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Principal Investigator: Hui-Kuan Lin
Organization: DUKE UNIVERSITY
Fiscal Year: 2024
Award: $491,137
Funding agency: National Cancer Institute
Non-small cell lung cancer (NSCLC) accounts for around 85% of all lung cancer. The
5-
year survival rate is about
14% for stage IIIA NSCLC, while it is about
5% for stage IIIB. However, once
NSCLC has reached to the stage IV
and metastasized to different places, it is very difficult to treat. The
5-
year survival rate for stage IV
NSCLC is
just about 1%. Targeted therapy such as anti-EGFR or anti-ALK is the frontline treatment for advanced NSCLC
with EGFR or ALK mutations, while platinum-based chemotherapy is the first line treatment for advanced
NSCLC without targetable mutations. Interestingly, recent studies suggest that anti-PD1/PDL1 immunotherapy
is a new and effective strategy for advanced NSCLC. While NSCLC patients initially show great benefit from these
treatments, the response is only transient with relatively short duration likely due to acquiring resistant
mechanisms. Identification of novel and effective therapeutic strategies is therefore an urgent need for advanced
NSCLC with metastasis. A small cell population with CSC properties contributes to cancer initiation, progression
and metastasis as well as drug resistance in various cancers such as NSCLC, but an effective strategy to eliminate
CSCs is currently lacking, representing an unmet clinical need for CSC and NSCLC targeting. While CSCs possess
immune escape properties, it is unclear how non-CSC cancer cells accounting for the majority of total cancer cell
populations could also resist from immune cell attack. The goal of this study is to characterize a novel and unique
CSC population in NSCLC and its regulatory mechanisms that can be harnessed for developing a novel effective
strategy for advanced NSCLC and/or for overcoming the resistance to current standard of care. Our study
identifies a novel druggable regulator localized in cell membrane for maintaining CSCs, cancer progression and
metastasis of NSCLCs and its overexpression predicts poor survival outcome NSCLC patients. Genetically or
pharmacologically targeting this newly identified regulator attenuates oncogenic signal for maintain CSC
properties and immune escape leading to cancer progression and metastasis of NSCLC. We hypothesized that a
unique cell population with CSC properties existed in cancer can transmit an oncogenic and immune escape
signal to non-CSC cancer cells, thereby endowing bulk cancer cells with immune escape properties. We proposed
three specific aims, which are highly supported by our innovative preliminary results, to further characterize the
roles and underlying mechanisms of this novel regulator and its ligand as well as their targeting in regulating
CSCs, progression and metastasis of NSCLC. Our proposal is highly original and significant, as we have proposed
a breakthrough concept, identified a novel checkpoint blocker with CSC and immune escape properties and
utilized cutting technologies including unbiased transcriptomics, Cas9/CRISPR editing, patient-derived
organoids, patient derived xenograft (PDX) models, and humanized mice and genetic knockin mouse models
with intact immunity to validate our provocative hypothesis and concept. Our study has revolutionized and
significantly advanced our understanding of CSC and cancer-immune regulation, but also offers a new paradigm
and strategy for targeting advanced NSCLC.
