Abstract 5155: Targeting nucleolin with doxorubicin-containing nanoparticle induces a significant tumor growth inhibition in an orthotopic animal model of standard of care-resistant mesothelioma

Abstract

Abstract Mesothelioma is a malignant tumor of the mesothelium, the thin lining of the surface of the body cavities and the organs within, and is often associated with asbestos exposure. It has a poor prognosis, with a mean overall survival of 8.8 months. Chemotherapy has been used for malignant pleural mesothelioma as an adjuvant treatment after surgical resection (often palliative) or in patients who have inoperable disease. A combination of cisplatin and pemetrexed remains as the current standard of care, with only a 9% 5-year survival rate. Herein, a novel targeted treatment for mesothelioma, based on a doxorubicin (DXR)-containing nanoparticle functionalized with the nucleolin-binding F3 peptide (named PEGASEMP), is proposed. It relies on nucleolin deregulated overexpression in cancer cells and the tumor microenvironment (endothelial cells from tumor blood vessels). Studies were performed in an orthotopic model of human mesothelioma. Mesothelioma cells harvested from a patient with disease progression who undergone chemotherapy, were stably transduced with luciferase-reporter gene, and orthotopically injected intrapleurally into female immunocompromised mice. Animals were randomly allocated to different treatment groups: vehicle, peptide-targeted DXR-containing nanoparticle (PEGASEMP) at 5.6 or 7 mg of DXR/kg alone (q7dx5w); cisplatin at 4.0 mg/kg alone or combined with PEGASEMP at 5.6 mg of DXR/kg (q7dx5w). A control group administered with the standard of care, a combination of cisplatin at 4.0 mg/kg (q7dx5w) plus pemetrexed at 100.0 mg/kg (q2dx3x5w) was also included. Bioluminescence was monitored weekly with live imaging using IVIS Spectrum In Vivo Imaging system. Peptide-targeted DXR-containing nanoparticle at 7.0 mg/kg enabled a tumor growth inhibition, by the end of the treatment, that was 183-fold higher than the standard of care. Moreover, treatment with DXR-containing nanoparticle targeting nucleolin, either at 5.6 or 7.0 mg/kg, enabled a 10- or 66-fold reduction of tumor burden, respectively, relative to non-treated mice. Conversely, treatment with the standard of care did not show any effect on tumor growth inhibition (being similar to the group injected with vehicle) nor on tumor burden. Importantly, DXR-containing nanoparticle targeting nucleolin, at the highest tested dose, enabled a marked decreased of the incidence of tumor infiltration into the chest cavity, as well as of the presence of severe lung lesions, as compared with the standard of care (57.1% versus 100% and 14.3% versus 50%, respectively). Overall, the novel mechanism of action associated with DXR-containing nanoparticle targeting nucleolin, enables a significant benefit in terms of efficacy (and safety) in the treatment of mesothelioma, as compared with the current standard of care, thus supporting future clinical evaluation. Citation Format: Nuno André Fonseca, Vera Moura, Fabiana Colelli, Daniela Pesce, Francesco Cardile, Claudio Pisano, Sérgio Simões, João Nuno Moreira. Targeting nucleolin with doxorubicin-containing nanoparticle induces a significant tumor growth inhibition in an orthotopic animal model of standard of care-resistant mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5155. doi:10.1158/1538-7445.AM2017-5155