Glioblastoma Multiforme (GBM), the most common brain cancer of adults, is among the most aggressive and deadly of neoplasm (WHO grade IV), and is accounted for more than 21% of all primary brain and CNS tumors. The annual incidence of GBM in the United States is 3.01 per 100,000 and is an incurable cancer with a median survival of approximately 12 months from diagnosis. Despite decades of intensive surgical treatment, chemotherapy, radiotherapy, and tremendous basic science and clinical research focused on combating this disease, the prognosis remains virtually unchanged, with survival rates still measured in months. The current genetic understanding of GBM has led to the identification of crucial intracellular molecules and their associated signaling pathways as potential therapeutic targets. We are taking the advantage of RNA interference (RNAi) technology for development of the targeted therapeutics. Three small interfering RNA (siRNA) cocktails targeting EGFR-VEGF-AGT, or EGFR-VEGF-MMP9, or EGFR-VEGF-TGF respectively, will be packaged with Histidine and Lysine polymer (HKP) and Saposin C DOPS liposome nanoparticles for treatment of GBM. The antitumor efficacy of these siRNA nanoparticle drugs will be evaluated with human glioma cell lines U87 and murine glioma cells SMA-560 cell tumor models. We will also characterize the HKP and SapC-DOPS nanoparticle systems with the most potent siRNA cocktail and selected a nanoparticle-siRNA cocktail formulation for GBM treatment with the favorable efficacy and safety profile. Lastly, we will evaluate combined regimen of the siRNA cocktail A with TMZ, or cocktail B and C with Avastin, using the U87 and SMA-560 cell tumor models, with the best nanoparticle delivery formulation. A novel therapeutic protocol will be ready for further preclinical study to support a Phase II grant application.
Public Health Relevance: Glioblastoma Multiforme (GBM), the most common brain cancer of adults, is among the most aggressive and deadly of neoplasm (WHO grade IV), and is accounted for more than 21% of all primary brain and CNS tumors. The annual incidence of GBM in the United States is 3.01 per 100,000 and is an incurable cancer with a median survival of approximately 12 months from diagnosis. Despite decades of intensive surgical treatment, chemotherapy, radiotherapy, and tremendous basic science and clinical research focused on combating this disease, the prognosis remains virtually unchanged. We are proposing here to take the advantage of RNA interference (RNAi) technology for development of a novel targeted therapeutic with three small interfering RNA (siRNA) cocktails targeting EGFR-VEGF-AGT, or EGFR-VEGF-MMP9, or EGFR-VEGF-TGF respectively. Two nanoparticle systems, HKP and SapC-DOPS, will be applied with the most potent siRNA cocktail and in combination with the small molecule antagonist drug (TMZ) and monoclonal antibody drug (Avastin) for their antitumor efficacy using both xenograft (U87 cell) and syngeneic (SMA-560 cell) mouse tumor models.
Thesaurus Terms: 21+ Years Old; 3,4-Dihydro-3-Methyl-4-Oxoimidazo[5,1-D]-1,2,3,5-Tetrazine-8-Carboxamide; 4-(3chloro-4-Flurophenylamine)-7-Methoxy-6(3-(4morpholinyl)Quinazoline; 4-Quinazolinamine, N-(3-Chloro-4-Fluorophenyl)-7-Methoxy-6-[3-4-Morpholin] Propoxy]; 8-Carbamoyl-3-Methylimidazo[5,1-D]-1,2,3,5-Tetrazin-4(3h)-One; Accounting; Adult; Animal Growth Regulators, Transforming Growth Factors; Apoptosis; Apoptosis Pathway; Applications Grants; Astrocytoma, Grade Iv; Avastin; Basic Research; Basic Science; Biopsy; Body Tissues; Brain; Clg4; Clg4a; Clg4b; Cns Tumor; Cns Neoplasm; Cancer Radiotherapy; Cancer Of Brain; Cancers; Cell Culture Techniques; Cell Death, Programmed; Cell Growth In Number; Cell Line; Cell Lines, Strains; Cell Multiplication; Cell Proliferation; Cellline; Cells; Cellular Proliferation; Central Nervous System Neoplasms; Characteristics; Chromosomal, Gene, Or Protein Abnormality; Cleaved Cell; Clinical Research; Clinical Study; Co-Beta-Glucosidase; Coglucosidase; Computer Simulation; Computerized Models; Cytogenetic Or Molecular Genetic Abnormality; Dna Repair Enzymes; Dna Sequence Rearrangement; Development; Diagnosis; Disease; Disorder; Down-Regulation; Down-Regulation (Physiology); Downregulation; Drug Formulations; Drugs; Egfr; Erbb