Translational studies on SAMHD1 as resistance factor, tumour suppressor, and regulator of immune responses

Our overarching goal is to rationally improve cancer treatments.

To this end, we study the key cancer protein SAMHD1 that has context-dependent roles for treatment resistance, tumour suppression and immunomodulation.1) SAMHD1 is a resistance factor for ara-C, backbone treatment of acute myeloid leukaemia, as well as for fludarabine. Combinations of these drugs (FLA) are used to treat relapsed and refractory AML.

We have identified inhibitors of SAMHD1 that combined with ara-C yielded promising results in our recently finalized a phase I trial which we aim to validate in a phase II study.

For relapsed and refractory AML, we plan to initiate a clinical study adding a SAMHD1 inhibitor to FLA. 2) In colorectal cancer (CRC), SAMHD1 functions as a tumour suppressor, but can also modulate innate immune responses triggered by chemotherapy.

We will study how 5-fluorouracil induces innate inflammatory responses in CRC cell lines (with and without SAMHD1) and use mouse models to investigate how SAMHD1 affects tumor growth and 5-FU-induced immune responses including T-cell infiltration in tumours.

In addition, by using immunohistochemistry we aim to examine if SAMHD1 expression correlates with survival as well as immune infiltration in tumour biopsies from CRC patients.

This project wants to generate knowledge leading to improved clinical therapy of leukaemias, through SAMHD1 inhibition, as well as introduce a biomarker guiding therapy decisions for CRC.