Science
More than 2 million cases of breast and ovarian cancer are diagnosed worldwide each year, causing the death of approximately 700,000 women. Over half of these cancers exhibit defects in DNA repair through homologous recombination (HR), most often due to mutations in the BRCA1 or BRCA2 genes.
Our science is built on a differentiated understanding of DNA repair biology and its therapeutic vulnerabilities. We focus on those cancers characterized by homologous recombination deficiency (HRD) where the DNA repair mechanism is impaired and forces tumor cells to rely on alternative pathways for survival.
While the introduction of PARP inhibitors (PARPi) has transformed the treatment of HRD cancers, at least 40% of patients do not respond, while around 50% of initially sensitive cases develop acquired resistance. Currently, no therapies are available to treat these chemoresistant tumors, significantly increasing patient mortality. This resistance and incomplete responses highlight the need for next-generation synthetic lethality approaches that exploit additional DNA repair vulnerabilities.
About HRD
Our DNA is constantly damaged. The body naturally repairs DNA damage through multiple pathways, including a process called homologous recombination.
Homologous Recombination Deficiency (HRD) arises when the homologous recombination DNA repair pathway is disrupted, leading tumor cells to depend on alternative and error-prone repair mechanisms. As a result, HRD-positive tumors become particularly vulnerable to therapies that target these compensatory repair pathways.
A New Synthetic Lethality Mechanism
In HRD-based tumors, uracil misincorporation into DNA creates a latent vulnerability. Unguard’s approach leverages this biology through novel synthetic lethality mechanisms to selectively induce tumor cell death, including in HRD cancers resistant to PARP inhibitors (PARPi), such as in breast, ovarian, and pancreatic tumors. Unlike current therapies, Unguard’s approach targets critical components of the uracil metabolism and excision pathway, selectively inducing cancer cell death in both PARPi-naive and PARPi-resistant tumors while sparing healthy tissues. We have developed first-in-class inhibitors of key enzymes involved in the uracil metabolism with exceptional potency and over 10,000-fold selectivity compared with closely related enzymes in the same family.