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

PREVENT Cancer临床前药物开发计划：临床前疗效和中间终点生物标志物——靶向PARP通路预防乳腺癌

• 批准号: 10629488
• 负责人: Powel Brown
• 金额: $ 112.11万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10629488
• 关键词: Age; Apoptosis; BRCA mutations; BRCA1 Mutation; BRCA1 gene; Biological Markers; Breast Cancer Prevention; Breast Cancer Risk Factor; Cell Proliferation; Cells; Chemoprevention; Chemopreventive Agent; Clinic; Clinical; DNA; DNA Damage; DNA Repair; DNA Repair Pathway; DNA Sequence Alteration; DNA biosynthesis; Development; Dose; Double Strand Break Repair; Enzymes; Epidermal Growth Factor Receptor; Estrogen Antagonists; Estrogen Receptors; Genetically Engineered Mouse; Genomic Instability; Goals; Hereditary Breast Carcinoma; Human; Individual; Intercept; Intervention; Isogeneic graft; Lead; Lesion; Malignant Neoplasms; Modeling; Mutate; Mutation; Noninfiltrating Intraductal Carcinoma; Normal Cell; Outcome; Pathway interactions; Poly(ADP-ribose) Polymerases; Preclinical Drug Development; Preventive; Progesterone Receptors; Prognosis; Program Development; Proteins; Role; Safety; Schedule; Single Strand Break Repair; TP53 gene; Testing; Therapeutic; Woman; brca gene; cancer cell; cancer therapy; chemotherapy; clinically relevant; high risk; homologous recombination; inhibitor; malignant breast neoplasm; mutation carrier; neoplastic cell; novel; preclinical efficacy; premalignant; prevent; preventive intervention; protein function; repaired; targeted biomarker; triple-negative invasive breast carcinoma; tumor

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.

患有雌激素受体（ER），孕酮受体（PR）和人表皮生长因子的女性 当前是受体2（HER2）阴性乳腺癌或“三阴性乳腺癌”（TNBC） 用化学疗法治疗。 TNBC是高度侵略性的肿瘤，即使 用化学疗法治疗，通常具有p53和BRCA1突变。另外，BRCA中的突变 基因是遗传性乳腺癌的最常见原因。 TNBC在年轻时折磨女性 比其他乳腺癌，与临床结果更差有关。目前存在 预防性干预策略对患有TNBC高风险的受试者或拦截 癌前病变（三阴性DCI）以防止其发展为癌症。几个FDAAPPRAD 存在用于预防乳腺癌的抗雌激素。但是，他们的效率可能是 有限的BRCA1突变载体。因此，防止TNBC在高风险中的发展 个人很重要。 聚ADP-核糖聚合酶（PARP）酶和BRCA1/2蛋白都在DNA修复中起作用。在 正常细胞，PARP酶的作用是修复单链断裂（SSB）（SSB） DNA复制或通过DNA损伤。 BRCA1/2蛋白的作用是修复双链断裂 （DSB）通过称为同源重组（HR）的修复机制在DNA中。在BRCA突变的细胞中，HR 有缺陷。除其他精确的修复外，这些细胞还取决于PARP酶 机制，以维持DNA修复和细胞增殖。癌细胞过度依赖这些替代方案 维修机制可以导致遗传突变的积累，促进形成和 肿瘤细胞的存活。已经表明，PARP蛋白是该DNA的重要组成部分 修复途径和阻断PARP蛋白功能会导致与癌症相关的BRCA1/2的细胞 死亡的突变。最近，PARP抑制剂已作为承诺的代理人出现 通过合成致死性患有BRCA1突变的癌症。研究表明，BRCA1缺陷型 细胞对PARP抑制剂高度敏感，因此，它们由于 基因组不稳定性增加。已经开发了几种PARP抑制剂，并正在测试 治疗目的的诊所。因此，患有BRCA1突变的妇女的风险增加 乳腺癌的发展将受益于PARP抑制剂的有效化学预防。 该项目的总体目标是确定有希望的新型PARP抑制剂的效率 在基因工程小鼠（GEM）模型中预防BRCA1相关的乳腺癌。