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Principal Investigator: Or P. Gozani
Organization: UNIVERSITY OF TX MD ANDERSON CAN CTR
Fiscal Year: 2024
Award: $612,325
Funding agency: National Cancer Institute
ABSTRACT
Our overarching goal is to elucidate the mode of action of and evaluate the therapeutic potential of the
epigenetic regulatory factor NSD3 in the regulation of lung squamous cell carcinoma (LUSC) pathogenesis. Lung
cancer is the most common cause of cancer-related mortality in the United States and worldwide, leading to over
a 1.8 million deaths each year. LUSC is the second most common subtype of lung cancer, accounting for ~30%
of all cases and tragically over 40,000 deaths each year in the US alone. While new targeted therapies have
shown promise in other malignancies, unfortunately, to date, there are no approved targeted therapies for LUSC.
Thus, there is a major unmet need to uncover new, clinically actionable, and compelling targets for the
development of new medicines to ultimately treat this difficult disease. A central hypothesis to be tested here is
that the histone H3 lysine 36 (H3K36) di-methyltransferase enzyme NSD3 is a promising epigenetic target for
the treatment of LUSC. In preliminary work we found that NSD3, which is commonly amplified in LUSC, is a
major driver of LUSC pathogenesis in mouse and human models of this cancer. In our proposal, we will
investigate the role of the NSD3-H3K36me2 axis in lung cancer in vivo and explore the molecular and epigenetic
basis of NSD3-driven tumorigenesis.
In Aim 1 we investigate the role of NSD3 in LUSC pathogenesis. We have developed novel mouse models
that recapitulate the most common genetic alterations in human LUSC, including NSD3 amplification, and
incorporated an inducible dual-recombinase approach to allow study of multi-step tumorigenesis in vivo. This
system will be used to dissect the specific functions for NSD3 in LUSC tumor initiation, progression,
maintenance, and metastatic transition using conditional NSD3 gain-of-function and knockout mice. A multistep
approach will also enable genetic validation of NSD3 as potential therapeutic target in advanced LUSC, a stage
for which new therapies are urgently needed. In Aim 2 we will elucidate the epigenetic pathways reguated by
the NSD3-H3K36me2 axis, utilizing new cutting-edge epigenomic technologies. We will also explore the role of
NSD3 in promoting intratumoral heterogeneity in human and mouse models of LUSC at the single cell level.
Together, this work will be the first to evaluate the therapeutic potential and mechanism-of-action of NSD3 in
LUSC.
Terms: <3q26><8p11><Accounting><Antigenic Determinants><Antioncogene Protein p53><Binding Determinants><Biochemical><CUT&RUN><Cancer Cause><Cancer Etiology><Cancer Model><CancerModel><Cancers><Cell Body><Cells><Cellular Tumor Antigen P53><Cessation of life><Chromatin><Cleavage Targets and Release Using Nuclease><Cleavage Under Targets and Release Using Nuclease><Clinical><Clinical Trials><DNA methylation profiling><Data><Death><Development><Diagnosis><Disease><Disorder><Drug Targeting><EC 2.1.1><Enzyme Gene><Enzymes><Epidermoid Cell Lung Carcinoma><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Epitopes><Evolution><FGFBR><FGFR1><FGFR1 Gene Activation><FGFR1 Gene Amplification><FGFR1 gene><FLG Gene><FLT2 Gene><FMS-Like Gene><FMS-Like Tyrosine Kinase 2 Gene><Fibroblast Growth Factor Receptor 1 Gene><Fibroblast Growth Factor Receptor 1 Gene Activation><Fibroblast Growth Factor Receptor 1 Gene Amplification><Gene Amplification><Generations><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genomic Segment><Goals><Heterogeneity><Histologic><Histologically><Histone H3><Human><Intratumoral heterogeneity><KO mice><Knock-out Mice><Knockout Mice><L-Lysine><Lysine><Maintenance><Malignant><Malignant - descriptor><Malignant Neoplasms><Malignant Tumor><Malignant Tumor of the Lung><Malignant neoplasm of lung><Medicine><Metastasis><Metastasize><Metastatic Lesion><Metastatic Mass><Metastatic Neoplasm><Metastatic Tumor><Methyl-Seq><MethylSeq><Methylation><Methylation sequencing><Methyltransferase><Mice><Mice Mammals><Modeling><Modern Man><Molecular><Murine><Mus><Mutation><Nature><Neoplasm Metastasis><Null Mouse><Oncogenesis><Oncogenic><Oncoprotein p53><Outcome><P53><Pathogenesis><Pathologic><Pathway interactions><Patient outcome><Patient-Centered Outcomes><Patient-Focused Outcomes><Patients><Pattern><Penetrance><Phosphoprotein P53><Phosphoprotein pp53><Pre-Clinical Model><Preclinical Models><Protein TP53><Pulmonary Cancer><Pulmonary malignant Neoplasm><Regulation><Research><Resolution><Role><Sampling><Secondary Neoplasm><Secondary Tumor><Squamous Cell Lung Carcinoma><Squamous cell lung cancer><System><TP53><TP53 gene><TRP53><Technology><Testing><Therapeutic><Tumor Cell><Tumor Promotion><Tumor Protein p53><Tumor Protein p53 Gene><United States><Validation><Work><cancer metastasis><cancer progression><clinically actionable><developmental><disease model><disorder model><driver lesion><driver mutation><drug candidate><epigenetically><epigenomics><experiment><experimental research><experimental study><experiments><gain of function><genome mutation><genome segment><genomic region><heterogeneity in tumors><histone H3 methyltransferase><histone methylase><histone methyltransferase><histone modification><human model><improved><in vivo><inhibitor><insight><intra-tumoral heterogeneity><intratumor heterogeneity><lung cancer><lung squamous cancer><lung squamous carcinoma><lung squamous cell carcinoma><malignancy><methylase><model of human><mortality><mouse model><multiomics><multiple omics><murine model><natural gene amplification><neoplasm progression><neoplasm/cancer><neoplastic cell><neoplastic progression><new approaches><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next generation therapeutics><novel><novel approaches><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel strategies><novel strategy><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><overexpress><overexpression><p53 Antigen><p53 Genes><p53 Tumor Suppressor><panomics><pathway><patient oriented outcomes><pre-clinical><preclinical><protein p53><recombinase><resolutions><social role><squamous cell carcinoma of the lung><targeted drug therapy><targeted drug treatments><targeted therapeutic><targeted therapeutic agents><targeted therapy><targeted treatment><therapeutic target><transcriptome profiling><transcriptomic profiling><transmethylase><tumor><tumor cell metastasis><tumor heterogeneity><tumor initiation><tumor progression><tumorigenesis><validations>