LAUSR

There is growing interest in the use of human tumor primary cultures for the prediction of response to drugs and drug combinations in cancer medicine. While the field has witnessed numerous attempts to apply human tissue for the prediction of response, fundamental errors in methodologic approaches severely limited the predictive validity and clinical applicability of these important technologies. The first error was a focus upon drug induced cell growth inhibition. This lead to the failure of the clonogenic (human tumor stem cell) and H3*Thymidine incorporation platforms in the 1970’s and 1980’s. As the concept of apoptosis arose following landmark observations in 1972, cell death endpoints became predominant including mitochondrial function (MTT, XTT), ATP content (luciferase) and delayed loss of membrane integrity (DISC, EVA/PCD) among others. These improvements led to more biologically relevant measures. However, a second hurdle arose as investigators chose to amplify subculture and propagate tumors into what are now referred to as human tumor organoids. While these 3-D cultures are more reflective of tumor cell-cell interactions found in cancers, they cannot recreate the cell-vasculature, cell-stroma, inflammatory environment nor cancer associated fibroblast interactions with human cancer cells required for accurate response prediction. To address these shortcomings we developed the ex vivo analysis of programmed cell death (EVA/PCD) platform that applies native state tumor explants directly from surgical specimens to select drugs and combinations. To date we have reported 11,680 individual analyses. Positive prospective results have been reported in breast cancer (TTP p < 0.03); ovarian cancer (TTP p = 0.05), lung cancer (2-fold improvement in ORR; TTP p =0.035) and recently ovarian and uterine cancer (DFS p = 0.038) with two meta-analyses confirming the predictive validity in hematologic and solid tumors. With over 20 years of CLIA-approved laboratory experience in the study of human tumor primary culture explants, the EVA/PCD platform provides improved response and time to progression and offers the opportunity to streamline drug development, curtail costs and avoid futile care in patients with advanced and refractory malignancies. Citation Format: Adam J. Nagourney, Steven S. Evans, Paulo D'Amora, Nise Yamaguchi, Paula Bernard, Federico Francisco, Joshua B. Gipoor, Robert Alan Nagourney. Human tumor primary culture analyses for the prediction of response to chemotherapy, targeted agents, drug combinations and metabolic inhibitors: The role of ex vivo analysis of programmed cell death in cancer therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4910.