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Principal Investigator: Jinjun Shi
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2020
Award: $540,226
Funding agency: National Cancer Institute
DESCRIPTION (provided by applicant): Given the capability of modulating individual gene expression in tumor cells, RNA agents such as small interfering RNA (siRNA) and messenger RNA (mRNA) have demonstrated tremendous potential in revealing the functionality of specific gene alterations and enabling novel classes of therapies for cancer treatment. The effective systemic RNA delivery to tumors, however, remains a formidable challenge for the widespread application of RNA technologies in cancer research and therapy. In this project, we propose to (i) develop robust nanoparticle (NP) platforms for effective in vivo delivery of siRNA and mRNA to tumor tissue, and (ii) apply this technology to relevant cancer therapeutic targets for treating
non-small cell lung cancer (NSCLC). In recent efforts, we have conceived and developed a new generation of lipid-polymer hybrid NPs with promising features for systemic siRNA delivery, including long blood circulation, high tumor accumulation, and impressive gene silencing efficacy. We have also successfully employed these hybrid NPs to explore a putative therapeutic target, Prohibitin1 (PHB1), in NSCLC and to deliver tumor suppressor-encoded mRNA to cancer cells, as evidenced by inhibition of tumor cell growth in vitro and following systemic delivery in vivo. In light of these extensive and encouraging preliminary results, we hypothesize that the new lipid-polymer hybrid NP-mediated systemic RNA delivery will become a useful platform for in vivo evaluation of cancer targets and for the development of novel RNA therapies for cancer treatment. In Aim 1, we will systematically optimize, understand and evaluate specific parameters that have been shown to control gene silencing efficiency and in vivo properties (e.g., pharmacokinetics, biodistribution, and side effects) of the hybrid NPs. In Aim 2, we propose to explore the mechanisms and pathways underlying the PHB1 silencing-induced anti-tumor effect, using the optimized siRNA NPs from Aim 1. The hybrid NPs for systemic delivery of anti-PHB1 siRNA will be extensively examined in multiple NSCLC xenograft and orthotopic models. In Aim 3, we will expand and refine the new hybrid NPs to deliver mRNA coding for tumor suppressors relevant to NSCLC, including PTEN and LKB1. This mRNA delivery approach for cancer therapy will be systematically investigated in vitro and in NSCLC xenograft and genetically engineered mouse models. At the conclusion of this project, we expect that the convergence of innovative RNA delivery strategy and significant discoveries in tumor biology will further strengthen our arsenal of therapies against NSCLC and other aggressive cancers.
Terms: <Address><Animals><Biodistribution><Biologic Sciences><Biological Sciences><Bioscience><Blood Circulation><Bloodstream><Cancer Cause><Cancer Etiology><Cancer Genes><Cancer Treatment><Cancer-Promoting Gene><Cancers><Cations><Cell Survival><Cell Viability><Cellular Expansion><Cellular Growth><Cessation of life><Charge><Circulation><Clinical Research><Clinical Study><Code><Coding System><Collaborations><DNA><DNA Alteration><DNA Sequence Alteration><DNA mutation><Death><Deoxyribonucleic Acid><Development><Development and Research><Dissociation><Drug Kinetics><Excretory function><Exhibits><Face><Formulation><GEM model><Gene Alteration><Gene Expression><Gene Inactivation><Gene Mutation><Gene Silencing><Generations><Genes><Genetic mutation><Genetically Engineered Mouse><Genomics><Goals><Heterograft><Heterologous Transplantation><Human><Hybrids><In Vitro><Individual><Kidney><Kidney Urinary System><Kinetics><LKB1><LKB1/STK11 Gene><Label><Lead><Life Sciences><Light><Lipids><MMAC1><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Messenger RNA><Methods><Micro RNA><MicroRNAs><Modeling><Modern Man><Mononuclear><Mutated in Multiple Advanced Cancers 1><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Nano platform><Nano-technological platform><Nano-technology platform><Nanoplatform><Nanotechnological platform><Nanotechnology><Non-Polyadenylated RNA><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Nonsmall Cell Lung Carcinoma><Nucleic Acids><Oncogenes><PHTS gene><PHTS protein><PTEN><PTEN Hamartoma Tumor Syndrome><PTEN Hamartoma Tumor Syndrome With Granular Cell Tumor><PTEN gene><PTEN1><Particle Size><Pathway interactions><Patients><Pb element><Phagocytes><Phagocytic Cell><Pharmacokinetics><Phosphatase and Tensin Homolog><Phosphatase and Tensin Homolog Deleted on Chromosome 10><Photoradiation><Physiologic><Physiological><Polymers><Predisposition><Property><Proteins><Pulmonary Cancer><Pulmonary malignant Neoplasm><R & D><R&D><RNA><RNA Gene Products><RNA delivery><Ribonucleic Acid><STK11><STK11 gene><Sequence Alteration><Short interfering RNA><Small Interfering RNA><Solid><Surface><Survival Rate><Susceptibility><Synthetic Immunogens><Synthetic Vaccines><System><Technology><Therapeutic><Time><Toxic effect><Toxicities><Transforming Genes><Translating><Tumor Biology><Tumor Burden><Tumor Cell><Tumor Load><Tumor Suppressor Proteins><Tumor Tissue><United States><Validation><Woman><Xenograft><Xenograft procedure><Xenotransplantation><amebocyte><anti-cancer research><anti-cancer therapy><anti-tumor effect><antibody inhibitor><anticancer research><anticancer therapy><antitumor effect><base><biomacromolecular><biomacromolecule><cancer cell><cancer cell genome><cancer genome><cancer research><cancer therapy><cease smoking><cell growth><cost><developmental><excretion><faces><facial><genetically engineered mouse model><genetically engineered murine model><genomic alteration><heavy metal Pb><heavy metal lead><humanized antibody><in vivo><in vivo evaluation><in vivo testing><innovate><innovation><innovative><liver kinase B1><lung cancer><mRNA><macromolecule><malignancy><men><men's><miRNA><miRNAs><nano particle><nano tech><nano technology><nano-sized particle><nano-technological><nanoparticle><nanosized particle><nanotech><nanotechnological><nanotechnology platform><neoplasm/cancer><neoplastic cell><nonsmall cell lung cancer><novel><nuclease><pathway><phase 1 trial><phase I trial><public health relevance><quit smoking><renal><research and development><restoration><self assembly><siRNA><side effect><small molecule><smoking cessation><stop smoking><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><transcriptional silencing><tumor><tumor genome><tumor growth><tumor suppressor><uptake><xeno-transplant><xeno-transplantation>