Research

Targeting Leukemia stem cells

Cancer stem cells represent a challenging subpopulation of malignant cells. The main features of these cells, namely quiescence/dormancy, resistance towards chemotherapy, and the ability to re-induce a tumor, represent major challenges for the curative treatment of cancer patients.

We have recently identified a rare subpopulation of long-term resting, treatment resistant leukemia initiating stem cells (LIC/LSC) within ALL samples, the so-called LRC (label retaining cells). Gene expression profiles of ALL-LRC were similar to those of cells isolated from ALL patients at minimal residual disease. However, these features were reversible – dissociation of ALL-LRC from the bone marrow niche re-induced proliferation and drug-sensitivity [Ebinger et al., Cancer Cell 2016].

image: Patient derived ALL cells contain a rare, dormant, treatment resistant population of leukemia stem cells. These phenotypic features are reversible and depend on the bone marrow niche. Image: AHS

Our data suggest that ALL patients might profit from therapeutic strategies that release dormant, therapy-resistant cells from the niche. Therefore, we are characterizing relevant surface molecules which are responsible for the interaction of ALL cells with the niche. Our goal is to be able to target crucial interaction partners, releasing tumor stem cells from the niche, and thereby re-sensitizing them towards apoptosis induction by i.e. chemotherapeutic drugs.

Induction of Apoptosis in Leukemia

Aim of anti-cancer therapy is the removal of tumor cells. An important mechanism for removing tumor cells is induction of cell death, mostly as programmed cell death or apoptosis. We study the mechanisms, how novel therapeutic compounds as well as established cytotoxic drugs or drug combinations act on cancer cells. Towards this aim, we perform stable or transient molecular manipulation on cell lines and patient-derived xenograft cells.

Image: Within the leukemic disease, subfractions of cells are dying, growing or resting; Group: Apoptosis

Likewise, we discovered that vinca alkaloids exert most efficient anti-cancer treatment efficiency, when used independently from cell cycle arresting cytostatic drugs such as anthracyclines (Blood 2011).

 

Image: Anthracyclines induce cell cycle arrest mediated by p53 and cyclines. Cell cycle arrest inhibits the ability of vinca alkaloids to phosphorylate and degrade anti-apoptotic Bcl-2 familiy members in order to induce cell death, Group Apoptosis

Caspase-8 represents an important intracellular mediator during anti-cancer treatment which is regulated by, e.g., Methotrexate and sensitizes towards TRAIL (Oncogene 2008) and drug induced apoptosis (Clin Cancer Res. 2012). Using our newly established transfection technique (Cell Commun Signal. 2012), we verified these molecular findings in tumor cells derived from leukemia patients. The pro-apoptotic Bcl-2 family member NOXA mediates apoptosis induction by drug combinations even if both single drugs induce apoptosis independently from NOXA (Cell Death Dis. 2012).

Preclinical treatment trials on PDX cells

Novel treatment options require robust preclinical testing before first use in men. To evaluate treatment efficiencies in vivo and on patients' tumor cells, we apply our model of the individualized xenograft mouse model of acute leukemias.

For a list of available AML PDX samples, please visit our DKTK Website

Patient derived xenografted (PDX) acute leukemia cells are systemically growing in mice. To improve the monitoring of treatment effects, PDX cells are lentivirally transduced to express firefly luciferase. This enables repetitive, sensitive and reliable disease monitoring by bioluminescence imaging (BLI) for both, leukemia outgrowth and treatment response. All clinically relevant disease stages are covered, including MRD [Vick et al., PLOS ONE 2015].

 

  Image: Monitoring treatment response by in vivo imaging. Mice are injected with PDX cells transgenic for luciferase. After visible engraftment, mice are treated with either solvent (black line) or cytostatic drugs (grey lines). Mice are repetitively imaged to monitor leukemic burden. Image: AHS

  In that line, we have recently analyzed

(A) the anti-tumor effect of a kinase inhibitor on AML cells with and without knock-down of a epigenetic modifier [Göllner et al., Nature Medicine 2016]
(B) treatment effects of a novel kinase inhibitor on FLT3 wt and FLT3-ITD AML cells [Klaeger et al., Science 2017].Images: AHS

The role of epigenetic regulators in acute leukemia

In acute leukemia, a majority of tumors reveal early, if not initiating mutations in epigenetic regulators, i.e. enzymes involved in DNA methylation, histone methylation, or histone acetylation [Metzeler et al., Blood 2016]. Therefore, acute leukemias might be considered as epigenetic diseases.

Our lab tries to understand how altered epigenetic regulation is required for tumor cell growth and survival and how epigenetic alterations can be addressed therapeutically. As example, we study chromosomal translocations involving the epigenetic regulator KMT2A (MLL) with the final aim to find new treatment options for the challenging subgroup of KMT2A-rearranged leukemias.

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