Large Scale Pharmacological Profiling of 3D Tumor Models of Cancer Cells. Mathews-Griner, L., Zhang, X., Guha, R., McKnight, C., Goldlust, I., Lal, M., Wilson, K., Michael, S., Titus, S., Shinn, P., Thomas, C., & Ferrer, M. J.~Biomol.~Screen., 2016. abstract bibtex The discovery of chemotherapeutic agents for the treatment of cancer mostly uses cell proliferation assays on plastic surfaces, referred to as 2D monolayer growth assays. Compounds identified using 2D cell proliferation assays do often fail to advance during clinical development because these assays do not reproduce the cellular complexity of tumors and their microenvironment in vivo. The use of three dimensional (3D) cellular systems has been explored as more predictive in vitro tumor models for drug discovery. Small scale screens have shown that pharmacological responses tend to differ between 2D and 3D cancer cell growth models. However, the limited scope of screens using 3D models has not provided a clear delineation of the cellular pathways and processes that differentially regulate cell survival and death in the different in vitro tumor models. Here we sought to further understand the differences in pharmacological responses between cancer tumor cells grown in different conditions by profiling a large collection of 1912 chemotherapeutic agents. We compared pharmacological responses obtained from traditional 2D monolayer to the effects see in cells that were forming spheres and cells in preformed 3D spheres. The target annotation of the compound library screened enabled the identification of those key cellular pathways and processes that when modulated by drugs induced cell death in all growth conditions or selectively in the different cell growth models. In addition, we also show that many of the compounds targeting these key cellular functions can be combined to produce synergistic cytotoxic effects, which in many cases differ in the magnitude of the synergism depending on the cellular model and cell type. The results from this work provide a high throughput screening framework to profile the responses of drugs both as single agents and in pairwise combinations in the 3D sphere models of cancer cells.
@article{Mathews-Griner:2015pi,
Abstract = {The discovery of chemotherapeutic agents for the treatment of cancer mostly uses cell proliferation assays on plastic surfaces, referred to as 2D monolayer growth assays. Compounds identified using 2D cell proliferation assays do often fail to advance during clinical development because these assays do not reproduce the cellular complexity of tumors and their microenvironment in vivo. The use of three dimensional (3D) cellular systems has been explored as more predictive in vitro tumor models for drug discovery. Small scale screens have shown that pharmacological responses tend to differ between 2D and 3D cancer cell growth models. However, the limited scope of screens using 3D models has not provided a clear delineation of the cellular pathways and processes that differentially regulate cell survival and death in the different in vitro tumor models. Here we sought to further understand the differences in pharmacological responses between cancer tumor cells grown in different conditions by profiling a large collection of 1912 chemotherapeutic agents. We compared pharmacological responses obtained from traditional 2D monolayer to the effects see in cells that were forming spheres and cells in preformed 3D spheres. The target annotation of the compound library screened enabled the identification of those key cellular pathways and processes that when modulated by drugs induced cell death in all growth conditions or selectively in the different cell growth models. In addition, we also show that many of the compounds targeting these key cellular functions can be combined to produce synergistic cytotoxic effects, which in many cases differ in the magnitude of the synergism depending on the cellular model and cell type. The results from this work provide a high throughput screening framework to profile the responses of drugs both as single agents and in pairwise combinations in the 3D sphere models of cancer cells.},
Author = {Mathews-Griner, L.A. and Zhang, X. and Guha, R. and McKnight, C. and Goldlust, I.S. and Lal, M. and Wilson, K. and Michael, S. and Titus, S. and Shinn, P. and Thomas, C. and Ferrer, M.},
Date-Added = {2015-10-27 01:36:36 +0000},
Date-Modified = {2016-01-02 15:50:17 +0000},
Journal = {J.~Biomol.~Screen.},
Title = {Large Scale Pharmacological Profiling of 3D Tumor Models of Cancer Cells},
Volume = {submitted},
Year = {2016}}
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