Lyazat Kurenbekova
A5005585106- Sarcoma Diagnosis and Treatment
- MicroRNA in disease regulation
- Cancer-related molecular mechanisms research
- X-ray Diffraction in Crystallography
- PI3K/AKT/mTOR signaling in cancer
- RNA modifications and cancer
- Crystallization and Solubility Studies
- Melanoma and MAPK Pathways
- Cancer Genomics and Diagnostics
- interferon and immune responses
- Cancer Research and Treatments
- Cancer, Hypoxia, and Metabolism
- Cancer Cells and Metastasis
- Virus-based gene therapy research
- Cancer-related gene regulation
- RNA Research and Splicing
- Epigenetics and DNA Methylation
- Neuroblastoma Research and Treatments
- CAR-T cell therapy research
- Ubiquitin and proteasome pathways
- Cancer-related Molecular Pathways
- Lanthanide and Transition Metal Complexes
- Molecular Biology Techniques and Applications
- Wnt/β-catenin signaling in development and cancer
- Cancer Mechanisms and Therapy
Baylor College of Medicine
2016-2025
Texas Children's Hospital
2023-2024
Children's Cancer Center
2015-2023
Abstract Background The Wnt/β-catenin pathway is closely associated with osteosarcoma (OS) development and metastatic progression. We investigated the antitumor activity of Tegavivint, a novel β-catenin/transducin β-like protein 1 (TBL1) inhibitor, against OS employing in vitro, ex vivo, vivo cell line patient-derived xenograft (PDX) models that recapitulate high risk disease. Methods efficacy Tegavivint was evaluated vitro using established PDX-derived lines. Use an three-dimensional...
Osteosarcoma (OS) is the primary bone tumor in children and young adults. Currently, there are no reliable, noninvasive biologic markers to detect presence or progression of disease, assess therapy response, provide upfront prognostic insights. MicroRNAs (miRNAs) evolutionarily conserved, stable, small noncoding RNA molecules that key posttranscriptional regulators ideal candidates for circulating biomarker development due their stability plasma, ease isolation, unique expressions associated...
Mechanistically unique <sup>19</sup>F-Eu<sup>II/III</sup> complex reports redox <italic>in vivo</italic> using both <sup>1</sup>H- and <sup>19</sup>F-MRI displays temperature-dependent contrast enhancement.
Ewing Sarcoma (ES) is a highly aggressive bone tumor with peak incidence in the adolescent population. It has high propensity to metastasize, which associated dismal survival rates of approximately 25%. To further understand mechanisms metastasis we investigated microRNA regulatory networks ES. Our studies focused on miR‐130b due our analysis that enhanced expression this clinical relevance multiple sarcomas, including provide insights into novel positive feedback network involving direct...
Osteosarcoma (OS) is the most common primary bone tumor of childhood. Approximately 20%-30% OSs carry amplification chromosome 8q24, which harbors oncogene c-MYC and correlates with a poor prognosis. To understand mechanisms that underlie ability MYC to alter both its surrounding microenvironment (TME), we generated molecularly characterized an osteoblast-specific Cre-Lox-Stop-Lox-c-MycT58A p53fl/+ knockin genetically engineered mouse model (GEMM). Phenotypically, Myc-knockin GEMM had rapid...
Abstract The efficacy of CAR T-cells (CART) in solid tumors is limited by immune inhibition. In our study, we observed that effector cytokines mediated the upregulation PD-L1 immune-checkpoint primary glioblastoma (GBM). To offset inhibitory signal, engineered PD-1 checkpoint reversal receptors (CPR) with a CD28 or 41BB co-stimulatory endodomain and co-expressed them first-generation CD28-containing second-generation HER2-specific (CPR/CART) using bicistronic vectors. We found bipartite...
