identification of new targets to overcome resistance to hypomethylating agents and venetoclax in acute myeloid leukemia

• Applicant: Dr. Constanze Schneider, Ph.D.
• Subject Area: Hematology, Oncology
• Term: from 2019 to 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 437546519

Acute myeloid leukemia is a heterogeneous, malignant diseases of the hematopoietic stem and progenitor cells, with a particularly poor prognosis in elderly patients (>65 years). This subgroup of patients has overall survival rates of a few months only, independently of the therapeutic strategy. Within the proposed project we aim to investigate resistance mechanisms for hypomethylating agents like azacytidine (AZA) and decitabine (DAC) used in combination with venetoclax which is a promising alternative therapy for elderly and unfit AML patients. Using CRISPR/Cas9 screens and functional analyses we will identify and mechanistically investigate key players for therapy failure and the development of drug resistance. Therefore, we have established AZA, DAC and Venetoclax resistant cell lines, which will be used as models for studying drug resistance mechanisms by genomic screens and additional mechanistic studies. After performing multi-drug screens to find synergistic drug combinations, we plan to validate therapeutic targets in vivo using the Public Repository Xenografts (ProXe). Taken together, the main objective of the proposed project is to characterize resistance mechanisms to hypomethylating agents and venetoclax in AML patients in order to improve future therapeutic approaches.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professorin Dr. Kimberly Stegmaier