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;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.
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.
|Basham, Kaitlin J; Leonard, Christopher J; Kieffer, Collin et al. (2015) Dioxin exposure blocks lactation through a direct effect on mammary epithelial cells mediated by the aryl hydrocarbon receptor repressor. Toxicol Sci 143:36-45|
|Gibbons, Joseph B; Salvant, Justin M; Vaden, Rachel M et al. (2015) Synthesis of Naamidine A and Selective Access to N(2)-Acyl-2-aminoimidazole Analogues. J Org Chem 80:10076-85|
|Basham, Kaitlin J; Bhonde, Vasudev R; Kieffer, Collin et al. (2014) Bis-aryloxadiazoles as effective activators of the aryl hydrocarbon receptor. Bioorg Med Chem Lett 24:2473-6|
|Vaden, Rachel M; Gligorich, Keith M; Jana, Ranjan et al. (2014) 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. Breast Cancer Res 16:472|
|DeRose, Yoko S; Gligorich, Keith M; Wang, Guoying et al. (2013) Patient-derived models of human breast cancer: protocols for in vitro and in vivo applications in tumor biology and translational medicine. Curr Protoc Pharmacol Chapter 14:Unit14.23|
|Gligorich, Keith M; Vaden, Rachel M; Shelton, Dawne N et al. (2013) Development of a screen to identify selective small molecules active against patient-derived metastatic and chemoresistant breast cancer cells. Breast Cancer Res 15:R58|
|Basham, Kaitlin J; Kieffer, Collin; Shelton, Dawne N et al. (2013) Chemical genetic screen reveals a role for desmosomal adhesion in mammary branching morphogenesis. J Biol Chem 288:2261-70|
|Pathak, Tejas P; Osiak, Jaroslaw G; Vaden, Rachel M et al. (2012) Synthesis and Preliminary Biological Study of Bisindolylmethanes Accessed by an Acid-Catalyzed Hydroarylation of Vinylindoles. Tetrahedron 68:5203-5208|
|Smith, Brittni A; Welm, Alana L; Welm, Bryan E (2012) On the shoulders of giants: a historical perspective of unique experimental methods in mammary gland research. Semin Cell Dev Biol 23:583-90|
|Lum, David H; Matsen, Cindy; Welm, Alana L et al. (2012) Overview of human primary tumorgraft models: comparisons with traditional oncology preclinical models and the clinical relevance and utility of primary tumorgrafts in basic and translational oncology research. Curr Protoc Pharmacol Chapter 14:Unit 14.22|
Showing the most recent 10 out of 17 publications