Abstract 4947: Exploration of Annamycin Organotropism to Target Primary and Metastatic Liver Cancers
Authors: Zielinski Rafal J. , Grela Krzysztof , Peng Shaohua , Felix Edd , Cardenas-Zuniga Roberto , Grybowski Damian , Skora Stanislaw , Fokt Izabela , Priebe Waldemar 
Published: April 2023

Abstract
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&lt;0.0001) and 28 vs 59 days (p&lt;0.0001), respectively). The significant delay in tumor progression was similar to that recorded in the CT26 experimental metastatic models, and L-ANN treatment strongly correlated with survival in this model as well (median survival 32 vs 53 days in L-ANN and vehicle groups, respectively, p&lt;0.0001).Conclusions. Annamycin is a potent, non-cardiotoxic anthracycline with proven in vivo activity against different types of tumors. It showed increased penetration and accumulation in the liver, which correlated with high antitumor activity in HEPA 1-6 hepatocellular carcinoma and CT26 colon cancer liver metastasis models. Expanded studies to assess L-ANN activity in different tumor liver metastasis models as well as HCC models are being planned. It should be noted that L-ANN is currently undergoing clinical trials in patients with pulmonary metastasis soft tissue sarcoma and acute myeloid leukemia.
Citation Format: Rafal J. Zielinski, Krzysztof Grela, Shaohua Peng, Edd Felix, Roberto Cardenas-Zuniga, Damian Grybowski, Stanislaw Skora, Izabela Fokt, Waldemar Priebe. Exploration of Annamycin Organotropism to Target Primary and Metastatic Liver Cancers. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4947.