Target Validation and Screening Laboratory at the Frederick National Laboratories for Cancer Research

The Target Validation and Screening Laboratory (TVSL), headed by Dr. Thomas S. Dexheimer, has the infrastructure and expertise to perform a wide range of biochemical and cell-based assays. Investigational and approved anticancer drugs are evaluated in high-throughput screens as single agents and combinations in panels of established cell lines and patient-derived tumor models. The established and patient-derived cell lines are grown as 2D monolayers or 3D spheroids of tumor cells or 3D tumor cells plus stromal cells. The monolayer and 3D tumor models are characterized in a fully-automated screening system with endpoint or multiplex assays by measurements of luminescence, fluorescence, absorbance, and high content imaging. The screening libraries are composed of compounds with largely defined mechanism(s) of action which are in routine clinical use or under active clinical investigation, providing a facile pathway for clinical translation of active compounds from the screen. Additionally, the results of these screens might define potential new targets for drug discovery against recalcitrant or neglected cancers.

References

Kaur G, Evans DM, Teicher BA, Coussens NP. Complex tumor spheroids, a tissue-mimicking tumor model, for drug discovery and precision medicine. SLAS DISCOVERY: Advancing the Science of Drug Discovery 2021; 26: 1298-1314.

Krushkal J, Silvers T, Reinhold WC, Sonkin D, Vural S, Connelly J, Varma S, Meltzer PS, Kunkel M, Rapisarda A, Evan, D. Epigenome-wide DNA methylation analysis of small cell lung cancer cell lines suggests potential chemotherapy targets. Clinical Epigen 2020; 12: 1-28.

Evans DM, Fang, J, Silvers T, Delosh R, Laudeman J, Ogle C, Reinhart R, Selby M, Bowles L, Connelly J, Harris E. Exposure time versus cytotoxicity for anticancer agents. Cancer Chemotherap Pharmacol 2017; 84: 359-71.

Selby M, Delosh R, Laudeman J, Ogle C, Reinhart R, Silvers T, Lawrence S, Kinders R, Parchment R, Teicher BA, Evans DM. 3D models of the NCI60 cell lines for screening oncology compounds. SLAS DISCOVERY: Advancing Life Sciences R&D 2017; 22: 473-83.

Teicher BA, Silvers T, Selby M, Delosh R, Laudeman J, Ogle C, Reinhart R, Parchment R, Krushkal J, Sonkin D, Rubinstein L. Small cell lung carcinoma cell line screen of etoposide/carboplatin plus a third agent. Cancer Medicine 2017; 6: 1952-64.

Polley E, Kunkel M, Evans D, Silvers T, Delosh R, Laudeman J, Ogle C, Reinhart R, Selby M, Connelly J, Harris E, Fer N, Sonkin D, Kaur G, Monks A, Malik S, Morris J, Teicher BA. Small cell lung cancer screen of oncology drugs, investigational agents, and gene and microRNA expression. J Nat Cancer Inst 2016; 108: djw122.

Teicher BA, Polley E, Kunkel M, Evans D, Silvers T, Delosh R, Laudeman J, Ogle C, Reinhart R, Selby M, Connelly J. Sarcoma cell line screen of oncology drugs and investigational agents identifies patterns associated with gene and microRNA expression. Molec Cancer Therap 2015; 14: 2452-62.