Document text
Principal Investigator: Rajagopal Ramesh
Organization: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
Fiscal Year: 2024
Award: $535,400
Funding agency: National Cancer Institute
Expression of immune check point (ICP) molecules on tumor cells and the host immune
cells, especially T-cells present in the tumor milieu, negatively impact the cancer treatment
outcome resulting in inefficient tumor eradication. Data also exist showing chemo- and radio-
therapy induce ICP proteins on tumor cells and thereby contributing to inactivation of tumor
infiltrating T-cells, resulting in the inability to host a robust antitumor response and culminating in
treatment failure, and disease recurrence. Hence, understanding how a cancer drug impacts
ICP will lead to development of new therapeutic strategies that can circumvent ICP-mediated
treatment failure. One such approach is to incorporate immune check point inhibitors (ICPi)
which can rekindle T-cell response and enhance the efficacy of anticancer drugs.
Studies from the PI's laboratory and others have demonstrated genetic and pharmacologic
inhibition of the human antigen R (HuR), an mRNA-binding protein that is overexpressed in
human cancer cells, results in growth inhibition, reduction in metastasis, and in increased
animal survival. While these findings support advancing HuR-targeted therapy for clinical
translation, the PI's lab has recently made a serendipitous discovery showing siRNA-
mediated silencing of HuR using a lipid-based nanoparticle (HuR-NP) induced programmed
death-ligand (PD-L)1 expression in lung cancer cells. PD-L1 is one among several ICP proteins
which when expressed by tumor cells suppress T-cell function. HuR-NP markedly induced PD-
L1 mRNA and protein expression in human lung cancer cell lines. Molecular studies showed
HuR binding site in the promoter region of PD-L1. Finally, a negative correlation between HuR
and PD-L1 expression was observed in human lung cancer tissues. To our knowledge, apart
from our own observation reported herein, there are no prior reports demonstrating the ability of
HuR to regulate PD-L1 and testing of HuR-nanotherapy with PD-L1 immunotherapy for cancer.
On the basis of our novel findings, we posit that combining HuR-nanotherapy with PD-L1
immunotherapy will demonstrate superior anticancer efficacy by eliciting strong immune
response, and reducing disease recurrence. We will test our hypothesis with three aims: Aim 1.
Determine the therapeutic benefit of LNP targeting HuR in combination with anti-PD-L1 therapy
in vitro. Aim 2. Demonstrate LNP targeted HuR treatment in combination with PD-L1
immunotherapy in in vivo using lung tumor models elicits immune response and enhanced
antitumor activity. Aim 3. Investigate the molecular mechanism by which LNP targeting HuR
modulates PD-L1 expression in lung cancer cells.
Terms: <APO2L><Address><Animal Model><Animal Models and Related Studies><Animals><Anti-Cancer Agents><Antigens><Antineoplastic Agents><Antineoplastic Drugs><Antineoplastics><Antitumor Response><Apo-2L><Apoptotic><B7-H1><B7H1><Binding Proteins><Binding Sites><Body Tissues><Breast Cancer Cell><CD152><CD152 Antigen><CD152 Gene><CD274><CDDP><CTLA 4><CTLA-4 Gene><CTLA4><CTLA4 gene><CTLA4-TM><Cancer Biology><Cancer Drug><Cancer Model><Cancer Patient><Cancer Treatment><Cancer cell line><CancerModel><Cancers><Cell Body><Cell Communication and Signaling><Cell Cycle Arrest><Cell Death><Cell Function><Cell Growth in Number><Cell Locomotion><Cell Migration><Cell Movement><Cell Multiplication><Cell Physiology><Cell Process><Cell Proliferation><Cell Signaling><Cells><Cellular Function><Cellular Migration><Cellular Motility><Cellular Physiology><Cellular Process><Cellular Proliferation><Checkpoint inhibitor><Cis-diammine-dichloroplatinum><Cis-diamminedichloridoplatinum><Cis-diamminedichloro Platinum (II)><Cis-dichloroammine Platinum (II)><Cis-platinous Diamine Dichloride><Cis-platinum II><Cis-platinum II Diamine Dichloride><Cisplatin><Cisplatina><Cisplatinum><Clinical><Combining Site><Cysplatyna><Cytotoxic T-Lymphocyte Protein 4><Cytotoxic T-Lymphocyte-Associated Antigen 4><Cytotoxic T-Lymphocyte-Associated Protein 4><Cytotoxic T-Lymphocyte-Associated Serine Esterase-4><Data><Dendrimers><Dendritic Compounds><Dendrons><Development><Dichlorodiammineplatinum><Disease Progression><Drug resistance><ETS domain protein pointed-P2><Embryo><Embryonic><Engineering><Exhibits><Gene Delivery><Generalized Growth><Genetic><Genotoxins><Growth><Human><Immune><Immune Globulins><Immune checkpoint inhibitor><Immune mediated therapy><Immune response><Immunes><Immunoglobulins><Immunological response><Immunologically Directed Therapy><Immunology><Immunomodulation><Immunotherapy><In Vitro><Intracellular Communication and Signaling><Intratumoral heterogeneity><Invaded><Investigators><Laboratories><Ligand Binding Protein><Ligand Binding Protein Gene><Lung Neoplasms><Lung Tumor><MICMET><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Ovarian Neoplasm><Malignant Ovarian Tumor><Malignant Tumor><Malignant Tumor of the Lung><Malignant Tumor of the Ovary><Malignant neoplasm of lung><Malignant neoplasm of