Science

DNA damage and repair in cancer

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 in cancer cells and prevent the repair of these lesions. Using DNA repair inhibitors, we can selectively introduce toxic DNA damage to cancer cells.

DNA replication, repair and transcription

The mammalian genome has to be constantly copied (replication), read (transcription) and repaired (DNA repair) which poses a great challenge to eukaryotic cells.

We are interested in deciphering the spatio-temporal coordination of these essential mechanisms using state of the art techniques. Our main interest lies in understanding the interplay of the repair of replication-associated DNA damage, which is induced by many anti-cancer drugs, with on-going transcription.

To this end we have identified various new proteins playing a crucial role at the crossroad of replication, repair and transcription. These new insights will help us to understand the molecular mechanisms of how these cellular processes are regulated and coordinated and might in the end lead to the discovery of new concepts for the treatment of cancer and other diseases.

Metabolism

It’s been known for decades that cancer cells are characterized by switching from predominantly using oxidative phosphorylation for energy to using anaerobic glycolysis for growth. Many are exploiting this switch to tailor novel treatments for cancer and with the modern molecular biology techniques available today we can now selectively inhibit different protein critically involved in cancer growth and potentially less important to normal cells. Examples of targets that we have are PFKFB3 and MTHFD2, see our pipeline for details.

Nucleotide metabolism

There are over thirty nucleoside analogs that have been approved as drugs (by FDA and EMA) and several of these are on the WHO list over essential medicines. Most of these drugs are used as antivirals and in the treatment of cancer but they are also used for other indications like immunosuppression and as antiplatelet drugs. By targeting proteins involved in nucleotide metabolism we can improve the efficacy of current nucleoside treatments. One example of this strategy is the EMA approval in 2016 of the thymidine phosphorylase inhibitor tipiracil to improve trifluridine treatment of metastatic colorectal cancer. For example, we show targeting of SAMHD1 for improved efficacy of AraC treatments (Herold et al., 2017 Nature Medicine). Also, targeting nucleotide metabolism itself can prove highly effective as a mono-therapy based treatment, based on the aberrant metabolism in disease.

Read more here (external link).

Inflammation

We are introducing a completely new approach for treatment of inflammatory diseases based on the cross-sectional research areas of DNA repair and inflammation. We have demonstrated proof of principle showing that therapeutic treatment with our tool compound, an OGG1 inhibitor, TH5487 significantly reduces the inflammation in mice with lung inflammation.

Publications

We have published… a lot!

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