A5012487132- Cancer-related gene regulation
- ATP Synthase and ATPases Research
- Biochemical and Molecular Research
- Cytokine Signaling Pathways and Interactions
- Glioma Diagnosis and Treatment
- Vitamin D Research Studies
- TGF-β signaling in diseases
- Estrogen and related hormone effects
- Cancer, Hypoxia, and Metabolism
- Colorectal Cancer Treatments and Studies
- Protein Kinase Regulation and GTPase Signaling
- Cancer Cells and Metastasis
- Lung Cancer Treatments and Mutations
- Ferroptosis and cancer prognosis
- MicroRNA in disease regulation
- Genetic factors in colorectal cancer
- Hedgehog Signaling Pathway Studies
- Synthesis and Catalytic Reactions
- Prostate Cancer Treatment and Research
- DNA Repair Mechanisms
- RNA and protein synthesis mechanisms
- Cell Image Analysis Techniques
- Cancer Research and Treatments
- Epigenetics and DNA Methylation
- Bioinformatics and Genomic Networks
St. Jude Children's Research Hospital
2017-2024
RIKEN BioResource Research Center
2023
VA Tennessee Valley Healthcare System
2015
Vanderbilt University Medical Center
2012-2015
Neurological Surgery
2015
Vanderbilt University
2015
Forest Institute
2011
Purdue University West Lafayette
2011
University of Colorado Health
2011
Wake Forest University
2011
Abstract Previous studies implicated protein arginine methyltransferase 5 (PRMT5) as a synthetic lethal target for MTAP-deleted (MTAP del) cancers; however, the pharmacologic characterization of small-molecule inhibitors that recapitulate phenotype has not been described. MRTX1719 selectively inhibited PRMT5 in presence MTA, which is elevated MTAP del cancers, and PRMT5-dependent activity cell viability with >70-fold selectivity HCT116 compared wild-type (WT) cells. demonstrated...
KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In with adenocarcinoma STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature pre-treatment biopsies correlates a poor response to adagrasib. Studies Lkb1-deficient KrasG12D cancer mouse models organoids treated KRAS reveal tumors invoke lineage plasticity program, adeno-to-squamous...
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Double minute chromosomes are extrachromosomal circular DNA fragments frequently found in brain tumors. To understand their evolution, we characterized the double minutes paired diagnosis and relapse tumors from a pediatric high-grade glioma four adult glioblastoma patients. We determined full structures of major using novel approach combining multiple types supporting genomic evidence. Among identified patient, only one carrying EGFR was maintained at high abundance both samples, whereas...
Abstract High throughput omics approaches provide an unprecedented opportunity for dissecting molecular mechanisms in cancer biology. Here we present deep profiling of whole proteome, phosphoproteome and transcriptome two high-grade glioma (HGG) mouse models driven by mutated RTK oncogenes, PDGFRA NTRK1 , analyzing 13,860 proteins 30,431 phosphosites mass spectrometry. Systems biology identify numerous master regulators, including 41 kinases 23 transcription factors. Pathway activity...
Pediatric high-grade glioma (pHGG) is a major contributor to cancer-related death in children. In vitro and vivo disease models reflecting the intimate connection between developmental context pathogenesis of pHGG are essential advance understanding identify therapeutic vulnerabilities. Here we report establishment 21 patient-derived orthotopic xenograft (PDOX) eight matched cell lines from diverse groups pHGG. These recapitulate histopathology, DNA methylation signatures, mutations gene...
Abstract Vitamin D3 is a promising preventative and therapeutic agent for prostate cancer, but its implementation hampered by lack of understanding about mechanism action. Upon treatment with 1α,25-dihydroxyvitamin [1,25(OH)2D3, vitamin D3], the metabolically active form D3, adult progenitor/stem cells (PrP/SC) undergo cell-cycle arrest, senescence, differentiation to an androgen receptor–positive luminal epithelial cell fate. Microarray analyses control- D3–treated PrP/SCs revealed global...
KRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of RTK/MAPK pathway. The Son Sevenless homolog 1 (SOS1) protein functions as a guanine nucleotide exchange factor (GEF) for RAS subfamily small GTPases represents druggable target Using structure-based drug discovery approach, MRTX0902 was identified selective potent SOS1 inhibitor that disrupts KRAS:SOS1 protein-protein interaction to prevent SOS1-mediated on translates...
