Research team Sean Rudd
The ultimate goal of our research is to provide cancer patients with better informed treatment options, and we believe this can be achieved by gaining a deeper understanding of the metabolic pathways operating inside cancer cells. In particular, we are interested in those pathways responsible for maintaining the DNA molecule and the DNA precursor pool, both of which play critical roles in cancer biology and the response to cancer therapy. By using a biochemical, molecular, and cell biology-focused approach, we aim to identify potential biomarkers and therapeutic targets involved in these pathways that can then be utilised for the rationale improvement of cancer treatment.
This approach, in particular the role of these metabolic pathways in the response to cancer therapy, is exemplified by our project focused upon the enzyme SAMHD1.
Understanding and overcoming therapy resistance – targeting SAMHD1
Manipulation of DNA precursor pools to influence genome integrity has long been exploited in cancer therapy, a prime example of which are a group of chemotherapies called antimetabolites (PMID: 30041457). Whilst these drugs remain standard treatment for many common malignancies, treatment efficacy can vary and the underlying mechanism can often remain unclear. Together with collaborators, we identified an enzyme – the deoxynucleoside triphosphate triphosphohydrolase SAMHD1 – capable of inactivating these drugs and thus contributing to worse treatment outcome. We characterised this extensively for the chemotherapeutic agent cytarabine (PMID: 28067901, PMID: 28401188), which remains standard-of-care for patients with acute myeloid leukaemia (AML). Furthermore, we implicated SAMHD1 in the control of several other drugs used to treat a range of malignancies (PMID: 28436707). In our current work, we continue to define this role of SAMHD1 as a drug resistance factor.
Another focus of our research is to develop strategies to inactivate SAMHD1, thus providing a potential mechanism to overcome this barrier to treatment efficacy. One approach we have taken, which we recently published (PMID: 31950591), was to utilise a phenotypic screening strategy. In this study, we identified clinically used anti-cancer drugs, inhibitors of the enzyme ribonucleotide reductase (RNR), that are capable of indirectly inactivating SAMHD1 in various models of AML. This work now forms the theoretical basis of a multicentre clinical study being undertaken in Sweden (HEAT-AML), which will evaluate the safety and efficacy of combining an RNR inhibitor, the drug hydroxyurea, with standard AML therapy. Continuing this work, we aim to understand the broader implications of this indirect approach of targeting SAMHD1, which highlighted how a single factor can dictate the synergistic efficacy of a combination chemotherapy. In addition, we continue to develop specific chemical probes towards this enzyme.
For more information about our research, please see our group website.
Ribonucleotide reductase inhibitors suppress SAMHD1 ara-CTPase activity enhancing cytarabine efficacy.
Rudd SG, Tsesmetzis N, Sanjiv K, Paulin CB, Sandhow L, Kutzner J, et al
EMBO Mol Med 2020 Jan;():e10419
Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies.
Herold N, Rudd SG, Ljungblad L, Sanjiv K, Myrberg IH, Paulin CB, et al
Nat. Med. 2017 Feb;23(2):256-263
Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism.
Tsesmetzis N, Paulin CBJ, Rudd SG, Herold N
Cancers (Basel) 2018 Jul;10(7):
Pathways controlling dNTP pools to maintain genome stability.
Rudd SG, Valerie NCK, Helleday T
DNA Repair (Amst.) 2016 08;44():193-204
Our research is generously supported by
- Swedish Research Council (Vetenskapsrådet)
- Swedish Cancer Society (Cancerfonden)
- The Swedish Childhood Cancer Foundation (Barncancerfonden)
- Karolinska Institutet