Nikolas Herold

Relapsed/refractory acute myeloid leukemia (R/R AML) is a devastating disease with median survival &lt

6 months. There is an urgent need to develop more potent salvage therapies. A new promising alternative is the quadruple combination FAVIDA, where a three-drug backbone of chemotherapy is complemented with the BCL2 inhibitor venetoclax.We previously demonstrated that SAMHD1 is a resistance factor to the important leukemia drug cytarabine, and that inhibition of SAMHD1 by hydroxyurea results in synergistic killing of leukemic cells. This has been successfully explored in a phase 1-2 trial called HEAT-AML where newly diagnosed AML patients were treated with the standard cytarabine and daunorubicin together with targeted inhibition of SAMHD1 with hydroxyurea. The response rate has been unexpectedly high, with deep molecular clearance of the disease.Parallel translational studies demonstrate increased levels of active cytarabine in the leukemic cells and synergistic killing of primary AML cells.The current proposal is an novel salvage treatment for R/R AML called FLAsH-IV. The concept is a placebo-controlled randomized trial where the FAVIDA regimen is complemented with hydroxyurea as a targeted drug to inhibit SAMHD1 and thereby potentiate the cytarabine effect to further enhance the efficacy.If the results are positive, the repurposed and cheap drug hydroxyurea can readily be used essentially worldwide as an add-on in order improve outcome in this severe disease.

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.

Acute myeloid leukemia (AML) affects 300,000 people annually. Only 3 out of 10 patients with AML can be cured. This is usually due to the fact that cancer cells in some patients are resistant to drugs. Likewise, resistance limits colon cancer survival. It is often unclear what differentiates tumors that can be cured from tumors that cannot be cured with chemotherapy. We therefore work partly to understand the mechanisms behind resistance and thereby develop improved treatments. With SAMHD1 we have found a resistance factor for AML, and with hydroxyurea we have found a drug that counteracts resistance. We are now researching whether this also applies to bowel cancer. We want (1) understand what is behind chemotherapy resistance for the important diagnoses of acute myeloid leukemia, bowel cancer and acute lymphoblastic leukemia, i.e. to gain an understanding of why only some patients respond well to the treatment. (2) develop strategies to combat chemotherapy resistance. (3) conduct clinical trials with the addition of a resistance blocker to chemotherapy SAMHD1 that limits treatment effects of several antimetabolites. We have found drug candidates that block SAMHD1. We are planning clinical studies to test whether the addition of SAMHD1 inhibitors can improve the efficacy of antimetabolites. If we can demonstrate improved treatment effects through the addition of our SAMHD1 inhibitor, AML treatments could be improved worldwide because hydroxyurea is a low-cost, patent-expired drug. As SAMHD1 is also an important resistance factor for colon cancer and ALL, we hope that the respective treatments can also be improved with the addition of hydroxyurea.