DNA Damage Response (DDR) Inhibitors
Healthy tissues rely on the DNA damage response (DDR) to protect them from DNA lesions that occur within cells on a continuous basis. The DDR prevents DNA damage from accumulating to toxic levels and is required both for normal cell survival and to prevent cancer-causing mutations.
Targeting the DDR in Cancer
Loss of DDR Pathways: Synthetic Lethality
DDR Pathway Dependencies eg, ALT
Tumor cells, however, require an elevated level of DNA mutations for disease progression and switch off DDR components early in their evolution. Although this promotes cancer development, it also makes cancer cells very reliant on remaining DDR pathways to keep DNA damage below levels that cause cell death. This delicate balance makes tumor cells much more vulnerable than normal cells to inhibitors of DDR proteins. In this way, by targeting selective DDR processes, our technology aims to kill cancerous cells and treat malignant disease while leaving healthy cells intact.
Similarly, rewiring of the DDR can cause resistance to DNA-damaging cancer therapeutics as well as targeted DDR inhibitors, such as PARP inhibitors. By understanding these processes, we develop novel medicines that can both synergize with these agents and in some cases overcome or prevent emerging drug resistance.
In addition, inhibiting DDR can cause specific types of aberrant DNA structures that generate a signal to the host immune system. Combining DDR inhibitors with immuno-oncology drugs may broaden their utility and effectiveness.
Our platform aims to target the DDR pathways with a multifaceted approach, exploiting the full range of therapeutic opportunities, including:
- Developing inhibitors with monotherapy potential by exploiting tumor vulnerabilities
- Overcoming acquired and de novo resistance to existing DDR-based therapies, primarily poly (ADP-ribose) polymerase (PARP) inhibitors
- Supercharging existing DNA targeted treatments through combination
- Expanding the reach of the immune system to detect cancer
Despite significant advances in oncology therapeutics, DNA-damaging modalities, such as chemotherapy and radiation therapy continue to be the most used treatment strategies across a wide range of cancer types. Unfortunately, these treatments come with limitations and a substantial proportion of cancers either fail to respond or acquire resistance over time.
Current DNA-damaging therapies are toxic to normal tissue
An inability to distinguish between cancerous and normal tissue yields toxicity, limits ability to dose, and compromises efficacy
Resistance to current anticancer agents, including PARP inhibitors
Up to 50% of patients with BRCA-deficient tumors fail to respond to PARP inhibition, the standard of care in many advanced cancers. Those who initially respond will eventually develop acquired resistance and the treatment will ultimately fail
Limited ability to reach the immune system
A substantial portion of malignant disease is not amenable to immunotherapy, a strategy that has been proven to be highly effective in treating select cancers
Dependence on DDR-driven processes
In approximately 10% to 15% of all tumors, telomeres—specialized structures that protect chromosome ends from progressive degradation—are extended through the DDR-driven ALT pathway and are able to achieve replicative immortality. Many ALT-positive tumors are associated with poor prognosis and have a lack of targeted therapies
Our portfolio exploits the totality of the DDR to address cancers with significant unmet needs.See Our Pipeline
We currently have two agents in clinical trials; ART0380 and ART4215
The clinical trial of the ATR (Ataxia telangiectasia and Rad3-related kinase) inhibitor is an open-label, multi-center, Phase I/IIa study designed to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of ART0380 as a monotherapy and in combination with gemcitabine in patients with advanced or metastatic solid cancers. The study will enroll up to 180 patients and will be conducted at multiple oncology centers across the USA and Europe. ART0380 is a new investigational medicinal product that is a potent and selective inhibitor of ATR. ATR is an important signaling protein in the cellular DNA damage response to replication stress and DNA double-strand breaks that occur as cells multiply. ART0380 is being developed as an oral anti-cancer agent for the treatment of patients with cancers harboring defects in DNA repair and in combination with agents including established and novel agents that cause DNA damage and/or suppress a cancer’s ability to repair DNA damage.
For more information, please click on the link: https://clinicaltrials.gov/ct2/show/NCT04657068
ART4215 (Pol Theta)
The open label, multi-center study will assess the safety, tolerability, pharmacokinetics, and clinical activity of ART4215 administered orally as a monotherapy and in combination with other anticancer medicines in patients with advanced or metastatic solid tumors. The study will enroll up to 206 patients and will be conducted at multiple oncology centers across the USA and Europe. ART4215 is the first selective, orally bioavailable, small molecule inhibitor of the Polθ polymerase domain to enter the clinic. Polθ, a DNA polymerase, is involved in the DNA double strand break repair process of microhomology mediated end joining (MMEJ) that is overexpressed in many tumors and found in low levels in healthy tissue. Extensive preclinical studies have demonstrated that ART4215 has broad potential clinical utility, as described in Artios’s recent Nature Communications publication, Zatreanu et al., 2021.
For more information, please click on the link: https://clinicaltrials.gov/ct2/show/NCT04991480