Abstract B123: Novel high content molecular characterization and anticancer drug sensitivity profiling of more clinically relevant tumor models derived from patient primary tumors.
Authors: Nair Kesavan Praveen , Streiner Nicole , Hoffmaster Steve , Vo Martin , Broudy Thomas , Mirsaidi Cyrus , O'Connor Patrick , Anderes Kenna 
Published: June 2012

The purpose of this study is to investigate whether the chemosensitivity of patient-derived primary tumor tissue when coupled with molecular characterization provides a stronger correlation to clinical outcomes than conventional preclinical anticancer drug testing. Current strategies for developing new anticancer drugs rely heavily on preclinical testing in cancer cell lines and their derived in vivo xenograft models. A significant limitation to current preclinical testing is the use of highly passaged cancer cell lines grown on plastic. Perhaps no aspect of life in a modern molecular biology lab is more ubiquitous, or more important than cell culture. The phenotype and behavior of a cell is significantly influenced by its microenvironment and an accumulating body of evidence highlights the importance and utility of 3D culture systems to better recapitulate the in vivo growth compartment. 3D models have emerged as a powerful method to interrogate the biological activities of cancer genes and oncogenic pathways. We have developed preclinical cancer models using patient-derived primary tumor cells (PTCs) grown in 3D cultures to conduct preclinical evaluation of molecularly targeted agents, identify sensitive and resistant subpopulations and design combinations based on the heterogeneity of the disease, and then explore these findings in vivo. We conducted a retrospective study in PTCs from solid tumor indications including breast, lung and melanoma and evaluated molecular targeted agents including lapatinib (Her2/EGF), trastuzumab (Her2), erlotinib (EFF), crizotinib (ALK/c-MET) and vemurafinib (B-RAF). We utilized a range of methods (PCR, FISH, IF, western blot) to determine the genetic and molecular features of the PTCs prior to performing drug treatments. We used high content imaging to evaluate colony segmentation, morphological features, proliferative and apoptotic endpoints to identify responder and non-responder populations. Our results indicate that 3D PTC models have predictive value and enable secondary interrogation beyond single agent antiproliferative activity to better profile the antitumor activity of targeted agents. Improved preclinical models are required to advance our understanding of the molecular aberrations that underpin cancer and are critical for developing and deploying targeted therapies that will improve patients' lives. Patient-derived primary tumor cell models grown in 3D culture conditions are essential for designing and conducting hypothesis driven studies as a foundation for subsequent in vivo studies from which data can make personalized medicine decisions actionable.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr B123.