Abstract 4203: Kinase inhibitor demonstrates efficacy in patient derived xenograft model of fibrolamellar hepatocellular carcinoma featuring DNAJB1-PRKACA gene fusion

Abstract

Abstract Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare and distinct primary hepatic malignancy that has conventionally been considered to be a histologic variant of hepatocellular carcinoma. However, it has more recently been recognized as a distinct clinical entity with respect to its epidemiology and prognosis. The etiology of FL-HCC is unclear and there is no clinical or histological evidence for association with chronic liver disease. Recent genetic studies have identified the fusion gene DNAJB1-PRKACA as a recurrent genetic lesion in the disease. Molecular pathogenesis of FL-HCC; however, is not well understood and has been reported to occur in association with focal nodular hyperplasia. Overexpression of genes in PIK3, MAPK and RAS pathways is observed in FL-HCC and in contrast to viral-associated HCC, epigenetic instability is rare in FL-HCC. Here we describe development of a novel FL-HCC Patient Derived Xenograft (PDX) model LI5132. RNASeq analysis revealed presence of DNAJB1-PRKACA gene fusion on chromosome 19, a molecular signature of FL-HCC. Clinical diagnosis as HCC of fibrolamellar type was confirmed by H&E staining in the PDX tumor. The PDX tumor had a distinctive intratumoral fibrosis with a lamellar pattern. PDX model was established by inoculating patient tumor cells subcutaneously in NOD-SCID mice. Robust tumor growth was observed with a 100% take rate in NOD-SCID mice. To evaluate the translational relevance of this model toward therapeutic development, the efficacy of a novel multi-target Aurora kinase A and angiokinase inhibitor, ENMD-2076, was evaluated in a therapeutic mode in this model. ENMD-2076 showed significant efficacy in suppressing tumor growth in NOD-SCID mice, at the 200 mg/kg dose evaluated in this study. Weight loss observed during the treatment period could not be attributed to ENMD-2076 as it was similar to weight loss observed with vehicle treatment. ENMD-2076 has now progressed in to phase II trials in the clinic for treatment of FL-HCC. This demonstrates the translational utility of this FL-HCC model in development of anti-cancer therapeutic agents. Citation Format: Jayant Thatte, Elvira C. Talaoc, Colleen Scott, Ken Ren, Thomas Broudy. Kinase inhibitor demonstrates efficacy in patient derived xenograft model of fibrolamellar hepatocellular carcinoma featuring DNAJB1-PRKACA gene fusion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4203. doi:10.1158/1538-7445.AM2017-4203