Protein; Erbb1; Encephalon; Encephalons; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Kinase; Epidermal Growth Factor Receptor Protein-Tyrosine Kinase; Erlotinib; Essex Brand Of Temozolomide; Exhibits; Forecast Of Outcome; Formulation; Formulations, Drug; Gelb; Gaucher Activator Protein; Gefitinib; Gene Expression; Gene Inactivation; Gene Silencing; Gene Targeting; Genes; Genetic; Genetic Abnormality; Genetic Alteration; Genetic Change; Genetic Defect; Glial Cell Tumors; Glial Neoplasm; Glial Tumor; Glioblastoma; Glioma; Glucosylceramidase Activator; Grade Iv Astrocytic Neoplasm; Grade Iv Astrocytic Tumor; Grant Proposals; Grants, Applications; Her1; Hand; Heterograft; Histidine; Histidine, L-Isomer; Histopathology; Human; Human, Adult; Human, General; In Vitro; Incidence; Investigation; Iressa; L-Histidine; L-Lysine; Lipids; Liposomal; Liposomes; Lysine; Mmp2; Mmp2 Gene; Mmp9; Mmp9 Gene; Mmps; Malignant; Malignant - Descriptor; Malignant Neoplasms; Malignant Tumor; Malignant Tumor Of The Brain; Malignant Neoplasm Of Brain; Mammals, Mice; Man (Taxonomy); Man, Modern; Mathematical Model Simulation; Mathematical Models And Simulations; Matrix Metalloproteinases; Measures; Mediating; Medication; Messenger Rna; Mice; Moab, Clinical Treatment; Modeling; Models, Computer; Molecular Abnormality; Monoclonal Antibodies; Murine; Mus; Mutation; N-(3-Chloro-4-Fluorophenyl)-7-Methoxy-6-(3-(4-Morpholinyl)Propoxy)-4-Quinazolinamide; Nature; Neoplasms; Neoplasms Of Neuroglia; Nervous System, Brain; Neuroglial Neoplasm; Neuroglial Tumor; Oncogenesis; Operation; Operative Procedures; Operative Surgical Procedures; Ptk Inhibitors; Patients; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Phenotype; Polymers; Post-Transcriptional Gene Silencing; Post-Transcriptional Gene Silencings; Posttranscriptional Gene Silencing; Posttranscriptional Gene Silencings; Prognosis; Protein Tyrosine Kinase Inhibitors; Protocol; Protocols Documentation; Quelling; Risc Multicomponent Nuclease; Rna Interference; Rna Silencing; Rna Silencings; Rna, Messenger; Rna, Small Interfering; Rna-Induced Silencing Complex; Rnai; Radiation Therapy; Radiotherapeutics; Radiotherapy; Rearrangement; Receptor Protein; Receptor, Egf; Receptor, Tgf-Alpha; Receptor, Urogastrone; Receptors, Epidermal Growth Factor-Urogastrone; Regimen; Resistance; Sap-C Protein; Safety; Saposin C; Schering Brand Of Temozolomide; Schering-Plough Brand Of Temozolomide; Sequence-Specific Posttranscriptional Gene Silencing; Series; Signal Pathway; Signal Transduction Pathway; Simulation, Computer Based; Small Interfering Rna; Sphingolipid Activator Protein 2; Surgical; Surgical Interventions; Surgical Procedure; Survival Rate; System; System, Loinc Axis 4; Tbe-1; Tk Inhibitors; Tarceva; Targetings, Gene; Temodal; Temodar; Therapeutic; Therapeutic Agents; Tissues; Toxic Effect; Toxicities; Transforming Growth Factor Alpha Receptor; Transforming Growth Factors; Transplantation, Heterologous; Tumor Cell; Tumor Growth Factors; Tumors; Tumors Of Neuroglia; Tumors, Central Nervous System; Tyrosine Kinase Inhibitor; United States; Vegfs; Vascular Endothelial Growth Factors; Vegf; Xenograft; Xenograft Procedure; Xenotransplantation; Adult Human (21+); Angiogenesis; Base; Beta-Glucosidase Activator Protein; Beta-Glucosidase Stimulating Protein; C-Erbb-1; C-Erbb-1 Protein; Chemotherapy; Cleaved; Combat; Computational Modeling; Computational Models; Computational Simulation; Computer Based Models; Computerized Modeling; Computerized Simulation; Cultured Cell Line; Cytokine; Disease/Disorder; Drug/Agent; Erbb-1; Erbb-1 Proto-Oncogene Protein; Erbbl; Genome Mutation; Glioblastoma Multiforme; Glioma Cell Line; Imidazo[5,1-D]-1,2,3,5-Tetrazine-8-Carboxamide, 3, 4-Dihydro-3-Methyl-4-Oxo-; In Silico; In Vivo; Inhibitor; Inhibitor/Antagonist; Irradiation; Mrna; Malignancy; Methazolastone; Nano Particle; Nanoparticle; Neoplasia; Neoplasm/Cancer; Neoplastic; Neoplastic Cell; Neoplastic Growth; New Therapeutic Target; New Therapeutics; Next Generation Therapeutics; Novel Therapeutics; Outcome Forecast; Overexpression; Preclinical Study; Proto-Oncogene Protein C-Erbb-1; Public Health Relevance; Receptor; Resistant; Response; Sirna; Small Molecule; Spongioblastoma Multiforme; Surgery; Technology Development; Temozolomide; Therapeutic Target; Tumor; Tumor Growth; Tumorigenesis; Tumors In The Central Nervous System; Virtual Simulation
