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Principal Investigator: Jinjun Shi
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2024
Award: $518,820
Funding agency: National Cancer Institute
ABSTRACT
The use of RNA technologies to specifically target genetic alterations in tumor cells has shown great potential of
becoming a novel therapy modality for cancer treatment. Nevertheless, systemic delivery of RNA agents such
as messenger RNA (mRNA) to tumor cells in vivo commonly faces multiple barriers, including low stability, rapid
elimination by renal excretion, insufficient cellular uptake, poor endosomal escape, and transient activities. Our
long-term objective is to develop robust nanoparticle (NP) platforms for effective and safe RNA delivery to solid
tumors, and along with cancer target validation in vivo, to eventually transition the RNA nanomedicines into
clinical development. In the last funding cycle, a lipid-polymer hybrid RNA NP system has been engineered with
favorable features, such as small size, high RNA encapsulation, efficient cytosolic translocation, and relatively
long blood circulation. We have also pioneered the application of these hybrid NPs for mRNA delivery to restore
tumor suppressors (e.g., PTEN) in different cancer types including prostate cancer (PCa) and non-small cell lung
cancer, which represents a novel approach to cancer treatment that is independent of oncogene antagonism. In
our latest work, we further reveal that PTEN restoration in PTEN-null/mutated murine tumor cell lines can induce
immunogenic cell death (ICD). Preliminary in vivo studies show that PTEN mRNA NP treatment triggers cytotoxic
T cell responses, modulates the immunosuppressive tumor microenvironment, and improves the responses of
immune checkpoint blockade therapy. In this renewal application, we propose to i) address the unique challenge
of transient bioactivity in mRNA delivery by developing a new generation of hybrid mRNA NPs, and ii) apply the
new hybrid mRNA NPs to explore PTEN restoration-induced ICD and evaluate the anti-tumor efficacy of PTEN
restoration along with immune checkpoint blockade. Specifically, the three Aims underlying the proposal are: 1)
To optimize the new generation of hybrid NPs and study the NP-mediated long duration of mRNA bioactivity with
the goal of achieving prolonged PTEN expression in PCa tumors using as infrequent injections as possible; 2)
To apply the optimized mRNA NPs to investigate the mechanisms underlying PTEN-mediated ICD and anti-
tumor immune responses and to evaluate the therapeutic effect and safety in subcutaneously grafted, orthotopic,
and transgenic models of PCa; and 3) To expand the new hybrid mRNA NPs to systemic co-delivery of PTEN
mRNA and CpG oligodeoxynucleotide (a toll-like receptor-9 agonist) for stronger ICD and to test the co-delivery
NPs for PCa treatment together with immune checkpoint inhibitors. We expect that successful completion of this
project will lead to development of a novel synthetic mRNA nanotherapy that could benefit cancer patients with
loss/mutation of PTEN. Moreover, this NP delivery strategy could be readily expanded to other tumor suppressor-
encoding mRNAs for various malignancies.
Terms: <Address><Adjuvant><After Care><After-Treatment><Aftercare><Agonist><American Cancer Society><Amphoterin><Amphoterin Gene><Animal Model><Animal Models and Related Studies><Antioncogene Protein p53><Apoptosis><Apoptosis Pathway><Autophagocytosis><Biodistribution><Biological Markers><Blood Circulation><Bloodstream><Cancer Genes><Cancer Patient><Cancer Treatment><Cancer-Promoting Gene><Cancers><Cell Body><Cell-Mediated Lympholytic Cells><Cells><Cellular Tumor Antigen P53><Cessation of life><Charge><Checkpoint inhibitor><Chromosomal Protein, Nonhistone, HMG1><Chromosomal Protein, Nonhistone, HMG1 Gene><Combined Modality Therapy><Cytolytic T-Cell><Cytotoxic T Cell><Cytotoxic T-Lymphocytes><Death><Development><Disease><Disorder><Drug Kinetics><Drugs><Economic Burden><Encapsulated><Endosomes><Engineering><Excretory function><FM1 Gene Product><Face><Formulation><Foundations><Funding><GEM model><GEMM model><Gene Expression><Generalized Growth><Generations><Genetic Alteration><Genetic Change><Genetic defect><Genetically Engineered Mouse><Goals><Growth><HMG-1><HMG-1 Gene><HMG-1 Protein><HMG1><HMG1 Gene><HMG3><HMG3 Gene><HMGB1><HMGB1 Protein><HMGB1 gene><Heparin-Binding Protein p30><High Mobility Group Box Protein 1><High Mobility Group Protein 1><High Mobility Group Protein 1 Gene><High-Mobility Group (Nonhistone Chromosomal) Protein 1><High-Mobility Group (Nonhistone Chromosomal) Protein 1 Gene><High-Mobility Group Box 1><High-Mobility Group Box 1 Gene><Hybrids><Immune><Immune checkpoint inhibitor><Immune memory><Immune response><Immunes><Immunocompetent><Immunologic Memory><Immunological Memory><Immunological response><In Vitro><Individual><Induction of Apoptosis><Injections><Kidney><Kidney Urinary System><Light><Lipids><Lytotoxicity><MMAC1><MMAC1 protein><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Prostate><Malignant neoplasm of prostate><Malignant prostatic tumor><Mediating><Medication><Messenger RNA><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modality><Modeling><Molecular><Molecular