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

NIH Pandemic-Era Grants

Pandemic Era Grants

2024

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Principal Investigator: Khosrow Samuel Rezvani
Organization: UNIVERSITY OF SOUTH DAKOTA
Fiscal Year: 2024
Award: $74,750
Funding agency: National Cancer Institute

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.

Terms: <20-(S)-camptothecine><20S Catalytic Proteasome><20S Core Proteasome><20S Proteasome><20S Proteosome><22-secocamptothecin-21-oic acid lactone 21><5-FU><5-Fluracil><5FU><APF-1><ATP-Dependent Proteolysis Factor 1><Adverse effects><Affinity><Animal Experiments><Animals><Anti-Hypertensive Agents><Anti-Hypertensive Drugs><Anti-Hypertensives><Apoptosis><Apoptosis Pathway><Applications Grants><Assay><Binding><Bioassay><Biological><Biological Assay><Body Tissues><CRISPR><CRISPR/Cas system><Camptothecin><Cancers><Caseins><Cell Body><Cell Line><Cell Locomotion><Cell Migration><Cell Movement><Cell division><CellLine><Cells><Cellular Migration><Cellular Motility><Characteristics><Clinical><Clinical Trials><Clustered Regularly Interspaced Short Palindromic Repeats><Collaborations><Colon><Colorectal Cancer><Complex><Cristobalite><Data><Death Rate><Digestion><Disseminated Malignant Neoplasm><Drug resistance><Drugs><Engineering><Enzyme Gene><Enzymes><Exposure to><FDA approved><Feedback><Fluoro Uracil><Fluorouracil><Fluoruracil><Fluouracil><Gene Transcription><Generalized Growth><Genetic Transcription><Grant Proposals><Growth><HMG-20><Hepatic Neoplasm Secondary><Hepatic Neoplasms><Hepatic metastasis><High Mobility Protein 20><Histologic><Histologically><Hospitals><Human><Hypotensive Agent><Hypotensive Drugs><In Vitro><Intratumoral heterogeneity><Invaded><Knock-out><Knockout><LS174-T><LS174T><LS174T colon cancer cell line><Liver><Liver neoplasms><Liver secondaries><Liver secondary cancer><Longitudinal Studies><MMP-7><MMPs><Macropain><Macroxyproteinase><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Matrilysin><Matrin><Matrix Metalloproteinase-7><Matrix Metalloproteinases><Mediating><Medication><Metabolic><Metastasis><Metastasize><Metastatic Cancer><Metastatic Lesion><Metastatic Malignant Neoplasm><Metastatic Mass><Metastatic Neoplasm><Metastatic Neoplasm to the Liver><Metastatic Tumor><Metastatic Tumor to the Liver><Metastatic malignant neoplasm to liver><Mice><Mice Mammals><Mitochondria><Mitochondrial Proteins><Modern Man><Molecular><Molecular Interaction><Multicatalytic Proteinase><Murine><Mus><NIH><National Institutes of Health><Neoplasm Metastasis><Normal Cell><Oncogenic><Organ><Organoids><Outcome><PUMP-1><Pathway interactions><Patients><Pharmaceutical Preparations><Plant Extracts><Plants><Primary Neoplasm><Primary Tumor><Probability><Productivity><Programmed Cell Death><Prosome><Proteasome><Proteasome Endopeptidase Complex><Proteins><Proteosome><RNA Expression><Rectum><Regulation><Role><Safety><Sampling><Sand><Secondary Neoplasm><Secondary Tumor><Signal Pathway><Silica><Silicon Dioxide><Site><Strains Cell Lines><Survival Rate><Technology><Therapeutic><Tissue Growth><Tissues><Transcription><Tridymite><Tumor Suppressor Proteins><Ubiquitin><Ubiquitin Like Proteins><United States National Institutes of Health><Veratridine><Vinblastine><Vincaleucoblastine><Vincaleukoblastine><angiogenesis><animal experiment><anti-cancer><anti-hypertension><anticancer activity><biologic><cancer cell><cancer metastasis><cancer progenitor><cancer progenitor cells><cancer stem cell><cell motility><chemotherapy><colon cancer patients><colorectal cancer patients><cultured cell line><drug resistant><drug/agent><experiment><experimental animal><experimental animals><experimental research><experimental study><experiments><hepatic body system><hepatic neoplasia><hepatic neoplasm><hepatic organ system><hepatic tumor><heterogeneity in tumors><high-throughput drug screening><human tissue><improved><inhibitor><interdisciplinary approach><intra-tumoral heterogeneity><intratumor heterogeneity><liver metastases><liver tumor><long-term study><longitudinal outcome studies><longterm study><malignancy><malignant liver neoplasm, specified as secondary><malignant progenitor><malignant stem cell><member><metastasis in the liver><metastasis to the liver><metastasize to the liver><metastatic cancer to liver><metastatic colo-rectal><metastatic colo-rectal cancer><metastatic colo-rectal carcinoma><metastatic colon cancer><metastatic colorectal><metastatic colorectal cancer><metastatic colorectal carcinoma><metastatic liver><metastatic liver neoplasm><migration><mitochondrial><mortalin><mortality rate><mortality ratio><mouse model><multicatalytic endopeptidase complex><multidisciplinary approach><murine model><nano particle><nano particle delivery><nano-sized particle><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><neoplasm/cancer><neuron toxicity><neuronal toxicity><neurotoxicity><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><ontogeny><pathway><pre-clinical><preclinical><progenitor cell fate><progenitor fate><protein complex><public health relevance><resistance to Drug><resistant to Drug><secondary liver malignancy><secondary malignant liver neoplasm><side effect><social role><stem and progenitor cell fate><stem cell fate><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic effectiveness><tumor><tumor cell metastasis><tumor heterogeneity><tumor suppressor><tumorigenic><ultrasound>