This project addresses the critical need for treatments of castration resistant prostate cancer (CRPC) by proposing to engineer and develop a novel, nanostructured pharmaceutical (P-TRIS5) which will target tumor cells and deliver two potent, synergistic therapeutics (an siRNA and a small molecule) to inhibit the androgen receptor and RUNX, two commonly implicated transcription factors in CRPC. We will study the new compound using in vitro and in vivo models that are well-established for CRPC and seek to show 1) effective in vitro targeting and cellular uptake, and 2) effective delivery and efficacy in two xenograft mouse models. Parabon NanoLabs has significant experience in the development and validation of rationally designed, nanostructured pharmaceuticals and will leverage existing infrastructure, expertise, and collaborations to investigate the potential for the proposed CRPC targeted drug. Our synthesis methodology begins with the design of P-TRIS5 using Parabons Essemblix Drug Development Platform, a powerful combination of computer-aided design (CAD) software for designing self-assembling DNA nanocarriers and proprietary nanofabrication methods for their production. Next, the two therapeutics and a targeting peptide will be conjugated to the nanocarrier using commercially available compounds and purified by standard protocols. We will measure the performance of P-TRIS5 by monitoring a fluorescent label on the compound for targeting (via fluorescent confocal microscopy in vitro) and tumor growth via bioluminescent full-body live imaging. Off-target cytotoxicity will also be measured in vivo to demonstrate selective targeting of the tumor. Post-mortem excised tissues will be analyzed to determine the extent of inhibition of downstream targets in the animal model. The success of this project will create new avenues to rationally design nanostructured pharmaceuticals against many kinds of cancer. Our focus on CRPC, a prostate cancer with a critical need for new therapies, is driven by an abundance of knowledge about the molecular biology involved and the synergy formed by a combination of small molecules and siRNA to target drivers of the most dangerous variants of this deadly disease. Public Health Relevance Statement Project Narrative This NIH STTR Phase I project will create a novel therapeutic for the treatment of castration resistant prostate cancer (CRPC). The proposed therapeutic will incorporate targeting molecules specific to prostate cancer that will enable it to bind and be taken up by prostate cancer cells. The therapeutic will carry a dual payload to inhibit the activity of key CRPC transcription factors, a class of proteins previously considered to be undruggable.
Project Terms: Affect ; inhibitor/antagonist ; inhibitor ; Autopsy ; necropsy ; postmortem ; Biological Assay ; Assay ; Bioassay ; Biologic Assays ; Malignant Neoplasms ; Cancers ; Malignant Tumor ; malignancy ; neoplasm/cancer ; Castration ; Surgical Castration ; Cell Count ; Cell Number ; Cell Differentiation process ; Cell Differentiation ; cell growth ; Cellular Expansion ; Cellular Growth ; Cell Line ; CellLine ; Strains Cell Lines ; cultured cell line ; Cell Survival ; Cell Viability ; Cells ; Cell Body ; Charge ; Dangerousness ; Diagnosis ; Disease ; Disorder ; DNA ; Deoxyribonucleic Acid ; Pharmaceutical Preparations ; Drugs ; Medication ; Pharmaceutic Preparations ; drug/agent ; Dyes ; Coloring Agents ; Engineering ; Glioblastoma ; Grade IV Astrocytic Neoplasm ; Grade IV Astrocytic Tumor ; Grade IV Astrocytoma ; glioblastoma multiforme ; spongioblastoma multiforme ; In Vitro ; Lead ; Pb element ; heavy metal Pb ; heavy metal lead ; Ligands ; Luciferases ; Luciferase Immunologic ; Methods ; Methodology ; Molecular Biology ; DNA Molecular Biology ; Mus ; Mice ; Mice Mammals ; Murine ; United