PREVENT Cancer Preclinical Drug Development Program: Preclinical Efficacy and Intermediate Endpoint Biomarkers-- Targeting the PARP Pathway for the Prevention of Breast Cancer

点击翻译按钮获取中文摘要

Women with estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2)‐negative breast cancers, or “triple‐negative breast cancer” (TNBC), are currently treated with chemotherapy. TNBCs are highly aggressive tumors that have a very poor prognosis, even if treated with chemotherapy, and often have p53 and BRCA1 mutations. Also, mutations in the BRCA gene are the most common cause of hereditary breast cancer. TNBC afflicts women at a younger age than other breast cancers and is associated with a worse clinical outcome. There is currently a paucity of preventive intervention strategies for subjects at high risk for developing TNBC or for interception of precancerous lesions (triple‐negative DCIS) to prevent their progression into cancer. Several FDAapproved antiestrogenic agents exist for breast cancer prevention; however, their efficacy may be limited for BRCA1 mutation carriers. Therefore, preventing the development of TNBC in high‐risk individuals is important. The poly ADP‐ribose polymerase (PARP) enzymes and BRCA1/2 proteins both function in DNA repair. In normal cells, the role of PARP enzymes is to repair single‐strand breaks (SSBs) in DNA generated during DNA replication or by DNA damage. The role of BRCA1/2 proteins is to repair double‐strand breaks (DSBs) in DNA via a repair mechanism called homologous recombination (HR). In BRCA‐mutated cells, HR is defective. These cells become dependent on PARP enzymes, in addition to other less accurate repair mechanisms, to maintain DNA repair and cell proliferation. Cancer cell overreliance on these alternative repair mechanisms can lead to the accumulation of genetic mutations, promoting the formation and survival of tumor cells. It has been shown that PARP proteins are important components of this DNA repair pathway and that blocking PARP protein function can cause cells with cancer‐associated BRCA1/2 mutations to die. Recently, PARP inhibitors have emerged as promising agents for the treatment of cancers with BRCA1 mutations via synthetic lethality. Studies have shown that BRCA1‐deficient cells are highly sensitive to PARP inhibitors and consequently, they undergo apoptosis because of increased genomic instability. Several PARP inhibitors have been developed and are being tested in the clinic for therapeutic purposes. Hence, women with BRCA1 mutations having an increased risk for breast cancer development would benefit from effective chemoprevention by PARP inhibitors. The overarching goal of this project is to determine the efficacy of promising novel PARP inhibitors to prevent BRCA1 associated breast cancer in a genetically engineered mouse (GEM) model.