Terms: <Accounting><Attenuated><CD47><CD47 Antigen><CD47 Glycoprotein><CD47 gene><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><Cancer Patient><Cancer Treatment><Cancer cell line><Cancers><Cas nuclease technology><Cell Body><Cell Communication and Signaling><Cell Signaling><Cell membrane><Cells><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><Cytoplasmic Membrane><Data><Drosophila Homolog of Large Tumor Suppressor 1><Drug resistance><EGF Receptor><EGFR><ERBB Protein><Endowment><Epidermal Growth Factor Receptor><Epidermal Growth Factor Receptor Kinase><Epidermal Growth Factor Receptor Protein-Tyrosine Kinase><Epidermal Growth Factor-Urogastrone Receptors><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Goals><HER1><Heterograft><Heterologous Transplantation><Immune><Immune Evasion><Immune mediated therapy><Immune signaling><Immunes><Immunity><Immunologically Directed Therapy><Immunomodulation><Immunotherapy><Impairment><Integral Membrane Protein><Integrin-Associated Protein><Intracellular Communication and Signaling><Intrinsic Membrane Protein><KI mice><Kinases><Knock-in Mouse><Knowledge><LATS1><LATS1 gene><Ligands><Light><Lung Adenocarcinoma><MER6><Macrophage><Malignant Cell><Malignant Neoplasm Therapy><Malignant Neoplasm Treatment><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Modeling><Mutation><Mφ><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Neoplasm Metastasis><Neoplastic Colony-Forming Units><Neoplastic Stem Cells><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Oncogenesis><Oncogenic><Organoids><PD-1/PD-L1><PD-1/PDL1><PD1-PD-L1><PD1/PD-L1><PD1/PDL1><PDX model><PP2A><PP2A Subunit B Prime><Patient derived xenograft><Patients><Phagocytosis><Phagocytosis Induction><Phosphotransferase Gene><Phosphotransferases><Phosphotyrosyl Phosphatase Activator><Photoradiation><Plasma Membrane><Platinum><Platinum Black><Population><Process><Prognosis><Property><Protein Family><Protein Phosphatase 2A Regulatory Subunit B Prime><Protein Phosphatase 2A Regulatory Subunit PR53><Pt element><Pulmonary Cancer><Pulmonary malignant Neoplasm><Regulation><Reporting><Resistance><Role><Sampling><Secondary Neoplasm><Secondary Tumor><Signal Transduction><Signal Transduction Systems><Signaling><Surface Antigen Identified by Monoclonal Antibody 1D8><Survival Rate><TGF-alpha Receptor><TSP-1><TSP1><Technology><Testing><Thrombospondin 1><Transforming Growth Factor alpha Receptor><Transmembrane Protein><Transmembrane Protein Gene><Transmission><Transphosphorylases><Tumor Cell><Tumor Escape><Tumor Immune Escape><Tumor Stem Cells><Urogastrone Receptor><Xenograft><Xenograft procedure><Xenotransplantation><aPD-1><aPD1><anti programmed cell death 1><anti-PD-1><anti-PD1><anti-cancer therapy><anti-programmed cell death protein 1><antiPD-1><antiPD1><attenuate><attenuates><biological signal transduction><c-erbB-1><c-erbB-1 Protein><cancer cell><cancer evasion><cancer immune escape><cancer immune evasion><cancer initiation><cancer metastasis><cancer progenitor><cancer progenitor cells><cancer progression><cancer stem cell><cancer therapy><cancer-directed therapy><check point blocker><checkpoint blockers><chemotherapy><cytokine><drug resistant><empowerment><erbB-1><erbB-1 Proto-Oncogene Protein><erbBl><genome mutation><humanized mice><humanized mouse><immune check point blocker><immune checkpoint blockers><immune evasive><immune modulation><immune regulation><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based therapies><immune-based treatments><immuno therapy><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><innovate><innovation><innovative><insight><knockin mice><lung cancer><lung cancer cell><malignancy><malignant progenitor><malignant stem cell><mouse genetics><mouse model><murine model><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><novel><overexpress><overexpression><patient derived xenograft model><pharmacologic><plasmalemma><progenitor cell function><progenitor cell population><progenitor function><progenitor population><proto-oncogene protein c-erbB-1><recruit><resistance mechanism><resistance to Drug><resistance to therapy><resistant><resistant mechanism><resistant to Drug><resistant to therapy><response><social role><standard of care><stem and progenitor cell function><stem and progenitor cell population><stem and progenitor function><stem cell function><stem cell population><survival outcome><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic resistance><therapeutically effective><therapy resistant><transcriptomics><transmission process><treatment resistance><tumor><tumor cell metastasis><tumor evasion><tumor immune evasion><tumor progenitor><tumor progression><tumorigenesis><xeno-transplant><xeno-transplantation><αPD-1><αPD1>