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

雌激素受体(ER)、孕激素受体(PR)和人表皮生长因子的女性 受体2(HER2)阴性的乳腺癌，或三阴性乳腺癌(TNBC)，目前 接受了化疗。TNBCs是高度侵袭性的肿瘤，预后非常差，即使 接受化疗，并经常出现P53和BRCA1突变。此外，BRCA的突变 基因是遗传性乳腺癌最常见的原因。TNBC困扰女性的年龄较小 与其他乳腺癌相比，并与更差的临床结果有关。目前有一个稀缺的 针对罹患TNBC或截获该病的高危人群的预防性干预策略 癌前病变(三阴性DCIS)，以防止其进展为癌症。几个FDA批准了 抗雌激素药物可以预防乳腺癌；然而，它们的疗效可能是 仅限于BRCA1突变携带者。因此，防止TNBC在高风险中发展 个人很重要。 多聚ADP核糖聚合酶(PARP)和BRCA1/2蛋白都在DNA修复中发挥作用。在……里面 正常细胞中，PARP酶的作用是修复DNA中的单链断裂(SSB) DNA复制或DNA损伤。BRCA1/2蛋白的作用是修复双链断裂 (DSB)通过一种称为同源重组(HR)的修复机制。在BRCA突变的细胞中，HR 是有缺陷的。这些细胞变得依赖于PARP酶，以及其他不太精确的修复 机制，以维持DNA修复和细胞增殖。癌细胞过度依赖这些替代品 修复机制可以导致基因突变的积累，促进基因的形成和 肿瘤细胞的存活。研究表明，PARP蛋白是该DNA的重要组成部分 修复途径和阻断PARP蛋白功能可导致肿瘤相关BRCA1/2细胞 突变致死。最近，PARP抑制剂作为一种很有前途的药物出现在治疗高血压的药物中。 具有BRCA1突变的癌症通过合成致命性。研究表明，BRCA1缺乏 细胞对PARP抑制剂高度敏感，因此，它们会因为 增加了基因组的不稳定性。已经开发了几种PARP抑制剂，并正在进行测试 以治疗为目的的诊所。因此，携带BRCA1突变的女性患癌症的风险增加 乳腺癌的发展将受益于PARP抑制剂的有效化学预防。 该项目的首要目标是确定有希望的新型PARP抑制剂的疗效 在基因工程小鼠(GEM)模型中预防BRCA1相关乳腺癌。

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.