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Principal Investigator: Marcus E. Peter
Organization: NUAGO THERAPEUTICS INC
Fiscal Year: 2024
Award: $400,000
Funding agency: National Cancer Institute
PROJECT SUMMARY
Prostate cancer (PC) is the most common cancer in men, and the second leading cause of cancer death among
men in the United States. There is a critical unmet need to develop novel, efficacious therapeutics for PC. NUAgo
Therapeutics, Inc. is developing an RNA-interference-based therapeutic for PC based on research conducted at
Northwestern University into a naturally occurring anti-cancer mechanism. This research identified a class of
short (19-22 nt long) double-stranded (ds) interfering RNA molecules (here termed “sRNAs”) that potently target
genes that are essential for cancer cell survival. These sRNAs are derived from CAG trinucleotide repeat (TNR)
sequences that are found in genes associated with several neurodegenerative diseases, including huntingtin
(the cause of Huntington’s disease) and the androgen receptor (AR) gene (the cause of spinobulbar muscular
atrophy [SBMA]/Kennedy disease). Both diseases are associated with reduced cancer incidence. Evidence
indicates that CAG expansions lead to increased production of short interfering RNAs that bind to complementary
transcripts and downregulate their expression. sRNAs containing the CAG repeat (“sCAG”) are extremely toxic
to cancer cells by targeting highly expressed CUG repeat-containing genes, providing both a mechanistic
explanation for the reduced incidence of cancer in patients with certain neurodegenerative diseases and a novel
therapeutic approach for cancer treatment. PC is a particularly attractive target for this novel therapeutic
approach. The number of CAG repeats in the AR gene is inversely correlated with PC incidence, the
aggressiveness of the disease, and the risk of distant metastasis. Longer CAG repeats thus appear to have an
anti-tumor effect, suggesting susceptibility of PC cells to sCAG. The goal of this STTR project is to develop an
sCAG-based therapeutic, which will be delivered to cells using lipopolyplex (LPP) nanoparticles, to treat PC. In
Aim 1, the uptake and activity of sCAG-LPP (“NU002”) will be evaluated in mouse models of prostate cancer,
quantifying both sCAG delivery and silencing activity in PC cells in vivo. Uptake and activity of the NU002 and a
non-toxic control sRNA will be evaluated in both tumor and normal cells in four mouse models, including two
xenograft models of PC and a syngeneic PC model. Uptake will be monitored by fluorescently labeling the
sRNAs, while silencing activity will be measured using a fluorescent reporter gene that includes a corresponding
target sequence. RNA sequencing will be used to measure the expression of target genes in tumors. In Aim 2,
the anti-tumor effects of NU002 will be characterized in vivo in the same four xenograft and syngeneic models
as in Aim 1, measuring the effect on excised tumor size at 4-6 weeks post-treatment. Histological and liver
enzyme analyses will be used to examine toxicity in normal tissues, and RNA sequencing will again be performed
on tumor and normal tissue samples to quantify the expression of targeted genes. This Phase I work will provide
proof-of-concept data supporting future work that will focus on preclinical IND-enabling studies and formulation
development in preparation for a first-in-human clinical trial.
Terms: <3' Untranslated Regions><3'UTR><AR gene><After Care><After-Treatment><Aftercare><Alpha Particle Radiation><Alpha Particles><Alpha Radiation><Androgen Receptor><Anti-androgen Therapy><Anti-androgen Treatment><Body Tissues><Bulbospinal Neuronopathy><CAG repeat><CAG trinucleotide repeat><CUG repeat><Cancer Cause><Cancer Etiology><Cancer Treatment><Cancer cell line><Cancers><Castration><Cell Body><Cell Death><Cell Growth in Number><Cell Multiplication><Cell Proliferation><Cell Survival><Cell Viability><Cells><Cellular Proliferation><Cessation of life><Clinical Trials><Cytotoxic agent><Cytotoxic drug><Data><Death><Degenerative Neurologic Disorders><Development><Diagnosis><Dihydrotestosterone Receptor><Disease><Disorder><Distant Cancer><Distant Metastasis><Drugs><Endocrine Therapy><Enzyme Gene><Enzymes><FDA approved><Fluorescence><Formulation><Future><GEM model><GEMM model><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Genes><Genetically Engineered Mouse><Genome Instability><Genomic Instability><Goals><HD Gene><HD protein><Hepatic Cancer><Heterograft><Heterologous Transplantation><Histologic><Histologically><Hormonal Therapy><Human><Huntingtin><Huntingtin Protein><Huntington Chorea><Huntington Disease><Huntington gene><Huntington protein><Huntington's><Huntington's Disease><Huntington's disease gene product><Huntingtons Disease><IT15 gene><Immune mediated therapy><Immunoblotting><Immunologically Directed Therapy><Immunotherapy><Incidence><Intratumoral heterogeneity><Intravenous><Kennedy Syndrome><Kennedy's Disease><Label><Lead><Liver><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Ovary><Malignant