Abstract 834: <i>In vivo</i>, <i>ex vivo</i>, and <i>in vitro</i> (2D and 3D) tumor models: Uses, strengths and limitations

Abstract Preclinical models are critical tools in the war on cancer, used in cancer biology &amp; genetics research, drug/therapeutic discovery &amp; development, and for identification of drugs &amp; drug combinations for use to treat specific tumors &amp; specific patients. Each preclinical model has strengths &amp; limitations &amp; varied endpoints. When driving an SAR, new compounds are compared with each other in solid tumor models &amp; tumor growth delay is the endpoint assessed. To determine tumor-cell kill in vivo in syngeneic or xenograft tumors, ex vivo assays are used after in vivo drug administration. To assess inherent potency &amp; potential depth of tumor cell kill, 3D in vitro models are used. The limitations of in vitro models include that prodrugs are non-functional, there is no normal tissue, &amp; the dynamics of drug metabolism are missing. A major limitation of in vivo tumor models is that the mouse is an inbred host in a controlled environment making it difficult to predict toxicity in patients. It is possible to extrapolate response to a drug or drug combination from a 3D cell culture model to the same model grown as a solid tumor in a mouse. Optimized 3D culture models include tumor cells &amp; normal cells such as endothelial &amp; mesenchymal cells. The log-kill hypothesis holds that 90% kill of tumor cells is required for a partial response, while 99% kill is required for a complete response. The 138582-377-R Merkel cell (PDX) treated with cediranib (6 mg/kg) &amp; erlotinib (90 mg/kg) Q5D for 3 wks resulted in 80% decrease in tumor vol compared with controls &amp; 80% cytotoxicity in complex spheroids from the same tumor. The 712881-215-R penile squamous cell ca PDX achieved a brief disappearance of measurable tumor on a complex regimen of cediranib (6 mg/kg) &amp; erlotinib (90 mg/kg), reaching a tumor vol 1% of the control tumor. In complex spheroids, exposure to the combination of cediranib &amp; erlotinib produced 99% cytotoxicity. When the 138582-377-R Merkel cell PDX was exposed to entinostat (30 mg/kg) Q5D for 3 wks, an 86% decrease in tumor vol was achieved compared with the control tumor vol. Less than 90% cytotoxicity was achieved in the complex spheroids in the estimated clinical Cmax concentration range of entinostat. The combination of ipatasertib (60 mg/kg) &amp; selumetinib (20 mg/kg) administered twice per day for 2-rounds of 10 days was less effective in the 171881-019-R breast ca PDX and the 845751-090-R head &amp; neck squamous ca PDX than would be predicted by the complex spheroid studies. Funded in part by NCI Contract No. 75N91019D00024. Citation Format: Beverly A. Teicher, Melinda G. Hollingshead, Nathan P. Coussens, Thomas S. Dexheimer, Thomas E. Silvers, Eric M. Jones, Larry Rubinstein, James H. Doroshow. In vivo, ex vivo, and in vitro (2D and 3D) tumor models: Uses, strengths and limitations. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 834.