Identification of Novel Cancer Selective Compounds in 3D Tumor Organoid Assays

在 3D 肿瘤类器官检测中鉴定新型癌症选择性化合物

• 批准号: 8278689
• 负责人: MATTHEW S SIGMAN
• 金额: $ 30.29万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278689
• 关键词: Affect; American Cancer Society; Antineoplastic Agents; Apoptosis; Biological; Biological Assay; Biological Process; Biological Response Modifier Therapy; Breast Cancer Cell; Breast Cancer Treatment; Cancer Etiology; Cell Cycle Arrest; Cessation of life; Characteristics; Chemicals; Clinical; Complex; DNA Damage; Development; Disease; Dose; Epithelial Cells; Evaluation; Exhibits; Future; Genetic Variation; Goals; Homeostasis; Human; Individual; Intervention; Malignant Neoplasms; Mammary gland; Mediating; Methods; Molecular; Molecular Profiling; Molecular Target; Mus; Nature; Normal Cell; Organoids; Pathway interactions; Patients; Pharmaceutical Preparations; Primary Neoplasm; Regimen; Research; Schedule; Signal Pathway; Structure; Structure-Activity Relationship; Therapeutic; Tumor Tissue; Woman; analog; cancer type; cytotoxicity; design; drug discovery; effective therapy; established cell line; human tissue; in vitro Model; killings; malignant breast neoplasm; mammary gland development; neoplastic cell; novel; pharmacophore; small molecule; small molecule libraries; statistics; therapeutic development; tumor; tumor progression

ABSTRACT Breast cancer is a pathologically and genetically heterogeneous disease, reflecting diverse signaling pathways responsible for cancer progression. In vitro models of breast cancer must integrate the complex nature of the disease with culturing methods that closely mimic different clinical types of cancer seen in patients. In 2007, there were more than 178,000 new cases and 40,000 deaths from breast cancer, making it the second leading cause of cancer related death in women and these statistics suggest the need for the development of more effective treatments (American Cancer Society; http://www.cancer.org). Over the past ten years, most advances in chemotherapeutic treatment of breast cancer have involved the optimization of doses and scheduling of standard therapeutics. Several new targeted therapies and biologics have been approved for the treatment of breast cancer; however, many cancers do not respond to or recur even with the ideal drug regimens. Because specific molecular signatures can classify breast cancer into multiple subtypes with distinct clinical characteristics, we can now pursue the development of therapeutics with selectiveness against each individual tumor type. Thus, breast cancer must be considered a multifaceted disease with each subtype offering unique opportunities for chemotherapeutic intervention. We have developed a novel anti-cancer drug discovery screen that encompasses the cellular and genetic diversity of breast cancer. This screen is unique in that it uses murine primary tumor organoids molecularly classified as similar to actual breast cancer subtypes observed in patients. The subtype-specific tumor organoids are screened against a chemical library to identify novel small-molecule anti-cancer compounds. In parallel, the compounds are also screened for their effect on normal primary organoids. Using this screen, we identified a novel small molecule, C-6, that kills primary tumor tissue derived from both mice and humans, and subsequent structure activity relationship analyses revealed the basic pharmacophore of the molecule. Importantly, C-6 exhibits selective cytotoxicity against both basal-like and luminal cancer organoids isolated from mice and human patients, but not organoids isolated from normal mice and human tissue. This compound is structurally novel and may kill tumor cells through a unique mechanism of action. We observed that C-6 delays epithelial cell apoptosis within the lumens of normal mammary organoids; however, it did not affect branching morphogenesis of mammary organoids. The selective cytotoxicity of C-6 combined with its minimal affect on normal biological processes suggests that this compound targets a molecular pathway vital to the homeostasis of breast cancer cells. Thus, the objectives outlined in this proposal will establish the optimal pharmacophore structure of C-6, identify the molecular target(s), and evaluate its biological effects in both tumor and normal cells.

抽象的 乳腺癌是一种病理和遗传性异构疾病，反映了各种信号通路 负责癌症进展。乳腺癌的体外模型必须整合 具有培养方法的疾病，这些方法紧密模仿患者中观察到的癌症的不同临床类型。 2007年 乳腺癌有超过178,000例新病例和40,000例死亡，使其成为第二大领先 妇女和这些统计数据与癌症相关的死亡原因表明需要发展更多 有效治疗（美国癌症协会； http://www.cancer.org）。在过去的十年中，大多数进步 在化学治疗乳腺癌中，涉及优化剂量和调度 标准治疗学。几种新的靶向疗法和生物制剂已被批准用于治疗 乳腺癌;但是，即使使用理想的药物方案，许多癌症也不会反应或复发。因为 特定的分子特征可以将乳腺癌分类为具有不同临床的多种亚型 特征，我们现在可以选择对每个人的选择性的疗法发展 肿瘤类型。因此，必须将乳腺癌视为一种多面性疾病，每种亚型提供独特的疾病 化学治疗干预的机会。 我们已经开发了一种新型的抗癌药物发现筛查，该筛查涵盖了细胞和遗传 乳腺癌的多样性。该屏幕是独一无二的 分类为类似于患者观察到的实际乳腺癌亚型。亚型特异性肿瘤器官 对化学文库进行筛选，以鉴定新型的小分子抗癌化合物。并行， 还筛选了它们对正常原代器官的影响。使用此屏幕，我们确定了 新型的小分子C-6，杀死源自小鼠和人类的原发性肿瘤组织，随后 结构活动关系分析揭示了该分子的基本药效团。重要的是，C-6 针对从小鼠分离的基础样和腔内癌器官表现出选择性细胞毒性 人类患者，但不是从正常小鼠和人体组织中分离出来的器官。该化合物在结构上是 新颖，可能通过独特的作用机理杀死肿瘤细胞。我们观察到C-6延迟上皮 正常乳腺癌的流明内的细胞凋亡；但是，它不会影响分支 乳腺癌的形态发生。 C-6的选择性细胞毒性结合其最小的影响 正常的生物学过程表明，该化合物的目标是一种分子途径，对 乳腺癌细胞。因此，本提案中概述的目标将建立最佳药效团 C-6的结构，识别分子靶标，并评估其在肿瘤和正常的生物学作用 细胞。