<p>Analysis of CAR immune synapse (CARIS) with HER2+ GBM cells.</p>
<p>Immunophenotype and immune-checkpoint receptor expression in patient-derived CPR/CART cells.</p>
<p>Expression of CAR/CPR on T cells and HER2/PD-L1 tumor cells.</p>
<p>Summary of CPR/CART design and characterization CARζ co-expressing CPR containing CD28 or 4-1BB signaling.</p>
<p>Assessment of PD-L1 expression and CARζ/CPR41BB cell cytotoxic function in osteosarcoma.</p>
<p>Immunophenotype and functional profile of CARζ/CPR41BB in comparison to CAR41BBζ cells.</p>
<p>Analysis of CAR immune synapse (CARIS) formation by CARζ/CPR41BB and CAR41BBζ cells with wild-type PD-L1 KO LN229-GBM cells.</p>
<p>Assessment of mitochondrial metabolism in CARζ/CPR41BB cells.</p>
<p>PD-L1 expression in GBM and PD-1 recruitment to the CARIS with GBM. <b>A,</b> Constitutive (UPN01) inducible (UPN06) surface of PD-L1 primary cells after 24–48 hours IFN-γ exposure. Representative results from two samples shown. UPN, unique patient number. <b>B,</b> median fluorescent intensity (MFI) on (<i>n</i> = 14) before at 48 (10 ng/mL) exposure; ***, <i>P</i> < 0.001, Wilcoxon signed-rank test. <b>C,</b>...
<div>Abstract<p>The efficacy of chimeric antigen receptor T cells (CART) in solid tumors is limited by immune inhibition. In our study, we observed that effector cytokines mediated the upregulation PD-L1 checkpoint primary glioblastoma. To offset inhibitory signal, engineered PD-1 reversal receptors (CPR) with a CD28 or 41BB costimulatory endodomain and coexpressed them first-generation CD28-containing second-generation HER2-specific CAR (CPR/CART) using bicistronic vectors. We...
<p>Dynamics of CARζ/CPR41BB T-cell activation and CARIS formation in comparison with CAR41BBζ cells. <b>A,</b> cells (<i>n</i> = 3 donors) demonstrated significantly lower IL-2 IFN-γ release compared at 24 hours coculture LN229-GBM cells, CAR28ζ consistently showing the higher Th1 cytokine production. Data are shown as mean ± SD. **, <i>P</i> < 0.000; ****, 0.0001; two-way ANOVA Tukey multiple comparisons test. <b>B,</b> Western blot...
<p>Metabolomic parameters of CARζ/CPR41BB cells in comparison with CAR41BBζ cells. <b>A,</b> OCR measurements resting (cultured media containing IL-7 and IL-15) (<i>n</i> = 3 donors; 200,000 T per well) under basal metabolic conditions after the addition mitochondrial inhibitors. <b>B,</b> Comparison maximal respiration between at baseline (day 0). <i>P</i> 0.059, Student two-tailed <i>t</i> test. <b>C,</b> Basal...
<p>Effect of decoupling signal 2 from the CAR on T-cell function. <b>A,</b> Illustration depicting bipartite activation through 1 delivery engaging HER2 antigen and binding CPR with PD-L1 (or PD-L2). <b>B,</b> Percent increase in IFN-γ production by CAR28ζ/CPR28 CARζ/CPR28 compared CAR28ζ cells (50,000 T cells/well) at 24 hours coculture autologous GBM (<i>n</i> = 5 patients). Effector (100,000 cells) to target ratio 1:1. **, <i>P</i>...
<p>Design and functional screening of PD-1<sub>TR</sub> CPR28 molecules. <b>A,</b> Schematic representation the bicistronic vectors encoding for HER2-CAR with truncated PD-1 (PD-1<sub>TR</sub>) or CPR28. The CPR28<sup>dimer</sup> included a membrane proximal extracellular cysteine residue (C141) required CD28 homodimerization, as indicated. <b>B,</b> Flow cytometry analysis showing coexpression CPR on T cells. CAR28ζ NT cells...
<p><i>In vivo</i> antitumor activity of locoregionally delivered CARζ/CPR41BB cells in an orthotopic GBM model. <b>A,</b> Experimental schema for <i>in functional testing a LN229-GBM xenograft Mice were injected with eGFP.FFluc-expressing tumor on day 0 and randomized to treatment groups 11. Treatment consisted two intracranial T-cell injections days 13 21. Tumors monitored by BLI. <b>B,</b> Comparison volumes between control after...
<p>Immunohistochemistry and histopathology findings in a metastatic osteosarcoma model after treatment with CARζ/CPR41BB cells.</p>
<p>PD-L1 expression in glioblastoma (GBM) cells and PD-1 upregulation CART.</p>