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Our research focuses on understanding the molecular determinants that govern why some patients respond to therapy – particularly standard‑of‑care chemotherapeutics – whilst others do not. By dissecting these mechanisms, we aim to develop more refined and mechanistically informed treatment strategies.
A central interest of our group is antimetabolite therapies, with particular emphasis on nucleoside analogues.
Nucleoside analogues are an essential class of medicines and are widely used in the treatment of cancer together with infectious diseases and autoimmune disorders. Despite their long‑standing clinical use and proven efficacy, these agents remain limited by interpatient variability in response, therapeutic resistance, and dose‑limiting toxicities.
We seek to address these challenges by uncovering the molecular pathways that shape nucleoside analogue activity.
Current research themes:
Current research themes:
Characterising & targeting drug metabolisers
Characterising & targeting drug metabolisers
Nucleoside analogues are prodrugs that require intracellular bio‑activation to become therapeutically effective. The extent to which their active metabolites accumulate inside cancer cells is a major determinant of treatment outcome. Yet, the enzymes and pathways that control this activation–inactivation balance remain poorly understood. Our research aims to define these metabolic bottlenecks and uncover vulnerabilities that can be therapeutically exploited.
One key regulator we have identified is the dNTP hydrolase SAMHD1, which can deactivate nucleoside analogue metabolites by converting them back to their inactive prodrug forms. In this project, we aim to define the role of SAMHD1 in chemotherapy resistance and to develop pharmacological strategies to inhibit this enzyme for therapeutic benefit.
Identification of drug targets & drivers of response
Identification of drug targets & drivers of response
Upon activation, nucleoside analogues can generate multiple active metabolites inside cancer cells. These metabolites can engage distinct molecular targets, resulting in complex and often poly‑pharmacologic mechanisms of action that remain poorly understood. This knowledge gap limits optimal use of these effective therapies.
To address this, we collaborate with the Chemical Biology and Genome Engineering platform at SciLifeLab, integrating functional genomics with proteomics. Through genome‑wide CRISPR knockout screens and thermal proteome profiling of cancer cells exposed to nucleoside analogues, we aim to identify drug targets and the molecular drivers of response. We currently focus these efforts on paediatric T‑cell acute lymphoblastic leukemia.
Design of molecularly-informed combination therapies
Design of molecularly-informed combination therapies
Current treatment regimens for many diseases use combinations of pharmacological agents, and this is particularly central to cancer therapy. Combining drugs can enhance cancer cell killing, reduce toxicity through dose‑sparing, and delay or prevent the emergence of treatment resistance.
We apply mechanistic insights from our studies of nucleoside analogues to rationally design such combination strategies. By understanding how these agents are activated, metabolised, and resisted at a molecular level, we can identify complementary pathways whose inhibition enhances their effectiveness. We also take advantage of drug repurposing approaches, using existing compounds with known safety profiles to target newly identified metabolic vulnerabilities. Together, these strategies enable the development of molecularly‑informed combination therapies with the potential to improve outcomes for patients.
Our research is generously funded by:
Our research is generously funded by:
Swedish Research Council (Vetenskapsrådet)
Swedish Cancer Society (Cancerfonden)
The Swedish Childhood Cancer Fund (Barncancerfonden)
The Cancer Research Foundations of Radiumhemmet (Radiumhemmets Forskningsfonder)
SciLifeLab
Karolinska Institutet
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