Screening and Validation of Combination Therapy in T Cell Leukemia

• Applicant: Dr. Marsilius Mues
• Subject Area: Hematology, Oncology ; Biochemistry
• Term: Funded in 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 258480544

T cell leukemia is an aggressive blood cancer of children and adults. Modern genotoxic treatments have markedly improved the outcomes, but carry substantial risk of toxicity during treatment and cause genotoxic stress that lasts after treatment. Furthermore, risk of relapse is high and prognosis is very poor for relapsed patients. Biologically distinct subtypes of T-ALL exist, however, stratification of patients has not been successful, and patients are typically treated with similar regimens. Thus, development of more specific and effective as well as less toxic therapies based on the underlying molecular pathogenesis is of high priority. A number of well known genes are frequently affected in T cell leukemia, which can activate and modulate existing cellular programs used in normal development. However, T cell leukemias have a complex make-up of multiple additional mutations that can either modulate these pathways or impact other cell biological functions. As a result, it is questionable if inhibition of single molecules in pathways will provide sufficient, long-term efficacy as therapy. In about 50% of T-ALL patients the oncogene "Ras" is affected, which regulates essential processes as cell growth or proliferation. Ras is regulated by several upstream enzymes and regulates a range of downstream signaling cascades, as the RAF-MEK-ERK or the PI3K-Akt-mTOR pathway. Unfortunately, so far no specific inhibitors for Ras are available, however, the inhibition of those downstream signaling pathways is possible and inhibition of e.g. PI3K (Phosphoinositide 3-kinase) is currently explored through the use of potent kinase inhibitors. Nonetheless, as already stated above, it remains questionable whether treatment with a single inhibitor is sufficient due to the additional tumor-specific gene mutations. To identify new combination therapies that will target more than only one signaling pathway, I will perform two high-throughput screens with human leukemia cell lines, which will uncover molecules that are essential for tumor cells. I will pair PI3K inhibitors with shRNA libraries targeting metabolic pathways or chromatin regulators to search for combinations that induce cell death in leukemic cells. For interesting targets from these screens I will characterize the underlying signaling pathways to identify the biochemical and cellular effects leading to cell death. Finally, in pre-clinical trials with leukemia mouse models I will determine the growth and survival characteristics of leukemia cells in vivo in response to new inhibitor combinations. I anticipate to uncover novel interdependent molecular pathways on which tumor cells are dependent on and which can be harnessed to efficiently target cancer cells via combination therapy.

• DFG Programme: Research Fellowships
• International Connection: USA
• Host: Professor Jeroen Roose, Ph.D.