Abstract 4385: Colorectal cancer lung metastasis treatment with lung-selective PI3K pathway inhibition

Abstract

Abstract Colorectal cancer (CRC) is the second leading cause of cancer death in the US, and its frequency is increasing worldwide. Lung metastases are seen in 10-20% of CRC patients with overall 25-40% 5-year survival after metastasectomy despite advances in imaging and surgical technique. Novel approaches are needed for the treatment of CRC lung metastasis. Selective lung delivery and release of potent PI3K inhibitors may offer a new approach to improve outcome of patients with CRC lung metastasis. The purpose of this study was to evaluate PI3K/Akt pathway activation and expression in CRC lung metastasis patient samples and to develop a nanocarrier for lung selective PI3K drug delivery. METHODS. Metastatic human (HT29, KM20) and mouse (CT26) CRC cell lines were used in our study. Primary colon cancer cultures were isolated from patient samples. Cell viability and IC50 concentrations were measured using a sulforhodamine B colorimetric (SRB) cytotoxicity assay. Expression of PARP, cyclin D1 and pAkt (p473) was assessed by western blot. Akt1, Akt2 and pAkt (S473) expression was analyzed in normal lung, primary and metastatic CRC patient samples by immunohistochemistry. Fluorescent nanoparticle accumulation patterns in vivo were analyzed with IVIS Spectrum imaging and confocal microscopy of fixed frozen tissue sections. Polymeric nanoparticles were loaded with hydrophobic PI3K inhibitors - Wortmannin, BEZ235, PIK-90, and PI-103. RESULTS. We found strong Akt2 and pAkt (S473) expression in all matched primary CRC and CRC lung metastasis patient samples. PI3K drug loaded nanoparticles effectively induced cell cycle arrest and apoptosis in metastatic cancer cell lines and primary cancer cultures. IVIS Spectrum imaging and confocal microscope imaging of fixed frozen tissue sections confirmed absence of fluorescent nanoparticle accumulation in liver, spleen and kidney after intravenous administration in vivo. Lung selective PI3K pathway inhibition in vivo was confirmed by western blot analysis of protein extracts from lung, liver, spleen and kidney. CT26 lung metastasis treatment with lung selective wortmannin-loaded nanoparticles demonstrated a marked suppression of lung metastasis growth and absence of side effects normally associated with PI3K drug treatment. CONCLUSIONS. The introduction of PI3K/Akt pathway inhibitors as anticancer agents against metastatic CRC is still in an early stage. We developed a safe and efficient lung selective drug nanocarrier and demonstrate that lung selective PI3K inhibition is a viable treatment strategy. Therefore, lung selective PI3K inhibition have a considerable promise to maximize the potential of PI3K/AKT inhibitors towards effective CRC lung metastasis treatment. Citation Format: Piotr G. Rychahou, Younsoo Bae, Yekaterina Zaytseva, Eun Y. Lee, Heidi L. Weiss, B. Mark Evers. Colorectal cancer lung metastasis treatment with lung-selective PI3K pathway inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4385. doi:10.1158/1538-7445.AM2015-4385