ScienceBLOCKING TUMOUR EVOLUTION
Artios is committed to developing new precision medicines for treating cancers with high unmet need. We believe that targeting the DNA damage response (DDR) has the potential to provide novel, life-extending therapies without the risk of major side-effects.
All cells are subject to continuous DNA damage caused by exogenous and endogenous sources which must be repaired for the cells to survive as well as to avoid propagating potentially tumourigenic mutations. The range of processes through which cells sense, signal and repair DNA damage is termed the DDR.
Development of cancer cells is driven by genomic instability and is dependent on the misregulation or dampening of the DDR. However, too much DNA damage is incompatible with life and so reducing DNA repair capacity in cancer cells also causes an increased dependency on the remaining processes for survival. Thus, cancer cells with defective DDR are susceptible to targeted DNA repair inhibitors. Exploiting this weakness, Artios has built a world-class platform for developing novel inhibitors of specific DNA repair enzymes that can be used as either monotherapy or in combination with other agents within predictable, identifiable, DDR-defective tumour populations.
Targeting the DDR explained:
Cancer cells may start to use alternative or reactivated DDR pathways, leading to resistance to treatment. This kind of resistance can occur to many known DNA damaging agents and new DDR inhibitors like PARP inhibitors. As such, identifying other potential targets in the DDR processes could have significant impact on treating cancers in the future – both through use as a single-agent, and in-combination approaches designed to limit resistance.
Working with its collaborators, Artios is drugging novel protein classes across a range of DDR pathways. Artios has in-licensed two lead programmes from Cancer Research Technology, 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.
Pol Theta (Polθ)
DNA polymerase theta (Polθ) is a critical component of the Polθ alt-EJ pathway, also termed the micro-homology mediated end joining (MMEJ) pathway, involved in DNA 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.
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 the first-in-human clinical study targeted in 2021.
In 2019 Artios licensed a preclinical stage ATR inhibitor from the MD Anderson Cancer Centre in collaboration with ShangPharma Innovation.
ATR is an important signalling protein responding to replication stress and DNA double-strand breaks. Through inhibition of ATR, tumours bearing an ATM deficiency can be selectively killed through a concept known as synthetic lethality. High levels of ATM mutations and protein loss have been characterised across many different tumour types, creating a large opportunity for ATR inhibitors. ATR inhibition has also been shown to be synthetic lethal with a range of other genetic backgrounds broadening the opportunity further. Combinations of ATR inhibitors with PARP inhibition and ionising radiation has also been proposed.
Artios is collaborating with Masaryk University in the Czech Republic on the discovery of small molecules targeting DNA nucleases involved in the DDR. DNA nucleases are key enzymes responsible for processing DNA following damage. Nucleases are one of the first enzyme mediators recruited to the site of DNA damage and play crucial roles in various DDR pathways ensuring the 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 DNA repair processes which become reliant on alternative DDR pathways 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.