Objetivo
Breast and ovarian carcinomas are aggressive tumors with few treatment options and high recurrence rates. About half of these tumors shows defects in homologous recombination (HR) repair. Defect in HR (HRD) causes genomic instability and dependence on poly (ADP-ribose) polymerase (PARP)-mediated DNA repair. As a result, PARP inhibitors (PARPi) are now widely used for the treatment of these tumors. However, resistance to PARPi is emerging as the major obstacle to clinical effectiveness. Consequently, many patients run out of treatment options and succumb to the disease. This prompts the development of novel therapeutics.
Beyond its well-known functions in regulating metabolic processes, we discovered that enzyme X maintains genomic stability in HRD cells. Enzyme X inhibition kills HRD cells without affecting HR-proficient cell survival pointing to a synthetic lethal interaction between enzyme X and HR genes. Moreover, we showed that enzyme X functions independently of PARP in the survival of HRD cells. As a result, enzyme X inhibition kills naive and PARPi-resistant HRD cells. Thus, targeting this enzyme has the potential to provide a new cure for HRD tumors.
No inhibitors nor patents on enzyme X exist. HRD tumors being a major economic burden worldwide, developing enzyme X inhibitors has high innovation and financial reward potentials. By screening chemical libraries, we identified a top hit inhibitor of enzyme X. Our TargetBRCA project aims at improving potency and specificity of our molecule inhibitor and provides a proof-of-concept on its use as a cure for HRD tumors. TargetBRCA relies on complementary teams of crystallographers, chemists and specialists of HRD tumor biology and associates structure-aided drug design with the use of preclinical in vivo models. Our ultimate goal is to foster the development of a clinical-grade inhibitor to be used for the treatment of HRD tumors either by licensing and co-development partnerships, or by the creation of a start-up.
Ámbito científico
Palabras clave
Programa(s)
- HORIZON.1.1 - European Research Council (ERC) Main Programme
Régimen de financiación
HORIZON-ERC-POC - HORIZON ERC Proof of Concept GrantsInstitución de acogida
75231 Paris
Francia