Document text
Principal Investigator: Nagaraj S. Nagathihalli
Organization: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
Fiscal Year: 2024
Award: $329,883
Funding agency: National Cancer Institute
PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDAC) is characterized by resistance to current therapies, a high degree of
desmoplasia, and an immunosuppressive tumor microenvironment (TME). This scientific proposal focuses on
cyclic AMP Response Element Binding protein 1 (CREB) as a transcriptional factor downstream of KRAS that
promotes disease aggressiveness and poor survival. Genetic loss or pharmacological inhibition of CREB leads
to significant attenuation of PDAC tumor burden and improved survival in multiple murine PDAC models. Utilizing
high throughput sequencing approaches, we have identified tumor cell-derived leukemia inhibitory factor (LIF)
as a key CREB-regulated immunomodulatory cytokine, serving as a possible paracrine mediator of tumor-
macrophage crosstalk in the TME. We hypothesize that targeting the CREB-LIF signaling axis can remodel the
immunosuppressive TME by significantly impacting tumor-associated macrophages (TAM)s and reinvigorating
the T cell-based adaptive anti-tumor immune response to improve the efficacy of checkpoint immunotherapy.
Based on our preliminary data, the critical role of the CREB regulated LIF signaling will be investigated through
three specific aims. 1) Elucidate the molecular mechanism and impact of CREB regulated LIF in PDAC
oncogenesis. Here, we will assess the CREB-mediated regulation and functional roles of tumor cell-derived LIF
by exploring the nucleo-cytoplasmic localization, interaction with transcriptional complexes, and gene regulatory
networks. We identify the CREB-LIF axis requirement in the tumor cell growth using CRISPR/Cas9 genome
editing with CREB on or off in vivo pancreas tissues and evaluate the expression of LIF relative to CREB in
patient PDAC tissues, patient-derived xenografts, and primary tumor derivative organoids. 2) Determine how
CREB-dependent LIFR signaling in macrophages impacts the tumor immune landscape. We hypothesize that
the CREB modulates LIF release and promotes TAM infiltration/polarization towards a tumor-promoting M2-like
phenotype via activating STAT3 in macrophages. We will determine the effect of CREB-regulated LIF release
on TAM activity using CREB on or off with LIF knockout tumor cells and assess the impact of CREB-regulated
LIF signaling on the adaptive immune response and TME during PDAC progression in myeloid-specific knockout
models of Lifr and Stat3, and 3) Determine if CREB inhibition and conventional immunotherapeutic approaches
reduce tumor growth and improve overall survival. We hypothesize that the tumor cell-intrinsic CREB-LIF
activation is a pivotal switch that drives immune suppression in the pancreatic TME, which can synergize with
immune checkpoint inhibition. We will use CREB inhibitor with checkpoint inhibitor to establish the safety of the
therapies and study tumor growth and overall survival in genetic mouse models, patient-derived xenografts, and
organoids to further complement these preclinical studies. Together, these results will provide new therapeutic
strategies to reduce mortality from this disease. Furthermore, these studies can be broadly applicable to the
myriad of other malignancies where CREB-LIF signaling is altered.
Terms: <Affect><Automobile Driving><B cell differentiation factor><B cell stimulating factor 2><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><BCDF><BSF-2><BSF2><Basal Transcription Factor><Basal transcription factor genes><Binding><Biological Response Modifiers><Biomodulators><Body Tissues><C-K-RAS><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CRE Binding Protein><CREB Protein><CRISPR approach><CRISPR based approach><CRISPR method><CRISPR methodology><CRISPR technique><CRISPR technology><CRISPR tools><CRISPR-CAS-9><CRISPR-based method><CRISPR-based technique><CRISPR-based technology><CRISPR-based tool><CRISPR/CAS approach><CRISPR/Cas method><CRISPR/Cas technology><CRISPR/Cas9><CRISPR/Cas9 technology><Cancers><Cas nuclease technology><Cell Body><Cell Communication and Signaling><Cell Line><Cell Signaling><CellLine><Cells><Cellular Expansion><Cellular Growth><Checkpoint inhibitor><Chemotaxis><Cholinergic Differentiation Factor><Clinical><Clustered Regularly Interspaced Short Palindromic Repeats approach><Clustered Regularly Interspaced Short Palindromic Repeats method><Clustered Regularly Interspaced Short Palindromic Repeats methodology><Clustered Regularly Interspaced Short Palindromic Repeats technique><Clustered Regularly Interspaced Short Palindromic Repeats technology><Complement><Complement Proteins><Complex><Cyclic AMP Response Element-Binding Protein><Cyclic AMP Responsive Element Binding Protein><Cyclic AMP-Responsive DNA-Binding Protein><D-Factor><Data><Development><Disease><Disorder><Fibrosis><GEM model><GEMM model><Gene Transcription><General Transcription Factor Gene><General Transcription Factors><Genetic><Genetic Models><Genetic Transcription><Genetically Engineered Mouse><HPGF><Hepatocyte-Stimulating Factor><High-Throughput Nucleotide Sequencing><High-Throughput Sequencing><Human><Hybridoma Growth Factor><IFN-beta 2><IFNB2><IL-6><IL6 Protein><Immune><Immune Mediators><Immune