Tumor Organoids for Therapeutic Discovery and Personalized Medicine
Recorded On: 02/07/2018
The past decade has seen a revolution in developing 3D tissue models of organ function, anatomy, and disease which can be employed for markedly improved drug screening approaches. These models are referred to as organoid, organotypic, or spheroid and these terms are used interchangeably within the literature. Organoids are defined by their ability to mimic in vivo organ function and/or disease, they can be engineered with multiple cell types and microenvironment components, and organoids have the distinct ability to self-assemble. Like organoids, tumor organoids mimic in vivo tumor biology and recapitulate key interactions between extracellular matrix (ECM) molecules and tumor cell receptors that initiate signaling events regulating and promoting cancer. Tumor organoids prove to be very useful for modeling epithelial-mesenchymal transition (EMT), a reversible process that allows adherent epithelial cells to undergo morphological changes acquiring the motile mesenchymal cell phenotype. This phenotypic plasticity is essential for human and animal body development and wound healing, allowing cells to shed from the epithelium and invade and migrate through the microenvironment to specific locations where mesenchymal cells differentiate or induce differentiation of other cells into specialized cell types and stem cells to produce tissues, organs and bones. However, aberrant EMT is linked as a major driving force in the pathology of the most prominent human diseases: fibrosis, cardiovascular disease, inflammatory disease, eye disease, and cancer progression and metastasis. Therefore, drug discovery targeting EMT has become an attractive strategy towards more effective therapies, particularly for the treatment malignant cancers. This presentation will discuss our recent innovative tumor organoid models of various cancers, which we have engineered for 3D HCS drug discovery targeting EMT. Our tumor organoid models feature an innovative dual fluorescent biomarker reporter of EMT that can effectively track the forward and reverse EMT transition in live tumor organoids. Moreover, we will discuss hit confirmation approaches and secondary assays used to validate compounds that specifically modulate or reverse EMT. Finally, we will discuss our most recent approaches to develop patient derived tumor organoid (PDTO) models suitable for high-content analysis and screening towards achieving the goal of personalized medicine in cancer.
University of Colorado Anschutz Medical Campus
Dr. LaBarbera is an associate professor of drug discovery and medicinal chemistry at the University of Colorado Anschutz Medical Campus. He received his PhD from Arizona State University in organic and medicinal chemistry focused on cancer drug design and development. He completed a NIH National Research Service Award postdoctoral training fellowship award focused on multidisciplinary cancer research. Dr. LaBarbera’s laboratory is engaged in preclinical drug discovery and development aimed at translating effective therapies targeting cancer, diabetes, and microbial infection. A major focus of his research is the molecular and cancer biology controlling epithelial-mesenchymal transition (EMT) and the
identification of novel therapeutics that specifically target these mechanisms. Dr. LaBarbera's laboratory has developed pioneering approaches to HTS/HCS drug discovery using 3D tumor organoids and we are applying our innovative approaches to develop patient derived tumor organoid models for drug discovery and personalized medicine.