Molecular mechanisms of AML with focus on translation

The project will change the paradigm of explicit genomics-based AML diagnostics to an in-depth functional approach of combined genomics and Mass Spectrometry-based PhosphoProteomics (MS-PP) diagnostics and high-throughput drug screening of AML trial patients. This novel approach is predicted to identify a broad spectrum of relevant druggable key signalling and DNA damage response (DDR) molecules that can be targeted by small molecule inhibitors to enhance chemotherapy efficacy, and ultimately improve clinical outcome of AML patients.

The current project will apply an existing MS-PP and high-throughput platforms, for real-time identification of known as well as novel druggable oncogenic signalling and DDR pathway molecules in AML patients and Genetically Engineered AML Mouse Models (GEMMs) before and after treatment with chemotherapy. Subsequently, novel “candidate” signalling and DDR pathway will be validated as druggable targets for therapeutic interventions in (i) in vitro drug tests, (ii) CRISPR knockout experiments, and (iii) in pre-clincial trials utilising AML Patient-Derived Xenografts (PDXs) and AML GEMMs.

Acute Myeloid Leukemia (AML) represents an aggressive cancer entity with a dismal 5 years survival rate of 25%, primarily due to relapse and primary resistance toward current standard chemotherapy regimens including anti-metabolic and DNA damaging drugs. AML is partially driven by genetic aberrations, which confer aberrant “oncogenic” activity of signalling and DNA Damage Response (DDR) pathways causally involved in malignant transformation and resistance toward chemotherapy. Consistently, clinical studies have demonstrated that cancer and AML patients, can be re-sensitised to chemotherapy by targeted inhibition of aberrantly activated signalling and DDR pathways. Although comprehensive genomics studies of large AML cohorts have identified novel therapeutic targets, these rarely identify the complete spectrum of druggable signalling and DDR molecules in AML patients, and have only led to the approval of very few targeted therapies for AML treatment during the last decade.
The current project will therefore address the unmet need to implement novel complementary diagnostic tools in the clinic to advance personalised therapeutic targeting of pathognomonic signalling and DDR molecules alone or in combination with conventional therapeutic regimens to overcome resistance and improve the clinical outcomes of AML patients.

The candidate should have an interest in cancer biology in general, as well as mechanisms of cancer, drug development, and translational projects including validation of novel drug modalities in pre-clinical trials utilising AML GEMM and AML PDX mouse models.

No specific medical background is required – but documented interest in haematology research as well as clinical training in haematology/oncology would be an advantage.