States National Institutes of Health ; NIH ; National Institutes of Health ; Patients ; Peptides ; Production ; Proteins ; Androgen Receptor ; RNA Splicing ; Splicing ; Messenger RNA ; mRNA ; Software Design ; Designing computer software ; Technology ; Testing ; Tissues ; Body Tissues ; transcription factor ; Basal Transcription Factor ; Basal transcription factor genes ; General Transcription Factor Gene ; General Transcription Factors ; Transcription Factor Proto-Oncogene ; Transcription factor genes ; Genetic Transcription ; Gene Transcription ; RNA Expression ; Transcription ; Measures ; Computer-Aided Design ; Computer-Assisted Design ; Label ; improved ; Site ; Surface ; Phase ; Variant ; Variation ; Nuclear Receptors ; Core-Binding Factor ; CBF ; Ensure ; Confocal Microscopy ; uptake ; docetaxel ; Taxotere ; docetaxol ; cyanine dye 5 ; Cy5 ; Antiandrogen Therapy ; Anti-androgen Therapy ; Anti-androgen Treatment ; Antiandrogen Treatment ; Collaborations ; Therapeutic Steroid Hormone ; steroid hormone ; Therapeutic ; Shapes ; Malignant Tumor of the Prostate ; Malignant prostatic tumor ; Prostate CA ; Prostate Cancer ; Prostatic Cancer ; Malignant neoplasm of prostate ; Knowledge ; Complex ; Dependence ; Protocol ; Protocols documentation ; cell type ; Heterograft ; Heterologous Transplantation ; Xenograft ; Xenotransplantation ; xeno-transplant ; xeno-transplantation ; Xenograft procedure ; Lytotoxicity ; cytotoxicity ; experience ; Tumor Cell ; neoplastic cell ; Performance ; success ; drug efficacy ; fluorophore ; tumor growth ; synergism ; Animal Models and Related Studies ; model of animal ; model organism ; Animal Model ; novel ; protein protein interaction ; drug development ; Short interfering RNA ; siRNA ; Small Interfering RNA ; Molecular Interaction ; Binding ; Pharmaceutical Agent ; Pharmaceuticals ; Pharmacological Substance ; Pharmacologic Substance ; small molecule ; FOLH ; FOLH1 ; Folate Hydrolase 1 ; GCP2 ; Glutamate Carboxypeptidase II ; N-Acetylated Alpha-Linked Acidic Dipeptidase 1 ; NAALAD1 ; NAALADase I ; PSM ; PSMA ; Prostate-Specific Membrane Antigen ; FOLH1 gene ; Address ; Length ; Tumor Load ; Tumor Burden ; nano-structures ; Nanostructures ; Data ; Drug Efflux ; Interruption ; pre-clinical testing ; Preclinical Testing ; in vivo ; in vivo Model ; Antigen Targeting ; therapy outcome ; therapeutic outcome ; Small Business Technology Transfer Research ; STTR ; Validation ; Monitor ; Tracer ; Development ; developmental ; Image ; imaging ; therapy resistant ; resistance to therapy ; resistant to therapy ; therapeutic resistance ; treatment resistance ; self assembly ; nanodrug ; nano drug ; nanopharmaceutical ; design ; designing ; nanofabrication ; nano fabricate ; nano fabrication ; nanofabricate ; nanocarrier ; nano carrier ; targeted delivery ; site targeted delivery ; Prostate Cancer therapy ; Prostate CA therapy ; prostate cancer treatment ; innovation ; innovate ; innovative ; Resistance ; resistant ; novel therapeutics ; new drug treatments ; new drugs ; new therapeutics ; new therapy ; next generation therapeutics ; novel drug treatments ; novel drugs ; novel therapy ; mouse model ; murine model ; therapeutic target ; VCaP ; CWR22Rv1 ; 22RV1 ; tumor ; standard of care ; effective therapy ; effective treatment ; prostate cancer cell ; prostate tumor cell ; Drug Targeting ; castration resistant prostate cancer ; castrate resistant PCa ; castrate resistant prostate cancer ; castration resistant PCa ; microscopic imaging ; microscope imaging ; microscopy imaging ; androgen deprivation therapy ; androgen ablation therapy ; androgen blockade therapy ; androgen deprivation treatment ; in vivo evaluation ; in vivo testing ; cancer drug resistance ; resistance to cancer drugs ; resistant to cancer drugs ; Infrastructure ; Visualization ; testing uptake ;
