Our DDR Pipeline
Working with its collaborators, Artios has set out to identify and exploit novel protein classes across DDR pathways. Artios has in-licensed two lead programmes from CRT, which target proteins that control key aspects of DNA repair and other cellular processes.
Mechanistically, these programmes have the ability to kill cancer cells as single agents, or to sensitise cancer cells to radiotherapy and other DNA-damaging agents, including novel treatments, such as PARP inhibitors or immunotherapies.
DNA polymerase theta (Polθ) is involved in multiple processes associated with DNA repair. It is a critical component of the Polθ alt-EJ pathway; the micro-homology mediated end joining (MMEJ) DNA repair pathway involved in double-strand break repair. Polθ expression is low in normal tissues but it is up-regulated in a number of tumour types such as breast, ovarian, HNSCC and lung.
As such, Polθ inhibitors have the potential to be used in a broad range of clinical settings, specifically HR-deficient tumours such as breast and ovarian cancer, or in combination with DNA-damaging agents – chemotherapy and radiotherapy.
Our goal is to develop this programme through to the clinic, with a first-in-human clinical study targeted in 2019/20.
Our second in-licensed programme targets a protein which has been identified as a novel DNA damage response target. It is recruited to sites of DNA damage, where it is required for lesion accessibility and to facilitate DNA repair. It is frequently over-expressed in multiple tumour types, giving an opportunity for the product to be used in a broad range of clinical settings.
Artios is collaborating with Masaryk University in the Czech Republic on the development of novel cancer treatments targeting DNA nucleases involved in the DDR. DNA nucleases are key enzymes responsible for processing strands of DNA following damage. Present in all cell types, nucleases are one of the first enzyme mediators recruited to the site of DNA damage in cells and play crucial roles in various DNA repair pathways ensuring stability of the genome. Artios believes that nuclease inhibitors could have broad potential as selective treatments for a range of cancers, particularly in tumours that have defects in their DNA repair processes and are reliant on alternative DDR pathways which are mediated by nucleases. The opportunity may also exist to use nuclease inhibitors in combination with other cancer therapies, including standard of care treatments such as ionizing radiation, and potentially together with emerging therapies such as immuno-oncology treatments.
Cellular DNA undergoes a lot of damage every day, leading to various types of damage events, including single strand breaks, cross linked lesions, mismatched base pairs, or double strand chromosomal breaks. DNA damage can be caused by many different external cytotoxic agents or intra-cellular processes that lead to free radical generation.
Once DNA becomes damaged or has lesions created, a process known as the DNA Damage Response (DDR) takes place to repair the DNA or instruct the cell to die. DNA repair processes have evolved to be very effective at repairing the different types of damage.