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Principal Investigator: Aiming Yu
Organization: UNIVERSITY OF CALIFORNIA AT DAVIS
Fiscal Year: 2024
Award: $394,349
Funding agency: National Cancer Institute
PROJECT SUMMARY
Lung cancer remains the most lethal cancer among both women and men in the United States. There is a clear
need for developing new and more effective therapeutics for the treatment of lung cancer, especially the most
predominant subtype non-small cell lung cancer (NSCLC). As posttranscriptional gene regulators, the
genome-derived microRNAs (miRNAs or miRs) govern many critical cancer cellular processes such as
proliferation, invasion, and stemness. Therefore, restoration of tumor suppressive miRNAs (e.g., miR-124-3p
(miR-124)) lost or downregulated in NSCLC cells represents a novel therapeutic approach. However, current
research relies primarily on the use of chemo-engineered miRNA mimics (ChemoRNAs) synthesized in vitro and
comprised of extensive and diverse types of artificial modifications at various locations, which are different from
natural RNA molecules produced and tolerated in vivo that do not contain any modifications or just a few
necessary posttranscriptional modifications. Our past and ongoing efforts have led to a patented platform
technology to achieve a robust, high-yield, and large-scale in vivo fermentation production and use of true
biologic or bioengineered RNA agents (BioRNAs). We have demonstrated that BioRNAs, consisting of only
several natural modifications, are precisely processed to target miRNAs (or siRNAs) to selectively regulate target
gene expression in human NSCLC cells and subsequently, inhibit NSCLC cell proliferation and invasiveness as
well as tumor progression and metastasis. Among the NSCLC-relevant biologic RNAs, we have identified a few
lead miRNAs (e.g., miR-124 and miR-22-3p (miR-22)) consistently exhibiting potent antiproliferative activities
against multiple NSCLC cell lines. Our preliminary studies have also showed that BioRNA/miR-124 is more
efficacious than commercial ChemoRNA/miR-124 to regulate target gene expression and NSCLC cell viability,
and miR-124 may control NSCLC immunity via modulating specific immune regulator and checkpoint protein
levels. Further, we have found that miR-22 controls NSCLC metabolism through the regulation of key nutrient
metabolic enzymes and transporters. Moreover, humanized BioRNA/miR-124 and miR-22 lipopolyplex
monotherapy effectively reduced tumor progression in animal models without causing any hepatic or renal
toxicity or severe immunogenic effects. Given such exciting preliminary findings, we hypothesize that novel
bioengineered RNA molecules can be utilized to modulate NSCLC metabolism and immunity to improve
therapeutic outcomes of current medications via pharmacodynamic and pharmacokinetic interactions. To test
the hypothesis, we propose to define the biosimilarities between model Bio- and Chemo-RNA molecules by
side-by-side comparing their efficacy and specificity in the regulation of target gene expression and inhibition of
NSCLC cell growth (Aim 1), delineate the molecular pharmacological actions of lead BioRNAs in the control of
NSCLC cell metabolism and immune checkpoint (Aim 2), and establish the effectiveness and safety of BioRNAs
to improve the therapeutic outcomes of co-administered drugs in vivo (Aim 3). The proposed research will
establish BioRNAs as one-of-a-kind RNA molecules for research and open new directions for the development of
novel biologic RNA therapeutics for the treatment of NSCLC.
