Abstract B26: Prometastatic effect of ICG-001, a β-catenin/CBP dependent transcription inhibitor, in osteosarcoma

Abstract

Abstract Osteosarcoma is the most common malignant bone tumor in the pediatric population, representing around 4 cases per million people per year in the world. Patient survival is closely related to the response of tumor cells to chemotherapy, reaching 70% at 5 years for patients with localized disease, but only 25% for high-risk patients with relapsed or metastatic disease. In 20% of cases, patients have detectable metastases at diagnosis, preferentially in the lungs, which is a sign of poor prognosis. However, it is estimated that around 80% of patients have pulmonary micrometastases, sometimes undetectable at diagnosis by imaging techniques. This makes metastatic dissemination a significant issue in the management of osteosarcoma. In addition, the survival rate has not evolved since the past decades and there is no current efficient therapy for these patients. Therefore, it is necessary to develop new therapeutic strategies. In this context, a dysregulation of the canonical Wnt signaling pathway (Wnt/β-catenin) has been reported in many osteosarcoma cases, but its implication in the development of primary and metastatic osteosarcoma is still controversial. An increase in β-catenin expression has been described in human osteosarcoma tissues compared to normal bones. Thus, we evaluated the antitumor potential of ICG-001, a small molecule that specifically binds to the transcriptional co-activator CREB-Binding Protein (CBP), disrupting its interaction with β-catenin and thus suppressing the Wnt/β-catenin target gene expression. First, we demonstrated that ICG-001 inhibits β-catenin/CBP-dependent transcription as evaluated by TCF-LEF reporter assay and RT-qPCR on β-catenin target genes in three human osteosarcoma cell lines, KHOS, MG63, and SJSA1. Moreover, ICG-001 decreases proliferation of osteosarcoma cells in a dose- and time-dependent manner, associated with a cell cycle blockade in G0/G1 phase after 24h of treatment, but without any effect on cell death. However, surprisingly, ICG-001 promotes KHOS, MG63, and SJSA1 cell migration in vitro and the development of pulmonary metastases in a murine xenograft model of osteosarcoma induced by injection of KHOS cells in a paratibial site. This study therefore raises new questions about the role of the Wnt/β-catenin pathway in the metastatic development of osteosarcoma. Thus, it is necessary to identify the different signatures of the signaling pathways potentially activated after disruption of the β-catenin and CBP interaction in osteosarcoma cells and responsible for the prometastatic effect of this drug. Citation Format: Geoffroy Danieau, Sarah Morice, Sarah Renault, Kevin Biteau, Régis Brion, Jérôme Amiaud, Frédéric Lezot, Franck Verrecchia, Françoise Rédini, Bénédicte Brounais-Le Royer. Prometastatic effect of ICG-001, a β-catenin/CBP dependent transcription inhibitor, in osteosarcoma [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B26.