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.

具有雌激素受体 (ER)、孕激素受体 (PR) 和人类表皮生长因子的女性 受体 2 (HER2) 阴性乳腺癌，或“三阴性乳腺癌”(TNBC)，目前 TNBC 是一种高度侵袭性的肿瘤，即使经过化疗，其预后也很差。 接受过化疗，并且经常有 p53 和 BRCA1 突变，还有 BRCA 突变。 TNBC 基因是导致年轻女性罹患遗传性乳腺癌的最常见原因。 与其他乳腺癌相比，其临床结果较差。 针对发生 TNBC 或拦截高风险受试者的预防性干预策略 FDA 批准了几种用于预防癌前病变（三阴性 DCIS）的药物。 存在用于预防乳腺癌的抗雌激素药物；然而，它们的功效可能是有限的。 因此，仅限于 BRCA1 突变携带者，防止高危人群发生 TNBC。 个人很重要。 聚 ADP 核糖聚合酶 (PARP) 和 BRCA1/2 两种蛋白均在 DNA 修复中发挥作用。 在正常细胞中，PARP 酶的作用是修复 DNA 生成过程中的单链断裂 (SSB) DNA 复制或 DNA 损伤 BRCA1/2 蛋白的作用是修复双链断裂。 DNA 中的 DSB 通过称为同源重组 (HR) 的修复机制在 BRCA 突变细胞中形成 HR。 除了其他不太准确的修复之外，这些细胞变得依赖于 PARP 酶。 机制，以维持 DNA 修复和细胞增殖。癌细胞对这些替代品的过度依赖。 修复机制可以导致基因突变的积累，促进形成和 研究表明，PARP 蛋白是该 DNA 的重要组成部分。 修复途径，阻断 PARP 蛋白功能可能导致细胞出现癌症相关 BRCA1/2 最近，PARP 抑制剂已成为治疗癌症的有希望的药物。 具有 BRCA1 突变的癌症通过合成致死率 研究表明，BRCA1 缺陷。 细胞对 PARP 抑制剂高度敏感，因此，它们会发生凋亡，因为 增加的基因组不稳定性已被开发并正在测试中。 因此，携带 BRCA1 突变的女性患乳腺癌的风险增加。 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前景的新型 PARP 抑制剂的功效 在基因工程小鼠 (GEM) 模型中预防 BRCA1 相关乳腺癌。