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Principal Investigator: ZHENG-RONG LU
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2020
Award: $356,947
Funding agency: National Cancer Institute
The goal of this project is to develop smart dual-targeted lipid ECO/siRNA self-assembly
nanoparticles to target oncogenic long non-coding RNAs (lncRNAs) as a novel therapy to
treat metastatic and drug-resistant triple negative breast cancer (TNBC). Metastasis and drug
resistance are the main causes for high mortality rate of women diagnosed with TNBC
worldwide. Although targeted therapies have been developed to treat some subtypes of
breast cancer, the TN subtype is particularly refractory to these therapies. Oncogenic
lncRNAs play a critical role in tumorigenesis, stemness, invasion, metastasis, and drug
resistance of cancer by simultaneously manipulating multiple cancer-associated signaling
pathways. Hence, lncRNAs are promising novel therapeutic targets for TNBC. We will
develop smart dual-targeted lipid ECO/siRNA nanoparticles to regulate the expression of an
identified lncRNA associated with cancer EMT, stemness, metastasis, and drug resistance as
a novel therapy for TNBC. This oncogenic lncRNA is highly expressed in TNBC tumors, but
not in normal tissues, making this smart nanoparticle therapy a highly feasible and promising
approach to effectively treating TNBC without any adverse effects in healthy tissues. We have
demonstrated the feasibility of silencing the oncogenic lncRNA for suppressing the survival
and aggressiveness of TNBC cells and for completely inhibiting tumor proliferation in a TNBC
mouse model. In this project, we will optimize and develop the smart ECO/siRNA
nanoparticles to improve tumor-specific cytosolic delivery of therapeutic siRNAs and to
effectively silence the cancer-promoting lncRNA in treating TNBC. We will also explore the
combination therapy of silencing lncRNA with the smart nanoparticles and chemotherapy to
have the synergistic effects of inhibiting metastasis, alleviating multidrug resistance and
enhancing chemotherapy to achieve curative outcomes and to eventually eradicate TNBC.
The specific aims of this project are 1) to design and optimize smart dual-targeted
ECO/siRNA nanoparticles for efficient and specific gene silencing in cancer cells via systemic
administration; 2) to determine the effects of silencing oncogenic lncRNA with the smart dual-
targeted ECO/siRNA nanoparticles on the invasiveness and drug-resistance of TNBC cells in
vitro; 3) to determine the efficacy of the smart dual-targeted ECO/siRNA nanoparticles alone
and in combination with chemotherapy for TNBC therapy in animal models. Our long-term
goal is to develop a novel and feasible therapy based on the smart nanoparticles to treat life-
threatening metastatic and drug-resistant breast cancer.
Terms: <Adverse effects><Affect><Animal Model><Animal Models and Related Studies><Attention><Beta Cadherin-Associated Protein><Beta-1 Catenin><Biological Function><Biological Process><Body Tissues><Breast Cancer><Breast Cancer Cell><Breast Cancer Model><Breast Cancer Patient><Breast Cancer Treatment><Breast Cancer therapy><Breast Tumor Patient><Breast tumor model><CUL-2><Cancer Genes><Cancer Patient><Cancer-Promoting Gene><Cancers><Cell Body><Cell-Extracellular Matrix><Cells><Cessation of life><Chemotherapy and Radiation><Chemotherapy and/or radiation><Code><Coding System><Combined Modality Therapy><Cytoplasm><Death><Development><Diagnosis><Differentiation and Growth><Disease><Disorder><Drug Sensitization><Drug resistance><ECM><EGF Receptor><EGFR><ERBB Protein><ERBB2><ERBB2 gene><Effectiveness><Endocrine Gland Secretion><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Estrogen Receptors><Evaluation><Extracellular Matrix><Formulation><Functional RNA><Gene Action Regulation><Gene Expression Regulation><Gene Inactivation><Gene Regulation><Gene Regulation Process><Gene Silencing><Gene Transcription><Genetic Transcription><Goals><HER -2><HER-2><HER1><HER2><HER2 Genes><HER2/neu><Hormones><In Vitro><Injections><Lead><Life><Lipids><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Mediating><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Metastatic breast cancer><Multi-Drug Resistance><Multidrug Resistance><Multimodal Therapy><Multimodal Treatment><Multiple Drug Resistance><Multiple Drug Resistant><NEU Oncogene><NEU protein><Neoplasm Metastasis><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Normal Tissue><Normal tissue morphology><Nucleotides><Oncogene ErbB2><Oncogenes><Oncogenesis><Oncogenic><Outcome><PRO2286><Patients><Pb element><Phenotype><Play><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Process><Progesterone Receptors><Progestin Receptors><Prognosis><Prostate CA><Prostate Cancer><Prostatic Cancer><Quelling><RNA><RNA Expression><RNA Gene Products><RNA Interference><RNA Silencing><RNAi><Radiation therapy><Radiotherapeutics><Radiotherapy><Refractory><Regimen><Relapse><Resistance development><Resistance to Multi-drug><Resistance to Multidrug><Resistance to Multiple Drug><Resistant development><Resistant to Multiple Drug><Resistant to multi-drug><Resistant to multidrug><Ribonucleic Acid><Role><Secondary Neoplasm><Secondary Tumor><Sequence-Specific Posttranscriptional Gene Silencing><Short interfering RNA><Signal Pathway><Small Interfering RNA><Survival Rate><TGF-alpha Receptor><TKR1><TNBC><Therapeutic><Therapeutic Hormone><Tissues><Transcript><Transcription><Transforming Genes><Transforming Growth Factor alpha Receptor><Untranslated RNA><Up-Regulation><Upregulation><Urogastrone Receptor><WNT Signaling Pathway><WNT signaling><Woman><Xenograft Model><base><beta catenin><breast tumor cell><c-erbB-1><c-erbB-1 Protein><c-erbB-2><c-erbB-2 Genes><c-erbB-2 Proto-Oncogenes><cancer cell><cancer drug resistance><cancer metastasis><cancer sub-types><cancer subtypes><cancer survival><chemotherapy><clinical development><colorectal cancer progression><combination therapy><combined modality treatment><combined treatment><design><designing><developing resistance><developmental><drug resistant><effective therapy><effective treatment><environmental change><erbB-1><erbB-1 Proto-Oncogene Protein><erbB-2 Genes><erbBl><heavy metal Pb><heavy metal lead><herstatin><improved><in vivo><ineffective therapies><ineffective treatment><malignancy><malignant breast neoplasm><malignant breast tumor><mammary cancer model><mammary tumor model><migration><model of animal><model organism><mortality><mouse model><multi-drug resistant><multi-modal therapy><multi-modal treatment><multidrug resistant><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><neoplasm/cancer><neu Genes><new drug target><new drug treatments><new druggable target><new drugs><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><noncoding><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><outcome forecast><overexpress><overexpression><pre-clinical development><preclinical development><proto-oncogene protein c-erbB-1><radiation treatment><radio-therapy><resistance to Drug><resistance to cancer drugs><resistant to Drug><resistant to cancer drugs><self assembly><siRNA><siRNA delivery><siRNA therapy><siRNA-based therapeutic><side effect><social role><standard of care><stemness><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic siRNA><therapeutic target><transcriptional silencing><treatment with radiation><triple-negative breast cancer><triple-negative invasive breast carcinoma><tumor><tumor cell metastasis><tumorigenesis><β-catenin>