Abstract Background: KRAS inhibitors are revolutionizing the treatment of NSCLC, but clinico-genomic determinants efficacy warrant continued exploration. Methods: Patients with advanced KRASG12C-mutant NSCLC treated adagrasib (KRYSTAL-1-NCT03785249) were included in analysis. Pre-treatment NGS data collected per protocol. HTG EdgeSeq Transcriptome Panel was used for gene expression profiling. Clinical endpoints objective response, progression-free and overall survival. cell lines xenograft...
<p>Supplementary Methods S1. LKB1/<i>KEAP1</i> over-expression; Western Blot Analysis; KRAS-GTP Pull-Down Assay.</p>
<p>Supplementary Figure S2. <i>In vitro</i> efficacy of adagrasib in <i>KRAS</i><sup><i>G12C</i></sup>-mutant lung cancer models based on <i>STK11</i>/LKB1 and <i>KEAP1</i> status.</p>
<p>Supplementary Figure S6. Correlation of NRF2 score and survival to adagrasib monotherapy according <i>KEAP1</i> <i>STK11</i> co-mutation status.</p>
<p>Supplementary Figure S3. Adagrasib combination drug screens in KRASG12C-mutant lung cancer models.</p>
<p>Supplementary Figure S4. NRF2 score in KRASG12C-mutant NSCLC patients treated with adagrasib.</p>
<p>Supplementary Figure S8. <i>STK11</i>/LKB1 and epithelial-mesenchymal transition – EMT scores in <i>KRAS</i><sup><i>G12C</i></sup>-mutant NSCLC patients treated with adagrasib.</p>
<p>Supplementary Figure S1. Clinical outcomes to adagrasib monotherapy according <i>TP53</i>, <i>ATM</i> and <i>CDKN2A</i> co-mutation status.</p>
<p>Supplementary Figure S5. NRF2 score is associated with survival upon treatment adagrasib monotherapy.</p>
<p>Supplementary Figure S7. Clinical outcomes to adagrasib monotherapy according NRF2 score and <i>STK11</i> co-mutation status in <i>KEAP1</i><sup><i>WT</i></sup>/<i>KRAS</i><sup><i>G12C</i></sup>-mutant NSCLC patients.</p>
<div>AbstractPurpose:<p>KRAS inhibitors are revolutionizing the treatment of non–small cell lung cancer (NSCLC), but clinico-genomic determinants efficacy warrant continued exploration.</p>Experimental Design:<p>Patients with advanced <i>KRAS</i><sup><i>G12C</i></sup>-mutant NSCLC treated adagrasib [KRYSTAL-1 (NCT03785249)] were included in analysis. Pretreatment next-generation sequencing data collected per protocol. HTG EdgeSeq...
// Michael W. Pickup 1,* , Laura D. Hover 2,* Yan Guo 3,4 Agnieszka E. Gorska 4 Anna Chytil Sergey V. Novitskiy Harold L. Moses and Philip Owens 1 Department of Surgery Center for Bioengineering Tissue Regeneration, University California at San Francisco, CA, USA 2 Pathology, Microbiology Immunology, Vanderbilt Medical Center, Nashville, TN, 3 Ingram Cancer Quantitative Sciences, Biology, University, * These authors contributed equally should be considered co-first Correspondence to: Owens,...
Bone Morphogenetic Protein (BMP) receptors mediate a diverse range of signals to regulate both development and disease. BMP activity has been linked tumor promoting suppressive functions in cells their surrounding microenvironment. We sought investigate the requirement for BMPR2 stromal fibroblasts during mammary formation metastasis. utilized FSP1 (Fibroblast Specific Protein-1) promoter driven Cre genetically delete mice expressing MMTV.PyVmT carcinoma oncogene. found that abrogation...
Abstract Background Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating MET receptor tyrosine kinase often occur infant-type hemispheric (IHG) but also other pHGG are associated with devastating morbidity mortality. Methods To identify new treatment options, we established characterized two novel orthotopic mouse models harboring distinct fusions. These included an...