Abstract B061: Targeting lymphomas with the novel first-in-class pan-NOTCH transcription inhibitor CB-103

Abstract

Abstract Background: NOTCH pathway is recurrently activated in human cancers, including lymphomas, and overactivation of the pathway has been correlated to a worse prognosis in patients with solid tumors, leukemias, and lymphomas, making it an attractive target for treatment (Rossi et al, JEM 2012; Rossi et al, Blood 2012; Kridel et al, Blood 2012). However, so far, pharmacologic approaches to inhibit its activity are limited to the use of nonspecific gamma secretase inhibitors and blocking antibodies with limited application. None of these therapeutic agents have been approved yet for cancer treatment. CB-103 is a novel first-in-class pan-NOTCH inhibitor that blocks signaling by directly and specifically targeting the NOTCH transcription complex, and it has shown preclinical activity in a variety of solid tumor and leukemia models (Lehal et al, AACR 2017). Here, we present the very first results with CB-103 in a large panel of B and T cell lymphoma cell lines. Methods: 58 human lymphoma cell lines [27 diffuse large B cell lymphomas (DLBCL); 9 mantle cell lymphomas; 6 marginal zone lymphomas; 9 T-cell lymphomas; 7 others], 2 murine and 1 canine, were exposed to increasing doses of CB-103 for 72h. Cell proliferation was measured by using the MTT assay. Transcriptome analysis was performed using the Illumina HumanHT 12 Expression BeadChips and with the HTG EdgeSeq Oncology Biomarker Panel, a targeted RNA-Seq investigating over 2500 genes, followed by a limma moderate t-test, and GSEA. Results: CB-103 presented a median IC50 above 20 μM across the whole panel of 61 lymphoma cell lines (range from 400 nM to > 20 μM), without significant differences among lymphoma subtypes. Importantly, 13/58 cell lines had an IC50 <10 μM and were defined as sensitive. These cell lines were derived from ABC DLBCL (3/7, 43%), GCB DLBCL (5/20, 25%), MCL (3/9, 33%), marginal zone lymphoma (1/6, 17%), and canine DLBCL (1/1, 100%). The sensitive cell lines, when compared with those presenting IC50 >10 μM, presented a gene expression signature significantly enriched with genes involved in the epithelial-mesenchymal transition (FDR 0.0014), a Notch-related process. Indeed, the transcripts higher in the sensitive cell lines included, among others, DLL1 (P 0.010; Log Fold Change 2.39), BAMBI (P 0.046; Log Fold Change 0.92), MCM7 (P 0.015; Log Fold Change 1), and ULK1 (P 0.045; Log Fold Change 2.39), all connected to NOTCH pathway. Finally, 10 of the CB-103 sensitive human cell lines were also exposed to another NOTCH inhibitor, the gamma secretase inhibitor LY-3039187, which resulted active only in one MCL cell line, while it had IC50 >20 μM in the other cell lines tested. Conclusions: CB-103 presented in vitro antilymphoma activity in a restricted number of B cell lymphoma cell lines, which were characterized by a NOTCH-related gene expression signature. Further studies with the compound are ongoing and a phase I is planned to start in Q3 2017 (EUDRACT Number 2017-001491-35). Citation Format: Filippo Spriano, Chiara Tarantelli, Alberto Arribas, Eugenio Gaudio, Luciano Cascione, Luca Aresu, Emanuele Zucca, Davide Rossi, Anastasios Stathis, Maximilien Murone, Dirk Weber, Rajwinder Lehal, Freddy Radtke, Francesco Bertoni. Targeting lymphomas with the novel first-in-class pan-NOTCH transcription inhibitor CB-103 [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B061.