ovary><Mediating><Messenger RNA><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Micrometastasis><Micromets><Modeling><Modern Man><Molecular><Molecular Target><Mucins><Mucus Glycoprotein><Murine><Mus><Mutagens><Neoplasm Metastasis><Neoplastic Disease Chemotherapeutic Agents><Oncogene Products><Oncogene Proteins><Oncoproteins><Ovary Cancer><PD 1><PD-1><PD-L1><PD-L1 therapy><PD-L1 treatment><PD1><PDL-1><PDL1><PDL1 therapy><PDL1 treatment><Pathology><Pathway interactions><Peyrone's Chloride><Peyrone's Salt><Platinum Diamminodichloride><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Promoter Regions><Promotor Regions><Protein Binding><Protein Family><Proteins><Pulmonary Cancer><Pulmonary Neoplasms><Pulmonary malignant Neoplasm><Radiation therapy><Radiosensitization><Radiotherapeutics><Radiotherapy><Reactive Site><Recurrent disease><Relapsed Disease><Reporting><Research Personnel><Researchers><Resistance><Secondary Neoplasm><Secondary Tumor><Short interfering RNA><Sight><Signal Transduction><Signal Transduction Systems><Signaling><Small Interfering RNA><Subcellular Process><Survival Rate><T cell response><T-Cells><T-Lymphocyte><TL2><TNFSF10><TNFSF10 gene><TRAIL><Testing><Therapeutic><Tissue Growth><Tissues><Treatment Failure><Treatment outcome><Tumor Cell><Tumor-Specific Treatment Agents><Vision><aPD-L1><aPD-L1 therapy><aPD-L1 treatment><aPDL1><anti programmed cell death ligand 1><anti programmed cell death ligand 1 therapy><anti programmed cell death ligand 1 treatment><anti programmed cell death protein ligand 1><anti programmed cell death protein ligand 1 therapy><anti programmed cell death protein ligand 1 treatment><anti-PD-(L)1><anti-PD-L1><anti-PD-L1 therapy><anti-PD-L1 treatment><anti-PDL-1><anti-PDL1><anti-PDL1 therapy><anti-PDL1 treatment><anti-cancer><anti-cancer drug><anti-cancer immunotherapy><anti-cancer therapy><anti-tumor response><antiPD-L1><antiPDL1><anticancer activity><anticancer immunotherapy><biological signal transduction><bound protein><breast tumor cell><cancer cell><cancer immunotherapy><cancer infiltrating T cells><cancer metastasis><cancer therapy><cancer-directed therapy><cell motility><chemo-/radio-sensitization><chemotherapy><cis dichlorodiammineplatinum><cis platinum compound><cis-Diaminedichloroplatinum><cis-Diamminedichloroplatinum><cis-Diamminedichloroplatinum(II)><cis-Dichlorodiammineplatinum(II)><cis-Platinum><clinical translation><clinically translatable><cytotoxic T-lymphocyte antigen 4><deliver short interfering RNA><deliver siRNA><deliver small interfering RNA><delivery system for siRNA><delivery system for small interfering RNA><delivery vectors for siRNA><developmental><drug resistant><effective therapy><effective treatment><efficacy study><genetic promoter element><genetic promoter sequence><genotoxic agent><heterogeneity in tumors><host response><immune check point><immune check point inhibitor><immune checkpoint><immune modulation><immune regulation><immune system response><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immunecheckpoint><immuno therapy><immunogen><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><immunotherapy for cancer><immunotherapy of cancer><in vivo><inhibitor><innovate><innovation><innovative><intra-tumoral heterogeneity><intratumor heterogeneity><lipid based nanoparticle><lipid nanoparticle><lung cancer><lung cancer cell><mRNA><mRNA Expression><malignancy><member><model of animal><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><multidisciplinary><nano engineering><nano formulation><nano particle><nano therapy><nano-sized particle><nanoengineering><nanoformulation><nanoparticle><nanosized particle><nanotherapy><necrocytosis><neoplasm/cancer><neoplastic cell><new drug treatments><new drugs><new pharmacological therapeutic><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapeutics><new therapy><new therapy approaches><new treatment approach><new treatment strategy><next generation therapeutics><novel><novel drug treatments><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapeutics><novel therapy><novel therapy approach><ontogeny><ovarian cancer><overexpress><overexpression><pathway><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><pharmacologic><pnt gene product><pointed gene product><pointed protein><pre-clinical study><preclinical study><programmed cell death 1><programmed cell death ligand 1><programmed cell death protein 1><programmed cell death protein ligand 1><programmed death 1><promoter sequence><protein death-ligand 1><protein expression><radiation sensitization><radiation treatment><radio-/chemo-sensitization><radio-sensitization><radiotherapy sensitization><resistance to Drug><resistant><resistant to Drug><short interfering RNA delivery><siRNA><siRNA delivery><sle2><small interfering RNA delivery><statistics><systemic lupus erythematosus susceptibility 2><targeted cancer therapy><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapy failure><thymus derived lymphocyte><treatment with radiation><tumor><tumor cell metastasis><tumor eradication><tumor growth><tumor heterogeneity><tumor infiltrating T cells><visual function><αPD-L1><αPD-L1 therapy><αPD-L1 treatment><αPDL1>