Sebastian Koschade

Explore the role of autophagy in the context of targeted and conventional AML therapies

Targeted therapies are currently revolutionizing the treatment of acute myeloid leukemia (AML). However, the development of drug resistance remains a significant obstacle to long-term survival. Previous research in the lab has demonstrated that acute myeloid leukemia cells are crucially dependent on well-functioning bulk and selective autophagy pathways for their maintenance and progression. The lab Brandts/Koschade currently explores the role of autophagy in the context of targeted and conventional AML therapies, using a multifaceted approach including CRISPR/Cas9, proteomics, metabolic and flow cytometry-based assays. The aim is to uncover autophagy-related dependencies that may be exploited to overcome resistance to targeted therapies.

Autophagy in the bone marrow microenvironment
Leukemic cells reside in the bone marrow microenvironment (BMM). This complex entity consists of various cell types, the extracellular matrix, cytokines, and chemical factors, all of which can contribute to AML maintenance and therapy resistance. Bone marrow adipocytes (BMAds) constitute the largest cell population in the BMM by volume, and their number expands during aging. The objective is to understand the role of autophagy pathways in the establishment and maintenance of the AML microenvironment, with a focus on autophagy in bone marrow adipocytes as the dominant population of BMM cells. The lab Brandts/Koschade utilizes in vitro and in vivo models of BMAd-AML interaction, as well as specialized assays to profile selective autophagy receptor candidates and autophagosome cargoes. 

Therapy-induced adaptive pathways in AML persistent cells
Chemotherapy failure due to primary therapy resistance represents a significant clinical challenge in the treatment of patients with AML. Some patterns of primary treatment resistance show AML cell persistence despite on-target therapy and are not well-explained by acquired genetic mutations, or by the failure to eradicate leukemic stem cells. Instead, data from this lab and others point towards rapid acquisition of temporary, reversible drug tolerance due to nongenetic cellular adaptation. The lab Brandts/Koschade is interested in further understanding this process and applies a toolbox of molecular and cellular technologies to obtain a comprehensive overview of the pathways and mechanisms involved.
 

Find our more about the Brandts / Koschade Lab here.