Tumor of the Prostate><Malignant neoplasm of liver><Malignant neoplasm of ovary><Malignant neoplasm of prostate><Malignant prostatic tumor><Measurement><Measures><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medication><Messenger RNA><Mice><Mice Mammals><Modeling><Modern Man><Monitor><Murine><Mus><NMR Imaging><NMR Tomography><NR3C4><Nervous System Degenerative Diseases><Neural Degenerative Diseases><Neural degenerative Disorders><Neurodegenerative Diseases><Neurodegenerative Disorders><Neuroendocrine Prostate Cancer><Neurologic Degenerative Conditions><Non-Polyadenylated RNA><Normal Cell><Normal Tissue><Normal tissue morphology><Nuclear Magnetic Resonance Imaging><Oral><Outcome><Ovary Cancer><Pathologic><Patients><Pb element><Pharmaceutical Preparations><Phase><Post-Transcriptional Gene Silencing><Posttranscriptional Gene Silencing><Predisposition><Preparation><Production><Prostate CA><Prostate CA therapy><Prostate Cancer><Prostate Cancer therapy><Prostate malignancy><Prostatic Cancer><RNA><RNA Binding><RNA Gene Products><RNA Interference><RNA Seq><RNA Silencing><RNA bound><RNA sequencing><RNAi><RNAseq><Receptor Signaling><Relapse><Reporter Genes><Research><Resistance><Ribonucleic Acid><Risk><SMAX1><STTR><Sequence-Specific Posttranscriptional Gene Silencing><Short interfering RNA><Small Business Technology Transfer Research><Small Interfering RNA><Specificity><Spinobulbar Atrophy><Spinobulbar Muscular Atrophy><Staining method><Stains><Surgical Castration><Susceptibility><Testing><Therapeutic><Tissue Sample><Tissues><Toxic effect><Toxicities><Transcript><Transcript Expression Analyses><Transcript Expression Analysis><Tumor Cell><Tumor Tissue><Tumor Volume><United States><Universities><Variant><Variation><Venus><Western Blotting><Western Immunoblotting><Work><X-Linked Bulbo-Spinal Atrophy><Xenograft><Xenograft Model><Xenograft procedure><Xenotransplantation><Zeugmatography><advanced prostate cancer><aged><analyze gene expression><androgen independent prostate cancer><androgen indifferent prostate cancer><androgen insensitive prostate cancer><androgen receptor gene><androgen resistance in prostate cancer><androgen resistant prostate cancer><anti-cancer><anti-cancer therapy><anti-tumor effect><antitumor effect><cancer cell><cancer therapy><cancer-directed therapy><castration resistant CaP><castration resistant PCa><castration resistant prostate cancer><clinical relevance><clinically relevant><compare to control><comparison control><degenerative diseases of motor and sensory neurons><degenerative neurological diseases><delivery vector><delivery vehicle><developmental><drug/agent><effective therapy><effective treatment><efficacy testing><experiment><experimental research><experimental study><experiments><first in man><first-in-human><gene expression analysis><gene expression assay><genetically engineered mouse model><genetically engineered murine model><heavy metal Pb><heavy metal lead><hepatic body system><hepatic organ system><heterogeneity in tumors><hormone refractory prostate cancer><hormone therapy><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunotherapy trials><improved><in vivo><in vivo Model><interesting transcript 15><intra-tumoral heterogeneity><intratumor heterogeneity><lipid based nanoparticle><lipid nanoparticle><liver cancer><liver malignancy><mRNA><male><malignancy><malignant liver tumor><men><mouse model><murine model><nano particle><nano-sized particle><nanoparticle><nanosized particle><necrocytosis><neoplasm/cancer><neoplastic cell><neurodegenerative illness><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutic target><new therapeutics><new therapy><new therapy approaches><new therapy target><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutic target><novel therapeutics><novel therapy><novel therapy approach><novel therapy target><ovarian cancer><patient population><post treatment><pre-clinical><preclinical><preparations><prevent><preventing><prostate cancer cell><prostate cancer model><prostate cancer resistant to androgen><prostate cancer treatment><prostate tumor cell><prostate tumor model><protein biomarkers><protein blotting><protein markers><resistance to therapy><resistant><resistant to therapy><response><response to therapy><response to treatment><scRNA-seq><siRNA><side effect><single cell RNA-seq><single cell RNAseq><single cell expression profiling><single cell transcriptomic profiling><single-cell RNA sequencing><site targeted delivery><targeted delivery><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapeutic response><therapeutically effective><therapy optimization><therapy resistant><therapy response><transcriptional profiling><transcriptome sequencing><transcriptomic sequencing><transplant model><treatment effect><treatment optimization><treatment resistance><treatment response><treatment responsiveness><tumor><tumor growth><tumor heterogeneity><ultrasound><uptake><xeno-transplant><xeno-transplantation><xenograft transplant model><xenotransplant model><α Particles>