Overview

Illustration of leukemia cells

The goal of our lab is to contribute to the improvement of treatments for patients with hematologcial malignancies. Research strategies focus on identifying novel vulnerabilities and treatment targets in myeloid disorders (AML, MDS, MPNs) and translating those into new therapy approaches.

The challenge is that many molecular aberrations in cancer may or may not be optimal therapy targets. While it is important to understand the disease pathobiology it is similarly important to identify the crucial vulnerabilities in leukemia cells/genomes that lead to cell death/killing when inhibited.

One methodology to address the shortcomings of lack of crucial vulnerability targets in leukemias is using RNA interference (RNAi) as an unbiased approach to screen 100s to 1000s of genes simultaneously for their anti-leukemic effect alone or in combination with cytotoxic drugs and other agents.

In this attempt the lab has succeeded in establishing a unique high-throughput RNAi platform for suspension cells using siRNA lipid based transfection conditions allowing unprecedented target discovery in leukemias and cancer research. Several RNAi sensitizer screens of the human kinome with FDA approved drugs (Cytarabine and 5-Azacytidine) have been conducted.

Novel targets whose inhibition sensitizes leukemia cells to these drugs were identified. Novel crucial sensitizer kinases have been validated for their mechanistic and biological synergy and properties in combination with Cytarabine and 5-Azacytidine. Results serve as the basis for design of rational combination therapies in leukemias and clinical trials concepts are in development.

Furthermore, "achilles heel" RNAi screens with several large RNAi libraries in leukemia cells with heterogenous genetic background were performed and have yielded gene targets selectively lethal to individual cell lines harboring distinct molecular abnormalities.

In summary, our lab has shown the application and feasibility of RNAi to leukemia suspension cells; and large scale RNAi screens provide highly valuable functional genetic targets in leukemias.

Identified targets show a tremendous functional selection and many hits have validated and can be exploited in drug discovery and development. Results are being immediately translated into design of novel rational combination therapies for patients with leukemias, MDS and other hematological disorders.