Abstract P218: Annamycin, a novel non-cardiotoxic anthracycline with high activity against sarcomas metastatic to lungs

Abstract

Abstract Introduction. Annamycin (ANN) is a non-cardiotoxic potent topoisomerase II poison structurally resembling doxorubicin (Dox). Specific structural modification altered ANN properties dramatically when compared with Dox. This novel drug also includes high activity against multidrug-resistant (MDR) tumors, unique subcellular distribution, and different tissue-organ distribution. Especially high differences have been noted in the lung uptake when compared with DOX. ANN is formulated in multilamellar liposomes (L-Annamycin, L-ANN), and such formulation additionally contributes to the high ANN lung uptake. Objective. The objective of this study was to reconfirm the unique tissue-organ distribution pattern in rats and explore ANN high lung uptake to target pulmonary sarcoma metastases by assessing the efficacy of L-ANN in the experimental models of lung metastases. Methods. Pharmacokinetics and biodistribution studies of ANN were performed in rats after bolus injection of L-ANN, free ANN, and Dox. Detection of Dox and ANN in plasma and different organs was accomplished using LC/MS/MS. In vivo efficacy was tested in two experimental lung metastatic models. The tumors were established by intravenous injection of MCA205 or K7M3 cells. The treatment consisted of weekly intravenous injections of 4 mg/kg of L-ANN or Dox. Metastatic nodules were visualized by computer tomography or bioluminescent imaging (BLI). Results. Pharmacokinetic and tissue-organ distribution of L-ANN in rats confirmed unusually high uptake of ANN in lungs: the Cmax of ANN was 30-fold higher than Dox after bolus administration of L-ANN or Dox. A remarkable extension of the survival was observed in two syngeneic sarcoma lung metastasis models. In the MCA205 fibrosarcoma model, the median survival of L-ANN treated mice was 87.5 days vs. 21 days for the vehicle-treated mice (p<0.0001), and 40% of animals were still alive when the experiment has been terminated on day 140. L-ANN also appeared highly efficacious in the osteosarcoma K7M3 model. Median survival has not been reached due to the high efficacy of L-ANN treatment. The experiment has been terminated on day 220 (the median survival for the vehicle-treated was 58 days, p=0.0002). Additionally, L-ANN and Dox were compared in the K7M3-Luc model. The BLI revealed a potent inhibition of the tumor growth by L-ANN-, but not in Dox-treated animals. Consequently, there was no extension of the survival in DOX-treated animals, while no deaths were recorded in L-ANN treated group as of day 90 (MS for Dox-treated mice was 59 days, ongoing study). Conclusion. Annamycin (ANN) is a novel non-cardiotoxic anthracycline that exhibits very high uptake in the lungs compared to Dox. Furthermore, ANN’s rapid cellular uptake and preferential nanomolar cytotoxicity against cancer led to major efficacy in sarcoma lung metastasis models. These promising preclinical results led to the initiation of a multicenter sarcoma-specific clinical study (NCT04887298). Citation Format: Rafal Zielinski, Krzysztof Grela, Roberto Cardenas-Zuniga, Stanislaw Skora, Izabela Fokt, Maria Poimenidou, Salah-Eddine Lamhamedi-Cherradi, Joseph Ludwig, Waldemar Priebe. Annamycin, a novel non-cardiotoxic anthracycline with high activity against sarcomas metastatic to lungs [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2021 Oct 7-10. Philadelphia (PA): AACR; Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P218.