Targeted drug development based on oxidative DNA damage and DNA damage response (DDR)
DDR – the processes the body uses to repair the damage that occurs to DNA is highly vulnerable, and DNA damage or defects in the DNA Damage Response (DDR) are linked to many common diseases such as cancer, inflammatory diseases, cardiovascular and neurodegenerative diseases. Oxygen metabolism is central for all life forms and some of the oxygen products, ROS (Reactive Oxygen Species), have both beneficial and deleterious functions in the cell. Fortunately, there are mechanisms in place to minimize ROS damage to DNA.
DNA damage response proteins involved in these mechanisms are for instance enzymes degrading oxidative nucleotides in the dNTP pool (e.g. MTH1), and glycosylases cutting out oxidative DNA lesions (e.g. OGG1) and polymerases repairing the DNA break. Cancer cells often have high oxidative stress and there are data showing that they also have elevated levels of protective proteins against oxidative DNA damage, which can be a way for the cancer cell to manage and survive the high oxidative stress and DNA damage. Similarly, inflammatory cells have altered redox status and can survive the high oxidative stress.
The DNA damage response (DDR) senses, signals and repairs DNA lesions. Surveillance proteins that monitor DNA integrity can activate cell cycle checkpoints and DNA repair pathways in response to DNA damage, to promote survival. These pathways are often altered in cancer which generates genetic instability as an enabling factor for the onset of cancer. This makes the cancer dependant on remaining functional DDR proteins to promote survival. These can be targeted to kill only the cancer DDR dependant cells.
Cancer cells have more replication stress and DNA damage than normal cells, due to uncontrolled cell growth. DNA repair allows cancer cells to survive and can result in DNA mutations, further driving carcinogenesis. DDR inhibitors block repair and cancer cell survival, leading to further damage to the DNA and death of the cancer cell. Normal cells are spared because they have limited DNA damage.
Professor Thomas Helleday (co-founder of Oxcia AB) and his team were first to demonstrate a new concept targeting DDR for treatment of cancer, that PARP inhibitors target BRCA mutated cancers. These PARP inhibitors are a novel and groundbreaking targeted cancer drug class approved to treat breast, ovarian, pancreatic and prostate cancers.
Oxcia is now taking the next step in DDR to improve cancer therapy, exploiting the high load of endogenous DNA damage and oxidative stress in cancer cells.
Oxcia is developing OXC-101 (Karonudib), a mitotic MTH1 inhibitor, fighting cancer by taking advantage of endogenous high oxidative stress and DNA damage. OXC-101 stops the division of the cancer cell, increases free radicals (e.g. ROS) and inhibits the MTH1 enzyme, an enzyme that cleanses oxygen-damaged DNA building blocks in the cancer cell. This means that the cancer cell can no longer repair the DNA and oxygen damage that occurs specifically in cancer cells. The cancer cell dies, and the tumour cannot grow. The healthy cells remain primarily unaffected (as they have limited DNA damage and therefore no need to repair it).
The development of OXC-101 is based on many years of research at Helleday lab at the Karolinska Institutet and in collaboration with academic groups in Sweden and world-wide.
What are the differences between a PARP inhibitor and OXC-101?
Both PARP inhibitors and OXC-101 target the DDR and repair pathways. PARP inhibitors target the protein PARP while OXC-101 targets the protein MTH1.
PARP inhibitors work in homologous recombination defective cancers mutated in the tumour suppressor BReast CAncer (BRCA) genes responsible for familial breast and ovarian cancer, making PARP inhibitors cancer specific and only effective in a particular type of cancer cells.
To date, no specific mutated tumour suppressor gene or oncogene have been identified to explain cancer cells sensitivity to OXC-101. When a healthy cell turns into a cancer cell, it upregulates proteins required to repair DNA that then become essential in cancer cells but not in normal cells. The MTH1 protein is upregulated in many cancers. OXC-101 has the ability to specifically block cancer cells in mitosis and cause incorporation of oxidative DNA damage to cancer cells by inhibition of MTH1 and disturbing tubulin polymerization. Therefore, OXC-101 is able to introduce toxic DNA damage to many different types of cancers.
Like PARP inhibitors OXC-101 is well tolerated and orally bioavailable in tablet form.
OGG1 inhibitor for treatment of inflammation and fibrosis
The development of the OGG1 inhibitor is also based on the DDR concept. The aim is to treat inflammation and fibrosis by stopping pro-inflammatory signaling. Potential indications include idiopathic pulmonary fibrosis (IPF), sepsis and ARDS.
In inflammation and fibrosis, the tissue is exposed to oxidative stress (e.g. reactive oxygen species (ROS), which causes oxidative damage to DNA. The protein OGG1 binds to these damaged bases and activates a pro-inflammatory response, which in turn causes inflammation and fibrosis. Oxcia’s OGG1 inhibitor stops the inflammatory response as well as the fibrosis production and hence arresting the disease.
The development of OGG1 inhibitors is based on many years of research at Helleday lab at the Karolinska Institutet and in collaboration with academic groups in Sweden and world-wide. A proof of concept has been demonstrated in disease models of acute lung inflammation, acute and chronic pulmonary fibrosis.