Abstract 201: Targeting colorectal cancer lung metastasis microenvironment with PI3K inhibitors and chemotherapy
Authors: Rychahou Piotr , Bae Younsoo , Reichel Derek A. , Zaytseva Yekaterina , Lee Eun Y. , Weiss Heidi L. , Evers B. Mark 
Published: July 2017

Introduction: Colorectal cancer (CRC) is the second leading cause of cancer deaths in the US; systemic metastasis to the lungs occurs in approximately 10-20% of patients with CRC. The toxicity of currently available anticancer drugs and the inefficiency of chemotherapeutic treatments, especially for advanced stages of the CRC metastatic disease, have severely limited the treatment options in patients with CRC lung metastasis. Here, we evaluated nanocarrier that accumulates selectively in normal lung stroma and lung metastasis tumor microenvironment. The purpose of our study was to: (i) demonstrate lung-selective delivery of nanoparticles into the tumor microenvironment and surrounding normal parenchyma as a targeted therapy for CRC lung metastasis, and (ii) evaluate effect of lung selective delivery of PX-866 and SN-38 loaded nanoparticles on CRC lung metastasis growth.

Methods: (1) HT29 LungM3 cell line was derived from the human CRC line HT29 following multiple rounds of in vivo selection for lung metastasis in immunodeficient mice. (2) Polymeric nanoparticles were constructed and loaded with fluorescent dye (Alexa 547), pan-PI3K inhibitor PX-866 or SN-38. Fluorescent nanoparticles were administered intravenously into mice at 1, 4, 8, 24h timepoints. (3) Nanoparticle drug delivery was quantified in lung, liver and kidney tissue samples by HPLC. (4) CT26 and HT29 LungM3 cell lines were injected intravenously to establish lung metastasis. Mice were then treated with PX-866 and SN-38 loaded nanoparticles every 3 days intravenously for 31 days.

Results: Lung selective accumulation of Alexa-546 fluorescently-labeled nanoparticles was confirmed by confocal imaging of frozen tissue sections from lung, liver, kidney and spleen. Selective PI3K inhibition in lung tissue was confirmed by western blot analysis of protein extracts from lung, liver, kidney and spleen for pAkt (S473) expression. HPLC analysis showed predominant PX-866 drug delivery to lungs and minimal drug delivery to kidney and liver tissues. Treatment with PX-866 loaded nanoparticles demonstrated a marked suppression of lung metastasis growth; CRC lung metastases were not detected after treatment with SN-38 loaded nanoparticles. Notably, administration of PX-866 and SN-38 nanoparticles had no deleterious effect on normal lung, kidney or liver parenchyma.

Conclusions: We demonstrate selective and efficient delivery of drug-loaded nanoparticles to lungs with minimal accumulation in kidneys, liver and immune system, suggesting that lung selective drug delivery is a viable treatment strategy for CRC lung metastasis. Moreover, treatment of mice with CRC lung metastases with either PX-866 or SN-38 loaded nanoparticles resulted in a marked suppression of metastatic growth. Polymeric nanocarriers have a potential to revolutionize drug delivery and to significantly improve current approaches to the treatment of patients with CRC lung metastasis.

Citation Format: Piotr Rychahou, Younsoo Bae, Derek A. Reichel, Yekaterina Zaytseva, Eun Y. Lee, Heidi L. Weiss, B. Mark Evers. Targeting colorectal cancer lung metastasis microenvironment with PI3K inhibitors and chemotherapy [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 201. doi:10.1158/1538-7445.AM2017-201