Abstract P222: Combinations of receptor tyrosine kinase inhibitors targeting the tumor and stromal cells of complex spheroids from the National Cancer Institute’s Patient-Derived Models Repository (PDMR; https://pdmr.cancer.gov/)
Authors: Dexheimer Thomas S. , Laudeman Julie , Silvers Thomas , Delosh Rene , Reinhart Russell , Ogle Chad , Jones Eric , Coussens Nathan P. , Teicher Beverly A. , Takebe Naoko , Chen Alice , Doroshow James H. 
Published: December 2021

Tumor stroma is critical in shaping the tumor microenvironment and promoting tumor growth and metastasis. Six stroma-targeted kinase inhibitors (cediranib, vandetanib, axitinib, pazopanib, cabozantinib, and lenvatinib) were tested both as single agents and in combination with five tumor cell-targeted kinase inhibitors (erlotinib, gefitinib, osimertinib, rociletinib, and erdafitinib)using a complex spheroid cell culture model. Complex spheroids, containing 60% tumor cells, 25% endothelial cells (HUVEC) and 15% mesenchymal stem cells (MSC), serve as a cell culture model of human solid tumors incorporating both malignant and stromal cells. Seventeen tumor cell lines were grown as complex spheroids, including varied sarcoma and non-small cell lung cancer types. Drug sensitivities of the HUVEC and MSC were also evaluated, both individually as monolayers and mixed as monolayers and spheroids. Overall, the HUVEC and MSC were more sensitive to the VEGFR inhibitors than to the EGFR inhibitors. Growth as complex spheroids reduced the sensitivity of HUVEC and MSC to several kinase inhibitors compared to each cell type alone or in mixed monolayer culture. A significant correlation was observed between the EGFR mRNA expression in patient-derived tumor lines and their sensitivity to the EGFR inhibitors. In combination regimens, Erlotinib was most effective when combined with the VEGFR inhibitors pazopanib, vandetanib and cediranib, which produced more than one log of cell killing at concentrations less than the clinical Cmax of each drug. Osimertinib and rociletinib, which irreversibly target EGFR variants, were more cytotoxic towards complex spheroids of NCI-H1975 NSCLC (EGFR L858R, T790M) than NCI-H522 NSCLC (EGFR wildtype). Combinations of the mutant-selective EGFR inhibitors with a VEGFR inhibitor (especially, vandetanib, lenvatinib or cediranib) increased the cytotoxicity in complex spheroids containing EGFR mutant and wildtype tumor lines. Highly effective combinations included erdafitinib with vandetanib and erlotinib with cediranib. The combination of cediranib and erlotinib was also evaluated in nine patient-derived xenograft (PDX) models and resulted in two partial responses in a penile squamous carcinoma and uterine sarcoma, while the remainder showed stable, slowed, or progressive disease. Using &gt;1 log of cell kill at drug concentrations less than the mouse Cmax concentration for each drug as a predictor for in vivo responsiveness, the complex spheroid assay was 88% accurate in predicting response or progressive disease in the PDX models. This criteria for predicting in vivo activity from in vitro model results will be further explored. This project was funded in part with federal funds from the NCI, NIH, under contract no. HHSN261200800001E.

Citation Format: Thomas S. Dexheimer, Julie Laudeman, Thomas Silvers, Rene Delosh, Russell Reinhart, Chad Ogle, Eric Jones, Nathan P. Coussens, Beverly A. Teicher, Naoko Takebe, Alice Chen, James H. Doroshow. Combinations of receptor tyrosine kinase inhibitors targeting the tumor and stromal cells of complex spheroids from the National Cancer Institute’s Patient-Derived Models Repository (PDMR; https://pdmr.cancer.gov/) [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P222.