Targeting DNA Damage Response (DDR) pathways
We believe that DDR represents one of the most promising frontiers for treating solid tumors. Our insights into the cell鈥檚 ensemble of DDR pathways drive the development of new classes of DDR medicines to deliver meaningful survival benefits to patients with cancers who have limited alternative treatment options.
DNA Damage Response (DDR)
The DNA Damage Response (DDR) is a crucial protective system of an interconnected network of signaling pathways that cells use to maintain genomic integrity. By detecting and repairing DNA damage, DDR pathways help prevent the accumulation of toxic damaged DNA. Key processes of the DDR include: (1) DNA repair mechanisms 鈥� these correct DNA damage to preserve genetic information; (2) cell cycle checkpoints 鈥� these checkpoints ensure that cells do not proceed through the cell cycle with damaged DNA; and (3) programmed cell death (apoptosis) 鈥� this process eliminates cells that have irreparable DNA damage. Together, these processes help preserve the health and stability of normal cells.
Targeting Cancer Cells Through DDR
Cancer cells rely heavily on DDR repair pathways to manage DNA damage and ensure their survival. Although some DNA repair pathways become defective, cancer cells adapt by becoming increasingly dependent on alternative DDR pathways to survive, continue dividing, and drive tumor growth. Over time, these adaptations can also contribute to tumor aggressiveness and resistance to existing therapies. As shown in the figure, by targeting vulnerabilities in tumor cells and inhibiting key DDR components, cancer cells can be selectively killed while sparing normal cells.
This approach offers a promising strategy for treating cancer while addressing the limitations of traditional DNA-damaging agents like chemotherapy and radiation.
Toxicity of current DNA-damaging therapies
The 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
Approximately one-half to three-quarters of patients with BRCA-deficient tumors fail to respond to PARP inhibition, the standard of care in many advanced cancers. Those who initially respond might eventually acquire resistance
Limitations of immunotherapies
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
Our portfolio exploits the totality of the DDR to develop medicines for patients with cancers who have no or few other treatment options.
黑料福利社鈥� Approach to Targeting DDR Pathways
Our drug development programs are designed around the biological principle that cancer cells often develop defects in DDR pathways, leading them to depend on alternative DDR mechanisms to survive and proliferate. We seek to further enhance the potential efficacy of our drug candidates through rational combination strategies with known and approved DNA-damaging therapies, such as chemotherapy and radioligand therapies (RLTs), and through attaching our DDRi candidates to monoclonal antibodies to create novel antibody drug conjugates (ADCs). By leveraging mechanistically informed combinations and selecting tumor types with relevant DDR dependencies, we aim to enhance overall survival (OS), expand the therapeutic potential of our product candidates, circumvent emergent resistance mechanisms, and create opportunities across multiple cancer indications and treatment settings.
Our goal is to develop highly potent and selective treatments that maximize anti-tumor activity while maintaining a tolerability profile that supports sustained dosing, broader combination strategies, and meaningful long-term clinical benefit across diverse patient populations. We believe this approach, which is anchored in our pioneering expertise in DDR biology and chemistry, enables us to bring forward new molecules that address the critical unmet needs that first-generation DDR therapies could not fully meet.
Our current pipeline includes two small molecule drug candidates in Phase 2 development, alnodesertib and ART6043, and our ADC preclinical platform, which includes our ART21934 candidate, that employs a novel DDRi payload.