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Research team Thomas Helleday/Ulrika Warpman Berglund

Many DNA damaging anti-cancer drugs cause replication-associated DNA damage that kill cancer cells. This is an effective way of treating cancer, but the problem is that also normal cells are damaged. Our strategy is to exploit the high level of DNA damage and dysfunctional redox status in cancer cells and prevent the repair of these lesions and even cause more oxidative lesions in the cancer cells. Using DNA repair inhibitors, we can selectively introduce toxic DNA damage to cancer cells.

Our focus is on the most common DNA lesions, base lesions, that are substrates for base excision repair (BER), a repair pathway discovered by Tomas Lindahl for which he got the Nobel Prize, and involves several glycosylases, AP-endonucleases, Poly (ADP-ribose) Polymerase (PARP) and ligases. Earlier, the Helleday group pioneered the synthetic lethal concept for treatment of cancer(Bryant et al., Nature 2005), which exploits that a mutated cancer requires a back-up pathway for survival, not normally required for normal cells to survive. Using this concept, we demonstrated an effective treatment of BRCA2 defective tumours with PARP inhibitors, which did not cause the side effects associated with chemotherapy treatments.

We are currently building on this strategy and expanding into targeting novel DNA repair enzymes. We demonstrated how targeting MTH1 can be used to target cancer in general without causing toxicity to non-transformed cells(Gad et al, Nature 2014; Huber et al., Nature 2014) and we have developed the MTH1 inhibitor (MTH1i) karonudib (Karolinska NUDT1 inhibitor) (Warpman Berglund et al., Ann Oncol 2016) and progressed it through GMP manufacturing, formulation, GLP safety assessment, IMPD, Medical Product Agency and ethical approvals. Presently two clinical Phase 1 trials (one in patients with advanced solid malignancies and one in haematological cancers) with karonudib are on-going at Karolinska University Hospital. Pharmacology and biology are often more complex than originally thought, and we continue to deepen our understanding of the mechanism of action of our MTH1i and the role of MTH1 in cancer pathology.

By targeting the OGG1 glycosylase, we show how this can be used to suppress the onset of inflammatory and immune processes in for instance sepsis (Visnes et al., Science 2018).

Overreaching goals:

  1. Mechanistic understanding of DNA repair and nucleotide synthesis proteins with focus on small base lesions.
  2. Purification of proteins, identify functions and novel inhibitors with co-crystal information and develop pharmacological drugs to progress into treatments.
  3. Develop targeted therapy in clinical trials
  4. Develop ex vivo screening as companion diagnostic to treatments.

 

Current projects/targets

1) MTH1 – We have identified novel functions of MTH1 in mitosis and have made potent MTH1 inhibitors one of which, karonudib, is currently evaluated in clinical phase I trials. We are investigating combination treatments, biomarkers, potential resistance mechanisms as well as MTH1 potential role in inflammation/immune processes.
2) OGG1 –We developed first-in-class OGG1 inhibitors that we are progressing in lead optimization for treatments of inflammation and to further understand the detailed role in DNA repair. We have also identified OGG1 enhancers and are evaluating their potential in various disease models. We are also exploring OGG1 as a potential treatment of cancer.
3) MTHFD2 – We are exploring novel biological roles of MTHFD2 and we have generated potent inhibitors to this target that show anti-cancer properties. We are fast tracking MTHFD2 inhibitors into the clinic.
4) NUDT22 – is an understudied enzyme and we have identified its biochemical and biological function. We have generated potent NUDT22 inhibitors to be tested for treatment applications and to further expand our understanding of the role of the enzyme.
5) Base excision repair proteins – we are purifying a number of DNA glycosylases and other base excision repair proteins and are probing their biochemical roles to develop inhibitors, which may be applied for treatment of human diseases.
6) Ex vivo screening – we are collaborating with Päivi Östling and Olli Kallionemi for ex vivo screening and precision cancer medicine in AML as well as collaborating with University of Sheffield.
7) Virus- we have found that some or our inhibitors kill virus. We are further investigating the underlying mechanism of actions and potential effects as treatments.

Targeting DNA repair and nucleotide metabolism
Schematic illustration how we are taking an idea to a clinical candidate and clinical trials.

Funding

The work is generously supported by;
Swedish Research Council,
European Research Council,
Swedish Cancer Society,
The Swedish Childhood Cancer Foundation,
Novo Nordisk Foundation,
The Swedish Foundation for Strategic Research,
Vinnova, Swelife,
Torsten and Ragnar Söderberg Foundations,
Sjöbergstiftelsen,
Radiumhemmets Forskningsfonder.

Group members

Ingrid Almlöf, Research engineer
Carlos Benitéz, Postdoc
Nadilly Bonagas, PhD student
Helge Gad, Researcher
Camilla Gokturk, Project leader
Maurice Grube, Postdoc
Bishoy Hanna, PhD student
Thomas Helleday, Professor, PI
Martin Henriksson, Research engineer
Evert Homan, Senior research specialist
Ann-Sofie Jemth, Researcher, Biochemistry team leader
Christina Kalderén, Research engineer
Stella Karsten, PhD student
Tobias Koolmeister, Research engineer
Mari Kullman Magnusson, Lab manager
Petra Marttila, PhD student
Oliver Mortusewicz, Project leader, Basic science team leader
Aleksandra Pettke, PhD student
Therese Pham, Research engineer
Marjo-Riitta Puumalainen, Postdoc, virus team leader
Azita Rasti, Research engineer
Varshni Rajagopal, Research assistant
Teresa Sandvall, Specialist, clinical development team leader
Kumar Sanjiv, Assistant professor
Louise Sjöholm, Research coordinator
Niklas Schultz, Researcher, pharmacology team leader
Martin Scobie, Research engineer, medicinal chemistry team leader
Olov Wallner, Research engineer
Ulrika Warpman Berglund, Deputy/Acting PI
Elisee Wiita, Research engineer