Abstract 2707: Therapeutic effects of WT1 silencing by respiratory administration of liposomal siRNA in a melanoma murine model

Abstract

Abstract Introduction: Cancer is considered among the main causes of death worldwide and the number of cases keeps rising every year, as there is not an effective treatment to offer for most of them. The lungs represent a frequent target of primary and metastatic tumors due to his high oxygenation and large air spaces to grow. Melanoma is the most aggressive type of skin cancer showing a high affinity to metastasize into the lungs, being the overexpression of the WT1 protein associated with the development of this cancer, as well as several other types. Methods: In this study, we evaluated the effects of siRNA silencing the WT1 protein in both, in vitro in the B16F10 melanoma cell line, and in vivo in a murine model of pulmonary metastatic melanoma implementing a novel delivery strategy of neutral DOPC liposomal-siRNA system administrated via inhalation. Results: In vitro studies showed an effective silencing of WT1 protein (86%) in the siRNAsWT1 treated cells when compared with controls, resulting in a loss of viability (40%) and proliferation (49%) of the cells, induced G1 cell-cycle arrest (11%), a restriction of migration (87%) and invasion (100%) capacities, as well as an activation of apoptosis (12%). In vivo, we tested our delivery system obtaining an efficient biodistribution in lungs, kidney, liver and spleen. The respiratory administration of LWT1siRNA after two weeks of treatment resulted in silencing of WT1 protein (59%), achieving an important antitumor activity with a 44% reduction in tumor weight. In the survival study 80% of the L-WT1siRNA treated mice were alive after all the controls mice had died, delaying the death almost a week at the end of the study. Conclusions: This work demonstrates the efficacy of the neutral DOPC liposomal-siRNA delivery system by respiratory administration as a novel therapy to reduce the malignancy of pulmonary tumors and to increase survivability by silencing specific cancer biomarkers as WT1. Citation Format: Martin Ramos-Gonzalez, Eduardo Vázquez-Garza, Gerardo García-Rivas, Cristian Rodríguez-Aguayo, Arturo Chávez-Reyes. Therapeutic effects of WT1 silencing by respiratory administration of liposomal siRNA in a melanoma murine model [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 2707.