SMART" nanoparticle delivery of veratridine overcomes clinical challenges in metastatic colorectal cancer.

Project Summary Colorectal cancer (CRC) has a high mortality rate due to metastasis and drug resistance. CRC cells develop metastatic characteristics by hijacking different signaling pathways to fuel tumor heterogeneity and facilitate cancer migration and invasion. Additionally, the metabolic adaptation supported by “oncogenic mitochondria” is

a survival strategy developed in CRC cells. Unfortunately, the above metastatic cascade is formed and evolved during the early tumor formation and progression stages. Activation of multiple tumorigenic pathways in CRC cells leads to a poor five-year relative survival rate in patients with colon (14%) or rectal (17%) metastatic

cancer. Current natural anti-cancer compounds such as camptothecin and vinblastine have a successful clinical profile. However, both camptothecin and vinblastine interfere with cell division, resulting in unwanted effects on normal cells. We have discovered that a natural plant-based anti-cancer molecule (veratridine [VTD]) induces the

expression of UBXN2A protein in CRC cells. UBXN2A’s ubiquitin-like activity suppresses the mTORC2-Rictor pathway and mitochondrial mortalin, two critical tumorigenic players in CRC. This project aims to develop “smart” nanoparticles (NPs) to selectively release VTD at tumor sites at high local concentrations while leaving

normal cells minimally exposed to the drug below its toxic concentrations. Our in vitro and animal experiments have demonstrated the anti-growth and anti-metastatic effects of VTD at the cellular level and have aided in elucidating its mechanisms. The proposed study will investigate the anti-growth and anti-metastatic

mechanisms of VTD delivered by casein-coated NPs in patient CRC-derived organoids (PDOs) (Aim 1). A CRC metastatic mouse model with liver tumors will confirm the anti-metastatic mechanisms of NPs-VTD (Aim 2). Our central hypothesis is that casein-coated nanoparticles loaded with VTD (NPs-VTD) suppress the

overdriven mTORC2 pathway and interfere with the oncogenic mitochondria in CRC cells. Human tissues and a human-like mouse model of metastatic CRC used in this study will open a platform for developing new therapeutic strategies in CRC, particularly its metastatic forms.