Mediators/Modulators><Immune Modulation Therapy><Immune Regulators><Immune checkpoint inhibitor><Immune mediated therapy><Immunes><Immunologic Subtyping><Immunologically Directed Therapy><Immunomodulation><Immunophenotyping><Immunosuppression><Immunosuppression Effect><Immunosuppressive Effect><Immunotherapeutic agent><Immunotherapy><Impairment><Infiltration><Inflammation><Interleukin-6><Intracellular Communication and Signaling><K-RAS2A><K-RAS2B><K-Ras><K-Ras 2A><K-Ras-2 Oncogene><KRAS><KRAS2><KRAS2 gene><Ki-RAS><Knock-out><Knockout><LIF><LIF gene><LIF receptor><LIF-R><LIF-binding protein><Laboratories><MGI-2><Macrophage><Malignant Neoplasms><Malignant Pancreatic Neoplasm><Malignant Tumor><Malignant neoplasm of pancreas><Mediating><Mediator><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Molecular Interaction><Murine><Mus><Myelogenous><Myeloid><Myeloid Differentiation-Inducing Protein><Myeloid-derived suppressor cells><Mφ><Nature><Neoplasm Metastasis><Neoplasms><Oncogene K-Ras><Oncogenesis><Oncogenic><Organoids><PDA model><PDAC Model><PDX model><Pancreas><Pancreas Cancer><Pancreas Ductal Adenocarcinoma><Pancreas Neoplasms><Pancreas Tumor><Pancreatic><Pancreatic Cancer><Pancreatic Ductal Adenocarcinoma><Pancreatic Tumor><Pathway interactions><Patient derived xenograft><Patients><Phenotype><Plasmacytoma Growth Factor><Primary Neoplasm><Primary Tumor><Production><Prognosis><RASK2><RNA Expression><Receptor Signaling><Regulation><Regulatory T-Lymphocyte><Resistance><Role><STAT3><STAT3 gene><Safety><Sampling><Secondary Neoplasm><Secondary Tumor><Shapes><Signal Transduction><Signal Transduction Systems><Signaling><Strains Cell Lines><T-Cell Activation><T-Cells><T-Lymphocyte><T8 Cells><T8 Lymphocytes><Therapeutic><Time><Tissues><Transcription><Transcription Factor Proto-Oncogene><Transcription factor genes><Treg><Tumor Burden><Tumor Cell><Tumor Load><Tumor Promotion><Tumor-associated macrophages><Up-Regulation><Upregulation><Work><activate T cells><adaptive immune response><anti-tumor immune response><attenuation><biological signal transduction><cAMP Response Element-Binding Protein><cAMP Responsive Element Binding Protein><cancer metastasis><cancer microenvironment><cell growth><check point immunotherapy><check point inhibition><check point inhibitor therapy><check point inhibitory therapy><check point therapy><checkpoint immunotherapy><checkpoint inhibition><checkpoint inhibitor therapy><checkpoint inhibitory therapy><checkpoint therapy><chemotherapeutic agent><clinical relevance><clinically relevant><complementation><cultured cell line><cytokine><developmental><driving><effective therapy><effective treatment><gene regulatory network><genetically engineered mouse model><genetically engineered murine model><genome editing><genomic editing><humanized mice><humanized mouse><immune check point inhibition><immune check point inhibitor><immune check point therapy><immune checkpoint inhibition><immune checkpoint therapy><immune drugs><immune microenvironment><immune modulating therapies><immune modulation><immune modulatory therapies><immune regulation><immune suppression><immune suppressive activity><immune suppressive function><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapeutics><immune-based therapies><immune-based treatments><immune-modulation treatment><immuno therapy><immunologic reactivity control><immunologic therapeutics><immunomodulation therapy><immunomodulation treatment><immunomodulator therapies><immunomodulator treatment><immunomodulator-based therapies><immunomodulatory><immunomodulatory biologics><immunomodulatory therapies><immunomodulatory therapy><immunomodulatory treatment><immunophenotype><immunoregulation><immunoregulatory><immunosuppressive activity><immunosuppressive function><immunosuppressive microenvironment><immunosuppressive myeloid cells><immunosuppressive response><immunosuppressive tumor microenvironment><immunotherapeutics><immunotherapy agent><improved><in vivo><inhibitor><insight><interferon beta 2><leukemia inhibitor factor><leukemia inhibitory factor><leukemia inhibitory factor receptor><malignancy><mortality><mouse model><murine model><myeloid suppressor cells><myeloid-derived suppressive cells><neoplasia><neoplasm/cancer><neoplastic cell><neoplastic growth><new therapeutic approach><new therapeutic intervention><new therapeutic strategies><new therapy approaches><new treatment approach><new treatment strategy><novel therapeutic approach><novel therapeutic intervention><novel therapeutic strategies><novel therapy approach><pancreatic ductal adenocarcinoma model><pancreatic malignancy><pancreatic neoplasia><pancreatic neoplasm><paracrine><pathway><patient derived xenograft model><pharmacologic><pre-clinical><pre-clinical study><preclinical><preclinical study><promoter><promotor><recruit><regulatory T-cells><release factor><resistance to therapy><resistant><resistant to therapy><response><social role><suppressive myeloid cells><synergism><therapeutic resistance><therapy resistant><thymus derived lymphocyte><transcription factor><transcription regulatory network><treatment resistance><treatment strategy><tumor><tumor cell metastasis><tumor growth><tumor immune microenvironment><tumor microenvironment><tumor-immune system interactions><tumorigenesis><v-Ki-RAS2 Kirsten Rat Sarcoma 2 Viral Oncogene Homolog>