Abstract 390: Colorectal cancer pulmonary metastasis treatment with lung-selective delivery of PAN-class I PI3K inhibitors

Abstract

Abstract Colorectal cancer (CRC) is the second leading cause of cancer death in the US, and its frequency is increasing worldwide. Phosphatidylinositol 3-kinase (PI3K) signaling is an important therapeutic target that is currently being evaluated in multiple clinical trials. The purpose of this study was to: i) determine expression of pAkt (Ser473), Akt1 and Akt2 in primary and metastatic CRCs, and ii) evaluate lung-selective delivery of PI3K inhibitors as a novel therapeutic approach against CRC lung metastasis. METHODS. i) To determine the expression of PI3K/Akt pathway components, we obtained primary CRCs (n = 12) and CRC lung metastases (n = 10). Akt1, Akt2 and pAkt (S473) expression was analyzed by immunohistochemistry (IHC) and blindly scored by a pathologist. ii) To confirm lung-selective nanoparticle accumulation, we used two methods. First, polymeric nanoparticles were constructed and loaded with fluorescent dye (Alexa547). IVIS Spectrum imaging and confocal imaging of frozen tissue sections was used to determine distribution of fluorescently-labeled nanoparticles after intravenous administration (50 μg/g; 300 μl). Second, polymeric nanoparticles were loaded with either wortmannin, PX866, BEZ235, PIK-90, ZSTK474 or GDC-094 and administered intravenously. Western blot analysis of protein extracts from lung, liver, spleen and kidney for pAkt (Ser473) expression was used to determine PI3K pathway inhibition. iii) The anti-metastatic potential of PI3K drug-loaded lung-selective nanoparticles was evaluated in a preclinical model of CRC lung metastasis. RESULTS. i) We found strong Akt2 and pAkt (S473) expression in all primary and metastatic lung CRC patient samples. ii) We confirmed lung-selective accumulation of fluorescent nanoparticles and absence of fluorescent nanoparticle accumulation in liver, spleen and kidney. Lung-selective drug delivery was confirmed by western blot analysis of PI3K pathway inhibition in protein extracts from lung, liver, spleen and kidney after a single (10 μg/g; 300 μl) intravenous administration of drug-loaded nanoparticles. PI3K pathway inhibition was observed only in lung tissue samples. iii) Mice with established lung metastases were treated with PI3K drug-loaded nanoparticles daily (10 μg/g; 300 μl). Treatment in vivo with wortmannin and PX866 showed marked suppression of CRC lung metastatic growth. BEZ235, PIK-90, ZSTK474 or GDC-0941 had no significant effect on growth in metastatic CRC to the lung when delivered by nanoparticles. CONCLUSIONS. We developed a safe and efficient lung selective drug nanocarrier and evaluated lung selective PI3K inhibition as a viable treatment strategy. Treatment of CRC lung metastasis with pan-PI3K-loaded nanoparticles demonstrated a marked suppression of metastatic lung growth, and suggests that lung selective PI3K inhibition is a viable treatment strategy for CRC lung metastasis. Citation Format: Piotr Rychahou, Younsoo Bae, Yekaterina Zaytseva, Eun Y. Lee, Heidi L. Weiss, B. Mark Evers. Colorectal cancer pulmonary metastasis treatment with lung-selective delivery of PAN-class I PI3K inhibitors. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 390.