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Principal Investigator: ZHENG-RONG LU
Organization: CASE WESTERN RESERVE UNIVERSITY
Fiscal Year: 2021
Award: $23,693
Funding agency: National Cancer Institute
3.8.1 Research, mentoring and career development
1). Research Plan
1.1). Abstract of the parent grant
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-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><Doctor of Philosophy><Drug Sensitization><Drug resistance><ECM><EGF Receptor><EGFR><ERBB Protein><ERBB2><ERBB2 gene><Effectiveness><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><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><Human><In Vitro><Injections><Life><Lipids><Malignant Cell><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Mediating><Mentors><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Modern Man><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><Ph.D.><PhD><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><Research><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><Scientist><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><Tissues><Training><Transcript><Transcription><Transforming Genes><Transforming Growth Factor alpha Receptor><Untranslated RNA><Up-Regulation><Upregulation><Urogastrone Receptor><WNT Signaling Pathway><WNT signaling><Woman><Xenograft Model><aggressive breast cancer><anti-cancer research><anticancer research><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 research><cancer sub-types><cancer subtypes><career development><chemotherapy><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><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><overexpress><overexpression><parent grant><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><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><xenograft transplant model><xenotransplant model><β-catenin>