Abstract 4947: Exploration of Annamycin Organotropism to Target Primary and Metastatic Liver Cancers

• Published in: Cancer research (Chicago, Ill.) Ill.), 2023-04, Vol.83 (7_Supplement), p.4947-4947
• Main Authors: Zielinski, Rafal J., Grela, Krzysztof, Peng, Shaohua, Felix, Edd, Cardenas-Zuniga, Roberto, Grybowski, Damian, Skora, Stanislaw, Fokt, Izabela, Priebe, Waldemar
• Format: Article
• Language: English
• ISSN: 1538-7445; 1538-7445
• DOI: 10.1158/1538-7445.AM2023-4947

Background. Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and is responsible for more than 12,000 deaths per year in the US. In addition to primary tumors, the liver is a common site for metastases of many types of cancer, including colorectal, and pancreatic cancer. The life expectancy and outlook for people with liver metastases are typically poor.Annamycin (ANN) is a novel anthracycline of our design that is clinically evaluated as a liposome formulated drug product, L-ANN. ANN and L-ANN display unique organotropism that differs from doxorubicin (DOX). In addition, ANN was shown to have increased potency against multidrug resistant cancer cell lines, and, importantly, L-ANN appeared to be non-cardiotoxic. Objective. The objective of this study was to analyze the pharmacokinetics of two formulations of ANN in the liver in comparison with DOX and to determine its tumoricidal potential in an HCC model in situ and in an experimental model of liver metastasis. Methods. The pharmacokinetics and tissue-organ distribution studies of L-ANN, free ANN, or DOX were performed in mice and rats. The levels of ANN and DOX in plasma and tissue homogenates were assessed using LC/MS. The antitumor efficacy of L-ANN was studied using HEPA 1-6 hepatocellular carcinoma models (subcutaneous, orthotopic, and experimental liver metastatic models) and compared with CT26 colon cancer liver metastasis experiments.Results. ANN exhibited dramatically higher accumulation in the liver parenchyma when compared to DOX (6-fold higher AUC values). We found that the increased liver uptake of the drug had a direct effect on activity of the drug in vivo. First, we observed clear, dose-dependent inhibition of the subcutaneous tumor growth after systemic (IV) administration of L-ANN. Next, remarkable activity of L-ANN was observed in orthotopic models. For instance, significant inhibition of the tumor growth and extension of the survival of L-ANN treated mice vs. vehicle-receiving animals was observed in HEPA 1-6 models (median survival 29.5 vs 50 days (p