Abstract 1231: In vitro anticancer activity of imidazo-acridinone (HKH40A) in panels of human patient-derived tumor xenografts (PDXs) and human leukemia and lymphoma cell lines

Abstract

Abstract HKH40A is a synthetic, DNA-intercalating (Kosakowska-Cholody et al., 2009) anticancer agent consisting of an imidazo-acridinone linked to a 1,8-naphthalimide moiety via a 1,4-dipropylpiperazine linker. It displayed strong inhibitory activity in the NCI-60 tumor cell line panel in vitro with an IC50 of about 1 nM in selected tumor cell lines (Hariprakasha et al. 2007). In addition, anticancer activity was observed in hepatoma models both in vitro and in vivo. We have investigated the in vitro anticancer activity of HKH40A in 3D cultures, using panels of 206 PDXs and 11 human leukemia and lymphoma cell lines. The 3D clonogenic assay was performed in a 96 well format using a metabolic readout as an equivalent for colony formation. PDXs and hematologic cell lines were propagated in immunedeficient mice. HKH40A proved to be very potent with a mean IC50 of 6 nM and a mean IC70 of 12 nM. Overall, the hematological cell lines were more sensitive than the solid tumor models. Selective activity (definition: IC50 < 1/3 of mean IC50) was seen in 4 out of 6 acute myeloid leukaemias (AMLs), in 1 out of 1 chronic lymphocytic leukemia (CLL) and in 1 out of 3 non-Hodgkin lymphomas (NHLs). Among the solid tumors, pleural mesotheliomas were most sensitive followed by soft tissue sarcomas and anal cancer. Selective activity was observed in a subset of 8 out of 30 colon cancer models, which presented IC50 values < 1/3 of the mean IC50 of all tumors. The drug sensitivity data will be correlated to mutational and transcriptomic (Whole Exome Sequencing and Affymetrix HG-U133 plus 2.0 array profiles) characteristics of the PDXs to identify predictive biomarkers of drug response and resistance. Overall, HKH40A is a novel imidazo-acridinone with high in vitro activity mainly in AMLs and NHLs as well as in pleural mesotheliomas, soft tissue sarcomas and in a subset of colon cancer models. The identification of predictive biomarkers is ongoing. *Deceased during an NCI retreat Citation Format: Heinz H. Fiebig, Armin Maier, Gerhard Kelter, Vincent Vuaroqueaux, Humcha K. Hariprakasha, Christopher Michejda. In vitro anticancer activity of imidazo-acridinone (HKH40A) in panels of human patient-derived tumor xenografts (PDXs) and human leukemia and lymphoma cell lines. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1231. doi:10.1158/1538-7445.AM2014-1231