Weight><Multimodal Therapy><Multimodal Treatment><Murine><Mus><Mutate><Mutated in Multiple Advanced Cancers 1><Mutation><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Nature><Neoplasm Metastasis><Non-Polyadenylated RNA><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Nonhistone Chromosomal Protein HGM1><Nonhistone Chromosomal Protein HGM1 Gene><Oncogenes><Oncoprotein p53><P53><PD 1><PD-1><PD-1 antibody><PD-1 antibody therapy><PD-1 therapy><PD1><PD1 antibody><PD1 antibody therapy><PD1 based treatment><PHTS gene><PHTS protein><PTEN><PTEN gene><PTEN protein><PTEN1><Pathway interactions><Pattern><Pharmaceutical Preparations><Pharmacokinetics><Phenotype><Phosphatase and Tensin Homolog><Phosphatase and Tensin Homolog Deleted on Chromosome 10><Phosphoprotein P53><Phosphoprotein pp53><Photoradiation><Polymers><Predisposition><Prevention><Programmed Cell Death><Prostate CA><Prostate CA therapy><Prostate Cancer><Prostate Cancer therapy><Prostate malignancy><Prostatic Cancer><Protein TP53><R-Series Research Projects><R01 Mechanism><R01 Program><RNA><RNA Gene Products><RNA delivery><Receptosomes><Regulatory T-Lymphocyte><Research Grants><Research Project Grants><Research Projects><Ribonucleic Acid><Role><SBP-1><SBP-1 Gene><Safety><Secondary Neoplasm><Secondary Tumor><Series><Short interfering RNA><Small Interfering RNA><Solid Neoplasm><Solid Tumor><Sulfoglucuronyl Carbohydrate Binding Protein><Sulfoglucuronyl Carbohydrate Binding Protein Gene><Surface><Susceptibility><System><T cell response><TLR9 gene><TLR9 protein><TLR9 receptor><TP53><TP53 gene><TRP53><Technology><Testing><Therapeutic><Therapeutic Effect><Tissue Growth><Transfection><Transforming Genes><Transgenic Model><Translations><Treg><Tumor Cell><Tumor Cell Line><Tumor Immunity><Tumor Protein p53><Tumor Protein p53 Gene><Tumor Suppressor Proteins><United States><Validation><Work><aPD-1 therapy><aPD-1 treatment><aPD1 therapy><aPD1 treatment><anamnestic reaction><antagonism><antagonist><anti-PD-1 Ab><anti-PD-1 antibodies><anti-PD-1 monoclonal antibodies><anti-PD-1 therapy><anti-PD-1 treatment><anti-PD1 Ab><anti-PD1 antibodies><anti-PD1 monoclonal antibodies><anti-PD1 therapy><anti-PD1 treatment><anti-cancer therapy><anti-programmed cell death 1 therapy><anti-programmed cell death protein 1 antibodies><anti-programmed cell death protein 1 therapy><anti-programmed death-1 antibody><anti-tumor immune response><anti-tumor immunity><antitumor immunity><autophagy><bio-markers><biologic marker><biomarker><cancer cell><cancer immunity><cancer metastasis><cancer microenvironment><cancer therapy><cancer type><cancer-directed therapy><check point blockade><checkpoint blockade><clinical development><combination therapy><combined modality treatment><combined treatment><cytokine><cytotoxic><cytotoxicity><deliver mRNA><deliver messenger RNA><deliver short interfering RNA><deliver siRNA><deliver small interfering RNA><delivery system for mRNA><delivery system for siRNA><delivery system for small interfering RNA><delivery vectors for siRNA><developmental><drug/agent><excretion><faces><facial><genetically engineered mouse model><genetically engineered murine model><genome mutation><host response><immune check point><immune check point blockade><immune check point inhibitor><immune checkpoint><immune checkpoint blockade><immune competent><immune microenvironment><immune system response><immunecheckpoint><immunogenic apoptosis><immunogenic cell death><immunoresponse><immunosuppressive microenvironment><immunosuppressive tumor microenvironment><improved><in vivo><killer T cell><mRNA><mRNA delivery><malignancy><messenger RNA delivery><model of animal><multi-modal therapy><multi-modal treatment><mutated in multiple advanced cancers 1 protein><nano medicinal><nano medicine><nano particle><nano particle delivery><nano therapy><nano-sized particle><nanomedicinal><nanomedicine><nanoparticle><nanoparticle delivered><nanoparticle delivery><nanosized particle><nanotherapy><neoplasm/cancer><neoplastic cell><new approaches><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutics><new therapy><next generation therapeutics><novel><novel approaches><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel strategies><novel strategy><novel therapeutics><novel therapy><nuclease><ontogeny><p53 Antigen><p53 Genes><p53 Tumor Suppressor><pathway><phosphatase and tensin homologue on chromosome ten><polymer><polymeric><post treatment><programmed cell death 1><programmed cell death protein 1><programmed cell death protein 1 therapy><programmed death 1><prostate cancer cell><prostate cancer model><prostate cancer treatment><prostate tumor cell><prostate tumor model><protein expression><protein p53><regulatory T-cells><renal><restoration><secondary immune response><short interfering RNA delivery><siRNA><siRNA delivery><sle2><small interfering RNA delivery><social><social role><subcutaneous><subdermal><systemic lupus erythematosus susceptibility 2><toll-like receptor 9><transgenic trait><translation><tumor><tumor cell metastasis><tumor growth><tumor immune microenvironment><tumor microenvironment><tumor suppressor><tumor-immune system interactions><uptake><validations>