Abstract 3194: Reverse engineering the interplay between multiple myeloma and microenvironment
Authors: Khin Zayar , Hazlehurst Lori , Shain Kenneth , Gillies Robert , Gatenby Robert , Silva Ariosto S. 
Published: August 2012

Abstract
We propose an innovative approach to build predictive computational models of chemotherapy response for multiple myeloma (MM) patients. The innovation of this work resides in the use of microfluidics to establish gradients to mimic the heterogeneity of the tumor microenvironment (bone marrow, BM) and detailed computational models to map the cancer cells response into the geometry of the BM. MM is a complex hematologic malignancy, where a phenotypically heterogeneous population of malignant plasma cells proliferates uncontrollably throughout the environmentally heterogeneous microenvironment of the BM. It is known that the BM microenvironment confers opportunities for MM cells to survive treatment by soluble factors or adhesion and that these are among the main causes of minimal residual disease and patient relapse. In this work we explore a combination of microfluidics and computational models to characterize the response of chemo-sensitive and chemoresistant human MM cell lines (HMCL) to different drug combinations and protocols in the microenvironment of the BM. First we cultured fluorescent HMCLs in microfluidics under stable gradients of chemotherapy, oxygen, glucose and pH, in single cell suspension or in co-culture with stromal cell lines. Using live imaging we quantified replication and death in two dimensions (time of exposure and drug concentration). We built cell-line specific computational models of dose response based on the extracellular cues, and integrated these models into a previously published spatial computational model of the BM. We used these models to simulate the growth and response to different drug combinations in hypothetical patients. To our knowledge, this is the first time that a high-throughput model of assessment of drug response in a controlled reconstruction of the tumor microenvironment is proposed for MM. Our in vitro experiments allowed the quantization of cell death, quiescence and proliferation across time, which is not possible in regular dose response assays. The use of a stable drug gradient also allowed us to observe migration of live cells from areas of low to high drug concentration, being a putative mechanism for evolution of drug resistance. The computational model built from the in vitro multi-dimensional data was capable of reproducing different levels of therapy response, ranging from complete to refractory, with a complex signature of minimum residual disease combining phenotypic and environmental resistance. Our simulations also proposed optimum regimens of drug combination which will be explored in pre-clinical models. This proof of principle, that such approach may be used to build models of therapy in complex microenvironments with unprecedented levels of details, has the potential of becoming a translational tool for individual patient response. Each experimental assay required ∼18K cells, making this approach feasible for MM patient cell aspirates.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3194. doi:1538-7445.AM2012-3194