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Principal Investigator: Tao Zou
Organization: DANA-FARBER CANCER INST
Fiscal Year: 2024
Award: $208,829
Funding agency: National Cancer Institute
PROJECT SUMMARY/ABSTRACT
Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related mortality worldwide. The development
of targeted molecular therapies that inhibit mutant oncogenic proteins and immunotherapies that inhibit the PD-
1/PD-L1 pathway have improved outcomes for subsets of patients with NSCLC. However, targeted therapies
are only effective against NSCLCs that harbor actionable genetic alterations. In addition, anti-PD-1/PD-L1
immune checkpoint inhibitors are most effective against NSCLCs that express high levels of PD-L1 or have a
high tumor mutation burden. Thus, patients with NSCLCs that lack these features do not benefit from targeted
therapies and are less likely to benefit from immunotherapies, emphasizing the need to identify novel therapeutic
targets in this disease. This project seeks to characterize the XRN1 exoribonuclease, which functions in cellular
RNA degradation, as a target that may have broad therapeutic potential in NSCLC. My preliminary data show
that XRN1 inactivation induces cell lethality in a subset of human NSCLC cell lines. In an implantable mouse
tumor model, XRN1 deletion can synergize with anti-PD-1 immunotherapy to enhance tumor eradication. Aim 1
will define the molecular signaling pathways that mediate cell lethality after XRN1 deletion in a subset of human
NSCLC cell lines. Aim 2 will assess the impact of XRN1 deletion in mouse NSCLC models of anti-PD-1
immunotherapy. Aim 3 will determine whether XRN1 gene expression in human NSCLC tumors may serve as a
predictive biomarker for treatment response to anti-PD-1 immunotherapy. The long-term goals of the proposed
research are to gain fundamental insights into how RNA metabolism regulates cancer cell survival and anti-
tumor immunity and to establish RNA metabolism pathways as potential therapeutic targets in NSCLC.
The applicant, Dr. Tao Zou, is an oncologist at Dana-Farber Cancer Institute (DFCI). He spends 80% of his time
engaged in research and career development activities and 20% of his time in clinical practice caring for patients
with lung cancer. Dr. Zou has outlined a five-year career development plan that will enable him to achieve his
goal of leading an independent laboratory that conducts basic and translational research at the intersection of
RNA biology and lung cancer immunotherapy. Dr. Zou will perform the proposed research under the mentorship
of Dr. Matthew Meyerson, an expert in lung cancer biology with a strong record of training independent
investigators in academic cancer research. Together with expert members of Dr. Zou’s Scientific Advisory
Committee, Dr. Meyerson will ensure that Dr. Zou will obtain additional training in innate immune RNA sensing,
tumor immunology, translational studies using human biospecimens, and computational biology. Dr. Zou will
conduct the proposed research primarily at DFCI and will leverage additional resources available to him at the
Broad Institute and Harvard Medical School. DFCI is a rich research community with a distinguished track record
of training successful physician-scientists. DFCI provides the ideal environment for Dr. Zou to build his research
expertise and engage in career development activities prior to transitioning to an independent academic position.
Terms: <2',3'-exoribonuclease><3'-exoribonuclease><Adenosine Cyclic Monophosphate-Dependent Protein Kinases><Advisory Committees><B7-H1><B7H1><Basic Research><Basic Science><Biology><Biopsy><CD274><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 Biology><Cancer Cause><Cancer Etiology><Cancer Model><Cancer cell line><CancerModel><Cas nuclease technology><Cell Body><Cell Communication and Signaling><Cell Death><Cell Signaling><Cell Survival><Cell Viability><Cells><Checkpoint inhibitor><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><Communities><Computational Biology><Cyclic AMP-Dependent Protein Kinases><Cytoplasm><DF/HCC><DNA Alteration><DNA Sequence Alteration><DNA mutation><Dana-Farber Cancer Institute><Data><Development><Development Plans><Development and Research><Disease><Disorder><Double-Stranded RNA><Ensure><Environment><Enzyme Gene><Enzymes><Eukaryotic Initiation Factors><Eukaryotic Peptide Initiation Factors><Eukaryotic Translation Initiation Factors><Exoribonucleases><Flow Cytofluorometries><Flow Cytofluorometry><Flow Cytometry><Flow Microfluorimetry><Flow Microfluorometry><Funding><Gene Expression><Gene Expression Monitoring><Gene