RESEARCH
The ultimate goal of our research is to provide cancer patients with better treatment options. We believe one way this can be achieved in a timely manner is by focusing research efforts upon commonly used chemotherapeutic agents. These therapies, which form standard-of-care for many cancers, typically kill tumour cells by targeting pan-essential pathways, principally metabolism of the DNA molecule or its nucleotide building blocks (deoxynucleoside triphosphates, dNTPs). In our research program we aim to define the molecular underpinnings of why some cancers respond to these therapies whilst others do not. This information can provide the basis for rational therapy improvements through the identification of biomarkers and therapeutic targets together with the design of mechanism-based drug combinations. We employ a multidisciplinary approach in our research – centred upon biochemical, biophysical, and cell-based methods – and use both hypothesis-driven and hypothesis-free approaches in our efforts to define and exploit the molecular mechanisms underpinning clinical efficacy of chemotherapeutic agents.
Understanding & exploiting drug resistance
Targeting the dNTPase SAMHD1
Manipulation of DNA precursor pools to influence genome integrity has long been exploited in cancer therapy (Rudd et al., 2016), a prime example of which are a group of chemotherapies called antimetabolites (Tsesmetzis et al., 2018). 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 (dNTPase) SAMHD1 – capable of inactivating these drugs and thus contributing to worse treatment outcome. We characterised this extensively for the chemotherapeutic agent cytarabine (Herold et al., 2017a; Rudd et al., 2017), 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 (Herold et al., 2017b). 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 (Rudd et al., 2020), 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, 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, along with methods to characterise these molecules (Yagüe-Capilla & Rudd, 2021, Zhang et al., 2024).
Key publications:
Identification and evaluation of small-molecule inhibitors against the dNTPase SAMHD1 via a comprehensive screening funnel. (2024). iScience
Targeting the DNA damage response and repair through nucleotide metabolism. (2022). Mol Oncol.
A High-Throughput Enzyme-Coupled Activity Assay to Probe Small Molecule Interaction with the dNTPase SAMHD1. (2021). J Vis Exp.
Ribonucleotide reductase inhibitors suppress SAMHD1 ara-CTPase activity enhancing cytarabine efficacy. (2020). EMBO Mol Med
Targeting SAMHD1 with the Vpx protein to improve cytarabine therapy for hematological malignancies. (2017). Nat Med.
Nucleobase and Nucleoside Analogues: Resistance and Re-Sensitisation at the Level of Pharmacokinetics, Pharmacodynamics and Metabolism. (2018). Cancers
Pathways controlling dNTP pools to maintain genome stability. (2016). DNA Repair.
Understanding the mechanism of action of commonly used chemotherapies
Antimetabolite-based cancer drugs typically have complex mechanisms of actions which are poorly understood. Defining their molecular mode(s) of action is key to refining their clinical use. Here we are working closely with the Chemical Biology & Genome Engineering platform at SciLifeLab to use unbiased proteome- and genome-wide methods to understand how these important drugs kill cancer cells.
Key publications:
Design of mechanism-based drug combinations
Current treatment regimens for many different diseases utilise combinations of pharmacological agents, and this is especially true in the treatment of cancer. The rationale behind the use of two or more drugs in cancer therapy is to enhance cancer cell killing, reduce treatment toxicity, and prevent the onset of treatment resistance. We’re interested in the design of mechanism-based combination therapies.
Key publications:
Drug synergy scoring using minimal dose response matrices. (2021). BMC Res Notes.
Ribonucleotide reductase inhibitors suppress SAMHD1 ara-CTPase activity enhancing cytarabine efficacy. (2020). EMBO Mol Med.
Mutant p53-reactivating compound APR-246 synergizes with asparaginase in inducing growth suppression in acute lymphoblastic leukemia cells. (2021). Cell Death & Disease
dNTP metabolism & oncogenesis
Oncogenes induce DNA replication stress in cancer cells, and although this was established more than a decade ago, we are still unravelling the molecular underpinnings of this phenomenon, which will be critical if we are to exploit this knowledge to improve cancer treatment. A key mediator of oncogene-induced replication stress is the availability of DNA precursors and here we are investigating the interplay between dNTP metabolic enzymes and oncogenesis.
Key publications:
SAMHD1 promotes oncogene-induced replication stress. (2020). bioRxiv [preprint].
With me or against me: Tumor suppressor and drug resistance activities of SAMHD1. (2017). Exp Hematol.
Pathways controlling dNTP pools to maintain genome stability. (2016). DNA Repair.
Our research is generously funded by:
Swedish Research Council (Vetenskapsrådet) (Starting grant in medicine and health)
Swedish Cancer Society (Cancerfonden) (Junior Investigator Award & Project grant)
The Swedish Childhood Cancer Fund (Barncancerfonden) (Project grant & Posdoctoral Fellowship)
Dr Åke Olsson Foundation for Hematological Research
Karolinska Institutet (Faculty-funded Assistant Professor position)