Terms: <Abbreviations><Action Potentials><Amino Acids><Animal Model><Animal Models and Related Studies><B7-H1><B7H1><Bio-Informatics><Bioinformatics><Biological><Biological Response Modifiers><Biomedical Engineering><Biomodulators><Blood><Blood Reticuloendothelial System><Blood Serum><CD274><Cancer Cause><Cancer Cell Growth><Cancer Etiology><Cancer cell line><Cancers><Carbon><Cell Body><Cell Function><Cell Growth in Number><Cell Multiplication><Cell Physiology><Cell Process><Cell Proliferation><Cell Survival><Cell Viability><Cell model><Cells><Cellular Function><Cellular Physiology><Cellular Process><Cellular Proliferation><Cellular model><Cessation of life><Death><Development><Development and Research><Drug Combinations><Drug Kinetics><Drug or chemical Tissue Distribution><Drugs><Effectiveness><Endotoxins><Engineering><Enzyme Gene><Enzymes><Exhibits><Fermentation><Folate><Folic Acid><Functional RNA><Gene Action Regulation><Gene Expression><Gene Expression Regulation><Gene Regulation><Gene Regulation Process><Gene Transcription><Genetic Transcription><Genome><Goals><HL-A Antigens><HLA Antigens><HPLC><Hepatic><High Performance Liquid Chromatography><High Pressure Liquid Chromatography><High Speed Liquid Chromatography><Human><Human Leukocyte Antigens><Immune><Immune Mediators><Immune Mediators/Modulators><Immune Regulators><Immunes><Immunity><In Vitro><Intermediary Metabolism><Invaded><Isotopes><Kidney><Kidney Urinary System><Knowledge><Lead><Legal patent><Leukocyte Antigens><Liposomal><Liposomes><Location><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Medication><Metabolic><Metabolic Processes><Metabolism><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Micro RNA><MicroRNAs><Mitochondria><Modeling><Modern Man><Modification><Molecular><Multitargeted Antifolate><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Neoplasm Metastasis><Non-Coding><Non-Coding RNA><Non-Polyadenylated RNA><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Non-translated RNA><Noncoding RNA><Nontranslated RNA><Nutrient><Oncolytic><PBMC><PD-L1><PDL-1><PDL1><PDX model><PK/PD><Patents><Patient derived xenograft><Pb element><Pemetrexed><Peptides><Peripheral Blood Mononuclear Cell><Pharmaceutical Preparations><Pharmacokinetics><Pharmacologic Actions><Platinum><Platinum Black><Post-Transcriptional Control><Post-Transcriptional Gene Silencing><Post-Transcriptional Regulation><Posttranscriptional Gene Silencing><Process><Production><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Proliferating><Property><Proteins><Proteomics><Pt element><Pteroylglutamic Acid><Pulmonary Cancer><Pulmonary malignant Neoplasm><R & D><R&D><RNA><RNA Expression><RNA Gene Products><RNA Interference><RNA Seq><RNA Silencing><RNA based therapeutics><RNA based therapy><RNA sequencing><RNA therapy><RNAi><RNAseq><Regulation><Regulator Genes><Research><Ribonucleic Acid><Role><Safety><Secondary Neoplasm><Secondary Tumor><Seminal><Sequence-Specific Posttranscriptional Gene Silencing><Serum><Short interfering RNA><Side><Small Interfering RNA><Small RNA><Specificity><Stem Cell like><Subcellular Process><Technology><Testing><Tissue Distribution><Toxic effect><Toxicities><Transcription><Transcriptional Regulatory Elements><Tumor Immunity><United States><Untranslated RNA><Vitamin M><Woman><aminoacid><anti-tumor immunity><antitumor immunity><bio-engineered><bio-engineers><bioengineering><biologic><biological engineering><cancer cell metabolism><cancer immunity><cancer metabolism><cancer metastasis><cancer progression><clinical relevance><clinically relevant><comparable efficacy><comparative efficacy><compare efficacy><determine efficacy><developmental><drug/agent><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><evaluate efficacy><examine efficacy><heavy metal Pb><heavy metal lead><immune check point><immune checkpoint><immunecheckpoint><immunogenic><immunomodulatory biologics><improved><in vivo><innovate><innovation><innovative><invention><lung cancer><lung cancer cell><malignancy><men><metabolome><metabonome><miR therapy><miR-based therapeutic><miR-based therapy><miRNA><miRNA therapy><miRNA-based therapeutic><miRNA-based therapy><miRNAs><microRNA therapy><microRNA-based therapeutic><microRNA-based therapy><mitochondrial><model of animal><mouse model><murine model><nanocomplexes><nanotherapeutic><neoplasm progression><neoplasm/cancer><neoplastic progression><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><noncoding><novel><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><patient derived xenograft model><pharmacodynamic biomarker><pharmacodynamic marker><pharmacokinetics and pharmacodynamics><pharmacologic><post-transcriptional gene regulation><posttranscriptional><posttranscriptional control><posttranscriptional regulation><programmed cell death ligand 1><programmed cell death protein ligand 1><protein death-ligand 1><protein expression><regulatory gene><renal><research and development><response><restoration><screening><screenings><siRNA><social role><stem cell characteristics><stemness><synergism><technology platform><technology system><therapeutic RNA><therapeutic miRNA><therapeutic miRs><therapeutic microRNA><therapeutic outcome><therapeutically effective><therapy outcome><tool><trans acting element><transcriptome sequencing><transcriptomic sequencing><translational opportunities><translational potential><tumor><tumor cell metabolism><tumor cell metastasis><tumor metabolism><tumor progression><vitamin Bc>