Expression Pattern Analysis><Gene Expression Profiling><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genetic mutation><Goals><Human><I-RNA><Immune><Immune checkpoint inhibitor><Immune infiltrates><Immune mediated therapy><Immunes><Immunologically Directed Therapy><Immunotherapy><Implant><Interferon Type I><Intracellular Communication and Signaling><Investigators><Laboratories><Laboratory Research><Link><Malignant Cell><Malignant Tumor of the Lung><Malignant neoplasm of lung><Mediating><Mentorship><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Mutation><NSCLC><NSCLC - Non-Small Cell Lung Cancer><Non-Polyadenylated RNA><Non-Small Cell Lung Cancer><Non-Small-Cell Lung Carcinoma><Oncogenic><Oncologist><PD-1 inhibitors><PD-1/PD-L1><PD-1/PDL1><PD-L1><PD-L1 pathway><PD1 inhibitors><PD1-PD-L1><PD1/PD-L1><PD1/PDL1><PDL-1><PDL1><PDL1 pathway><PKA><Pathway interactions><Patient Care><Patient Care Delivery><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Phosphorylation><Physicians><Position><Positioning Attribute><Programmed Cell Death 1 Ligand 1><Programmed Death Ligand 1><Protein Kinase A><Protein Phosphorylation><Proteins><Pulmonary Cancer><Pulmonary malignant Neoplasm><R & D><R&D><RNA><RNA Degradation><RNA Gene Products><RNA metabolism><Regimen><Research><Research Personnel><Research Proposals><Research Resources><Researchers><Resistance><Resources><Ribonucleic Acid><Scientist><Sequence Alteration><Signal Induction><Signal Pathway><Signal Transduction><Signal Transduction Systems><Signaling><Task Forces><Therapeutic><Time><Training><Transcript Expression Analyses><Transcript Expression Analysis><Translational Research><Translational Science><Tumor Immunity><United States><aPD-1><aPD1><advisory team><analyze gene expression><anti programmed cell death 1><anti programmed cell death protein 1 inhibitor><anti-PD-1><anti-PD-1 inhibitors><anti-PD-1/PD-L1><anti-PD1><anti-PD1 inhibitors><anti-cancer immunotherapy><anti-cancer research><anti-programmed cell death protein 1><anti-tumor immune response><anti-tumor immunity><antiPD-1><antiPD1><anticancer immunotherapy><antitumor immunity><biological adaptation to stress><biological signal transduction><cAMP-Dependent Protein Kinases><cancer cell><cancer immunity><cancer immunology><cancer immunotherapy><cancer microenvironment><cancer research><care for patients><care of patients><career development><caring for patients><check point inhibition><checkpoint inhibition><clinical practice><cohort><computer biology><cytokine><developmental><dsRNA><experiment><experimental research><experimental study><experiments><flow cytophotometry><gene expression analysis><gene expression assay><gene induction><genome mutation><genome scale><genome-wide><genomewide><genomic alteration><immune RNA><immune cell infiltrate><immune check point inhibition><immune check point inhibitor><immune checkpoint inhibition><immune therapeutic approach><immune therapeutic interventions><immune therapeutic regimens><immune therapeutic strategy><immune therapy><immune-based cancer therapies><immune-based therapies><immune-based treatments><immuno therapy><immunotherapy for cancer><immunotherapy of cancer><improved><improved outcome><in vivo><induction of genes><innovate><innovation><innovative><insight><loss of function><lung cancer><lung cancer cell><medical college><medical schools><member><molecular targeted therapeutics><molecular targeted therapies><molecular targeted treatment><mortality><mutant><necrocytosis><neoplasm immunology><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><pathway><patient oriented outcomes><patient subclass><patient subcluster><patient subgroups><patient subpopulations><patient subsets><patient subtypes><pharmacologic><poly A specific exoribonuclease><predictive biomarkers><predictive marker><predictive molecular biomarker><programmed cell death ligand 1><programmed cell death ligand 1 pathway><programmed cell death protein ligand 1><programmed cell death protein ligand 1 pathway><programs><protein death-ligand 1><protein kinase R><reaction; crisis><recruit><research and development><resistant><response biomarker><response markers><response to therapy><response to treatment><school of medicine><sensor><stress response><stress; reaction><synergism><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic response><therapeutic target><therapy response><transcriptional profiling><translation research><translational investigation><translational study><treatment response><treatment responsiveness><treatment strategy><tumor><tumor eradication><tumor immunology><tumor microenvironment><αPD-1><αPD1>