Molecular determinants of drug efficacy and tumour suppression in haematopoietic and solid malignancies

Resistance to chemotherapy causes failure of cancer treatment.

We investigate how the resistance factor SAMHD1 on the one hand limits treatment efficacy in acute leukaemias and colorectal cancer, develop SAMHD1 inhibitors and evaluate how those can improve cancer therapies. On the other hand, we examine how SAMHD1 paradoxically improves survival in melanoma patients.

We also want to identify novel factors that determine chemotherapy responses in osteosarcoma.

Within 4-years, in our own lab and through collaborations under my lead, we employ in vitro enzyme activity assays, phenotypic cell-based assays, gene expression data and animal experiments to evaluate how SAMHD1 and novel factors modulate the effects of chemotherapy and influence tumour progression.

We use gene expression from patient tumours and correlate those to treatment outcome. Crystallography will be used to see how our SAMHD1 inhibitors block its enzymatic function.

Analysing leukemic cells of patients enrolled in our clinical trial, we assess whether a SAMHD1 inhibitor leads to improved therapy responses.

We will test how chemotherapy and knockout of genes affects the abilty of immune cells to kill cancer cells in vitro and in immunocompetent animals.

We plan to understand how inhibition of SAMHD1 can improve cancer therapies and which role SAMHD1 plays for tumour progression.

Identification of novel chemoresistance factors for osteosarcoma will establish predictive biomarkers and provide new druggable targets.