权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
8467688
负责人：
MATTHEW S SIGMAN
金额：
$ 28.47万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2015-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8467688
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

项目摘要

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.

摘要

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Synthesis and Preliminary Biological Study of Bisindolylmethanes Accessed by an Acid-Catalyzed Hydroarylation of Vinylindoles.

DOI：
10.1016/j.tet.2012.03.075
发表时间：
2012-07-01
期刊：
Tetrahedron
影响因子：
2.1
作者：
Pathak TP;Osiak JG;Vaden RM;Welm BE;Sigman MS
通讯作者：
Sigman MS

The small molecule C-6 is selectively cytotoxic against breast cancer cells and its biological action is characterized by mitochondrial defects and endoplasmic reticulum stress.

小分子C-6对乳腺癌细胞具有选择性细胞毒性，其生物学作用以线粒体缺陷和内质网应激为特征。

DOI：
10.1186/s13058-014-0472-0
发表时间：
2014
期刊：
Breast cancer research : BCR
影响因子：
0
作者：
Vaden,RachelM;Gligorich,KeithM;Jana,Ranjan;Sigman,MatthewS;Welm,BryanE
通讯作者：
Welm,BryanE

Synthesis of Naamidine A and Selective Access to N(2)-Acyl-2-aminoimidazole Analogues.

DOI：
10.1021/acs.joc.5b01703
发表时间：
2015-10-16
期刊：
JOURNAL OF ORGANIC CHEMISTRY
影响因子：
3.6
作者：
Gibbons, Joseph B.;Salyant, Justin M.;Vaden, Rachel M.;Kwon, Ki-Hyeok;Welm, Bryan E.;Looper, Ryan E.
通讯作者：
Looper, Ryan E.

Synthesis of the reported structures for kealiinines B and C.