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: 8082794
• 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/8082794
• 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; Health; 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to determine the optimal pharmacophore structure of a novel anti breast cancer compound called C-6, identify its molecular target, and evaluate its biological activity in both tumor and normal cells using a novel tumor-organoid assay. Our collaborative research plan encompasses both the chemical and biological evaluation of C-6, and may identify a unique molecular pathway that selectively regulates cancer homeostasis.

描述（由申请人提供）：乳腺癌是一种病理和遗传异质性疾病，反映了导致癌症进展的不同信号通路。乳腺癌的体外模型必须将疾病的复杂性质与培养方法结合起来，以密切模拟患者中所见的不同临床类型的癌症。在2007年，有超过178，000例新病例和40，000例乳腺癌死亡，使其成为女性癌症相关死亡的第二大原因，这些统计数据表明需要开发更有效的治疗（美国癌症协会; http://www.cancer.org）。在过去的十年中，乳腺癌化疗治疗的大多数进展都涉及剂量的优化和标准治疗的时间表。一些新的靶向治疗和生物制剂已被批准用于治疗乳腺癌;然而，许多癌症即使使用理想的药物方案也没有反应或复发。由于特定的分子特征可以将乳腺癌分为具有不同临床特征的多种亚型，因此我们现在可以针对每种肿瘤类型进行选择性治疗。因此，乳腺癌必须被认为是一种多方面的疾病，每种亚型都提供了独特的化疗干预机会。我们开发了一种新的抗癌药物发现筛选，包括乳腺癌的细胞和遗传多样性。该筛选的独特之处在于它使用了在分子上分类为与患者中观察到的实际乳腺癌亚型相似的小鼠原发性肿瘤类器官。针对化学文库筛选亚型特异性肿瘤类器官，以鉴定新型小分子抗癌化合物。同时，还筛选化合物对正常初级类器官的作用。使用这个屏幕，我们确定了一种新的小分子，C-6，杀死原发性肿瘤组织来自小鼠和人类，和随后的结构活性关系分析揭示了基本药效团的分子。重要的是，C-6对从小鼠和人类患者中分离的基底样和管腔癌类器官表现出选择性细胞毒性，但对从正常小鼠和人类组织中分离的类器官则没有。该化合物结构新颖，可通过独特的作用机制杀死肿瘤细胞。我们观察到C-6延迟正常乳腺类器官腔内的上皮细胞凋亡;然而，它并不影响乳腺类器官的分支形态发生。C-6的选择性细胞毒性及其对正常生物过程的最小影响表明，这种化合物靶向对乳腺癌细胞的稳态至关重要的分子途径。因此，本提案中概述的目标将建立C-6的最佳药效团结构，鉴定分子靶标，并评估其在肿瘤和正常细胞中的生物学效应。公共卫生相关性：这项研究的目的是确定一种名为C-6的新型抗乳腺癌化合物的最佳药效团结构，确定其分子靶标，并使用新型肿瘤类器官测定法评估其在肿瘤和正常细胞中的生物活性。我们的合作研究计划包括C-6的化学和生物学评估，并可能确定一个独特的分子途径，选择性地调节癌症的稳态。