In spite of recent advances, cancer remains a major killer posing a dire need for more effective therapy, and unfortunately this is particularly true for metastatic non-small cell lung cancer (NSCLC), which afflicts an extremely large number of patients and is one of the least treatable cancers. With the growing success of targeted therapeutics, it has become clear that a greater understanding of NSCLC biochemistry and pathology is a crucial bottleneck in identifying new and better treatments. To that end considerable efforts are underway developing advanced genomic and proteomic methods applicable to clinical samples, with a major advance coming from a capability for using laser micro-dissection and protein extraction and analysis with the large libraries of formalin fixed tissue sections. However, a remaining major barrier to using this extremely valuable information for development of targeted therapeutics is to characterize the functional role of the tumor associated proteins. Yet another major advance helping address this need is the recent development of RNA interference (RNAi) but this revolutionary capability to characterize gene function has been confined largely to cell culture studies, with limited methods for in vivo administration in animal disease models such as NSCLC xenograft tumor models, and none available as a research reagent. Our hypothesis is that we can adapt our cationic polypeptide nucleic acid nanoparticle technology, which we have found effective for in vivo delivery of RNAi agents to a primary breast cancer xenograft model, for a set of metastatic and primary NSCLC xenograft tumor models. The planned research to determine feasibility of a commercializable reagent for in vivo RNAi application to metastatic and primary NSCLC xenograft tumor models has the following objectives for Phase I: 1) establish two pair of metastatic and primary NSCLC xenograft models, 2) adapt and optimize the HK polypeptide and nanoparticle structure for in vivo delivery with these models using a positive control RNAi agent, and 3) evaluate the effectiveness of the optimized HK RNAi nanoparticle for target validation using a set of candidate targets found to be differentially expressed in metastatic tumor or primary tumor lesions but not both from patient tissue samples. If successful, Phase II will undertake commercial development of a reagent for in vivo RNAi for NSCLC xenograft model gene function target validation with capabilities including metastatic cancer.
Public Health Relevance: Metastatic non-small cell lung cancer (NSCLC) afflicts an extremely large number of patients and is one of the least treatable cancers and thus is a major area for research applying advances in genomic and proteomic methods with the objective to identify better drug targets. However, a remaining major barrier is a need for commercial reagents for using RNA interference (RNAi) directly in animal models of metastatic NSCLC. The RNAi revolutionary capability to characterize gene function and identify candidate drug targets has been confined largely to cell culture studies. Our planned studies are to adapt our cationic polypeptide nucleic acid nanoparticle technology for in vivo delivery of RNAi agents for a set of metastatic and primary NSCLC xenograft tumor models. If successful, the resulting reagent is expect to enable rapid advances in understanding this life threatening disease that produce better targeted therapeutic treatment options for patients.
Thesaurus Terms: A549; Address; Advanced Cancer; Advanced Malignant Neoplasm; Animal Cancer Model; Animal Disease Models; Animal Model; Animal Models And Related Studies; Animalmodel; Area; Artifacts; Biochemistry; Body Tissues; Breast; Cancer Cause; Cancer Etiology; Cancer Genes; Cancer Model; Cancer Patient; Cancer Of Breast; Cancer Of Lung; Cancer-Promoting Gene; Cancermodel; Cancers; Carcinoma, Non-Small-Cell Lung; Cell Culture Techniques; Cell Line; Cell Lines, Strains; Cellline; Cessation Of Life; Chemistry, Biological; Clinical; Complex; Dissec; Death; Development; Diagnosis; Disease; Disorder; Dissection; Disseminated Malignant Neoplasm; Drug Delivery; Drug Delivery Systems; Drug Targeting; Drug Targetings; Egfr; Egfr Gene; Erbb; Erbb Protein; Erbb1; Erbb1 Gene; Effectiveness; Electromagnetic, Laser; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Genes; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Event; Formalin; Foundations; Gene Targeting; Generalized Growth; Genes; Genes, Egfr; Genes, P53; Genomics; Growth; Her1; Head And Neck Cancer; Heterograft; Iv Drip; Immune; In Vitro; Intravenous Drip; Intravenous Infusion; Investigation; Knock-Out; Knockout; Lasers; Lesion; Libraries; Life; Literature; Malignant Head And Neck Neoplasm; Malignant Neoplasms; Malignant Tumor; Malignant Tumor Of The Breast; Malignant Tumor Of The Head And Neck; Malignant Tumor Of The Lung; Malignant Neoplasm Of Breast; Malignant Neoplasm Of Lung; Metastasis; Metastasize; Metastatic Cancer; Metastatic Malignant Neoplasm; Metastatic Neoplasm; Metastatic Tumor; Metastatic To; Methods; Modeling; Molecular; Morphologic Artifacts; Nsclc; Nsclc - Non-Small Cell Lung Cancer; Neoplasm Metastasis; Non-Small Cell Lung Cancer; Non-Small-Cell Lung Carcinoma; Nucleic Acids; Oncogenes; P53; Pathology; Patients; Phase; Plasmids; Play; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Primary Neoplasm; Primary Tumor; Proteins; Proteomics; Pubmed; Pulmonary Cancer; Pulmonary Malignant Neoplasm; Quelling; Rna Interference; Rna Silencing; Rna Silencings; Rna, Small Interfering; Rnai; Rt-Pcr; Rtpcr; Radiation, Laser; Reagent; Receptor, Egf; Receptor, Tgf-Alpha; Receptor, Urogastrone; Receptors, Epidermal Growth Factor-Urogastrone; Reporter; Research; Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Screening Procedure; Secondary Neoplasm; Secondary Tumor; Sequence-Specific Posttranscriptional Gene Silencing; Small Interfering Rna; Sorting - Cell Movement; Structure; Structure-Activity Relationship; Study Models; Tp53; Tp53 Gene; Trp53; Targeted Research; Targetings, Gene; Technology; Testing; Therapeutic; Time; Tissue Growth; Tissue Sample; Tissues; Transforming Genes; Transforming Growth Factor Alpha Receptor; Translating; Translatings; Transplantation, Heterologous; Tumor Cell; Tumor Cell Migration; Tumor Protein P53 Gene; Validation; Xenograft; Xenograft Model; Xenograft Procedure; Xenotransplantation; Base; C-Erbb-1; C-Erbb-1 Gene; C-Erbb-1 Protein; C-Erbb-1 Proto-Oncogenes; Cancer Metastasis; Cell Behavior; Chemical Structure Function; Cost; Cultured Cell Line; Disease/Disorder; Drip Infusion; Effective Therapy; Erbb-1; Erbb-1 Proto-Oncogene Protein; Erbbl; Expression Vector; Functional Genomics; Gene Function; Gene Product; Head & Neck Cancer; Head & Neck Tumor; Improved; In Vivo; Inhibitor; Inhibitor/Antagonist; Interest; Intravenous Administration; Language Translation; Lung Cancer; Malignancy; Malignant Breast Neoplasm; Meetings; Model Organism; Nano Particle; Nanoparticle; Neoplasm/Cancer; Neoplastic Cell; New Therapeutic Target; Nonsmall Cell Lung Cancer; Novel; Ontogeny; Plasmid Dna; Polypeptide; Proto-Oncogene Protein C-Erbb-1; Public Health Relevance; Response; Reverse Transcriptase Pcr; Screening; Screenings; Shrna; Short Hairpin Rna; Sirna; Small Hairpin Rna; Social Role; Sorting; Structure Function Relationship; Success; Therapeutic Target; Tissue Fixing; Tumor; Tumor Growth; Tumor Xenograft; Vein Infusion
