Abstract 3891: Efficacy of dinaciclib in hepatoblastoma through inhibition of cyclin dependent kinases

Abstract Introduction: Hepatoblastoma (HB) is the most frequent liver malignancy of childhood with an annual incidence of 1.5 per million and a survival rate less than 50%. Due to significant side effects and ineffectiveness of standard chemotherapy for relapse refractory disease, the treatment options are now shifting towards targeted therapies. Cyclin-dependent kinases (CDKs) are potential cancer therapeutic targets because of their critical role in promoting cell growth and regulating transcriptional processes. This study aims to assess the therapeutic efficacy of dinaciclib, cyclin-dependent kinase inhibitor, with HB in preclinical in vitroand in vivo models. Method: Dinaciclib was tested in patient derived cell lines (PDCL) from different patient derived xenograft (PDX) models using CellTiter-Glo Luminescent Viability assays. Dinaciclib was also assayed in vitro for cytotoxicity (MTT assay) and proliferation (CCK-8 assay). Differential expression of CDKs was checked by microarray analysis between normal liver and HB patients. Results were confirmed by immunoblotting assays. Immunoblotting assays were also used to see the effect of dinaciclib on CDK 1/2/5/9 and to assess the induction of apoptosis (PARP cleavage) in vitro. Dinaciclib was also tested in our orthotopic PDX models of high-risk HB. MRI and alpha-fetoprotein (AFP) ELISA were done to evaluate tumor growth. Tumor weights and volumes, as well as, immunohistochemistry were also used to assess effects of dinaciclib in vivo. Result: Dinaciclib suppressed cell proliferation and viability in a dose-dependent manner in all HB cell lines tested with IC50 in the low micromolar range (HepG2- 3.75; HepT1- 0.007; Huh6- 1.42; HB17- 0.72). Microarray analysis showed significant upregulation of CDK1 (p=0.0003), CDK2 (p=0.00023) and CDK9 (p=0.015) in HB patient samples, however, immunoblotting with dinaciclib-treated cells showed decreased expression of CDKs 1/2/5/9 as well as induction of apoptosis. Dinaciclib also showed in vivo inhibition of tumor growth compared to placebo in both PDX models (HB47: relative tumor volume p = 0.03, T/C ratio= 0.36, tumor weight p = 0.02; HB52: relative tumor volume p = 0.06, T/C ratio= 0.16, tumor weight p = 0.07). Conclusion: Dinaciclib treatment showed promising effects with preclinical HB cell lines and PDX models. Citation Format: Rohit K. Srivastava, Roma Patel, Andres F. Espinoza, Yang Yu, Richard S. Whitlock, Samuel Larson, Andrew Badachhape, Jianhua Yang, Sarah E. Woodfield, Sanjeev A. Vasudevan. Efficacy of dinaciclib in hepatoblastoma through inhibition of cyclin dependent kinases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3891.