Abstract 5738: Napabucasin analogues with increased bioavailability and efficacy in fibrolamellar hepatocellular carcinoma

Fibrolamellar Hepatocellular carcinoma (FLC) is a very rare liver cancer which occurs in young adults and children under the age of 40. This cancer is lethal and was first recognized in 1980. The term “fibrolamellar” refers to the fibrous bands that are visible when examining tumor tissue under a microscope. In FLC, a deletion of 400,000 base pairs occurs in a chromosome 19 copy, leading to the formation of a fusion protein comprising heat shock protein DNAJB1 and the catalytic subunit of Protein Kinase A (DNAJB1-PRKACA). Patients show no symptoms in the early stage of the disease. The reported survival rate over the past five years is below 50%. Surgery remains the sole partially effective treatment for FLC, with no currently approved systemic therapies available. The primary model compound of this project is Napabucasin. It is also known as BBI608 is a naphthoquinone natural product isolated from the plants Newbouldia laevis, Ekmanianthe longiflora, and Handroanthus impetiginosus. It has shown wide spectrum anti-cancer activities and is now in trials for cancer treatment. The Napabucasin was found to be a top hit in drug screening showing potency against all FLC patient derived xenografts (PDX) models. Napabucasin is known to work in multiple signaling pathways and have been shown cytotoxic against both PDX and direct-from-patient FLC tumor cells. We anticipate that the organic synthesis and development of optimized Napabucasin analogues, along with the evaluation of their cytotoxicity and proliferation effectiveness compared to the parent compound, Napabucasin, will result in compounds with improved bioavailability and efficacy, particularly in FLC model cell lines (FLX1 and Huh7-Chimera). Citation Format: Shalini Rawat, Jared Alderman, Priscilla Baeza, Lianna Hartshorn, Celeste Villasenor, Jakim Brazil, Barbara Lyons. Napabucasin analogues with increased bioavailability and efficacy in fibrolamellar hepatocellular carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 5738.