A5037713496- Multiple Myeloma Research and Treatments
- Protein Degradation and Inhibitors
- CAR-T cell therapy research
- Monoclonal and Polyclonal Antibodies Research
- Nanoparticle-Based Drug Delivery
- Cancer, Hypoxia, and Metabolism
- Immune Cell Function and Interaction
- Cancer-related Molecular Pathways
- Peptidase Inhibition and Analysis
- Metabolism, Diabetes, and Cancer
- Microtubule and mitosis dynamics
- Ubiquitin and proteasome pathways
- Cell Adhesion Molecules Research
- Immunotherapy and Immune Responses
- Cancer Genomics and Diagnostics
- Glycosylation and Glycoproteins Research
- Computational Drug Discovery Methods
- CRISPR and Genetic Engineering
- T-cell and B-cell Immunology
- Acute Myeloid Leukemia Research
- Viral Infectious Diseases and Gene Expression in Insects
- PI3K/AKT/mTOR signaling in cancer
- Chronic Myeloid Leukemia Treatments
- RNA Research and Splicing
- Dendrimers and Hyperbranched Polymers
Washington University in St. Louis
2015-2024
Molecular Oncology (United States)
2022
Webster Groves Nature Study Society
2018-2020
University of Louisville
2011-2016
James Graham Brown Foundation
2014
Roslin Institute
2013
University of Edinburgh
2013
Advanced Cancer Therapeutics
2013
Institute of Biomedical Science
2008
University of Chicago
2004-2005
In human cancers, loss of PTEN, stabilization hypoxia inducible factor-1α, and activation Ras AKT converge to increase the activity a key regulator glycolysis, 6-phosphofructo-2-kinase (PFKFB3). This enzyme synthesizes fructose 2,6-bisphosphate (F26BP), which is an activator 6-phosphofructo-1-kinase, step glycolysis. Previously, weak competitive inhibitor PFKFB3, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), was found reduce glucose metabolism proliferation cancer cells. We have...
The control of glucose metabolism and the cell cycle must be coordinated in order to guarantee sufficient ATP anabolic substrates at distinct phases cycle. family 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFB1-4) are well established regulators via their synthesis fructose-2,6-bisphosphate (F2,6BP), a potent allosteric activator 6-phosphofructo-1-kinase (Pfk-1). PFKFB3 is overexpressed human cancers, regulated by HIF-1α, Akt PTEN, required for survival growth multiple cancer...
NF-κB inducing kinase (NIK) is required for osteoclastogenesis in response to pathologic stimuli, and its loss leads functional blockade of both alternative classical caused by cytoplasmic retention p100. We now show that deletion p100 restores the capacity NIK-deficient osteoclast (OC) precursors differentiate normalizes RelB p65 signaling. Differentiation NIK −/− also restored overexpression RelB, but not p65. Additionally, fail form OCs culture, this defect rescued re-expression To...
Abstract Multiple myeloma (MM) is characterized by the uncontrolled proliferation of plasma cells. Despite recent treatment advances, it still incurable as disease progression not fully understood. To investigate MM and its immune environment, we apply single cell RNA linked-read whole genome sequencing to profile 29 longitudinal samples at different stages from 14 patients. Here, collect 17,267 cells 57,719 cells, discovering patient-specific profiles expression changes. Patients with same...
Chimeric antigen receptor (CAR) T cell therapy is routinely used to treat patients with refractory hematologic malignancies. However, a significant proportion of experience suboptimal CAR cytotoxicity and persistence that can permit tumor escape disease relapse. Here we show prototype pro-lymphoid growth factor able enhance efficacy. We demonstrate long-acting form recombinant human interleukin-7 (IL-7) fused hybrid Fc (rhIL-7-hyFc) promotes proliferation, cells in xenogeneic mouse models,...
The t(8;21)(q22;q22) translocation, occurring in 40% of patients with acute myeloid leukemia (AML) the FAB-M2 subtype (AML maturation), results expression RUNX1-CBF2T1 [ AML1 - ETO ( AE )] fusion oncogene. AML/ETO may contribute to leukemogenesis by interacting nuclear corepressor complexes that include histone deacetylases, which mediate repression target genes. However, is not sufficient transform primary hematopoietic cells or cause disease animals, suggesting additional mutations are...
Unlike glycolytic enzymes that directly catabolize glucose to pyruvate, the family of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFKFBs) control conversion fructose-6-phosphate and from fructose-2,6-bisphosphate, a key regulator enzyme phosphofructokinase-1 (PFK-1). One member, PFKFB3, has been shown be highly expressed activated in human cancer cells, derivatives PFKFB3 inhibitor, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), are currently being developed clinical...
T-cell-based immunotherapy, such as CAR-T cells and bispecific T-cell engagers (BiTEs), has shown promising clinical outcomes in many cancers; however, these therapies have significant limitations, poor pharmacokinetics the ability to target only one antigen on cancer cells. In multiclonal diseases, confer development of antigen-less clones, causing tumor escape relapse. this study, we developed nanoparticle-based (nanoBiTEs), which are liposomes decorated with anti-CD3 monoclonal antibodies...
Despite improvement in treatment options for myeloma patients, including targeted immunotherapies, multiple remains a mostly incurable malignancy. High CS1 (SLAMF7) expression on cells and limited normal makes it promising target CAR-T therapy. The protein has two extracellular domains - the distal Variable (V) domain proximal Constant 2 (C2) domain. We generated tested CS1-CAR-T targeting V of (Luc90-CS1-CAR-T) demonstrated anti-myeloma killing vitro vivo using mouse models. Since...
Abstract Multiple myeloma (MM) is a highly refractory hematologic cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single-cell transcriptomic profiling, yielding 38 marker genes encoding cell-surface proteins and 15 intracellular proteins. Of...
Abstract Multiple myeloma (MM) is a disease of copy number variants (CNVs), chromosomal translocations, and single-nucleotide (SNVs). To enable integrative studies across these diverse mutation types, we developed capture-based sequencing platform to detect their occurrence in 465 genes altered MM used it sequence 95 primary tumor-normal pairs mean depth 104×. We detected cases hyperdiploidy (23%), deletions 1p (8%), 6q (21%), 8p (17%), 14q (16%), 16q (22%), 17p (4%), amplification 1q (19%)....
Abstract Multiple myeloma (MM), a malignancy of mature plasma cells, remains incurable. B-cell maturation antigen (BCMA) is the lead protein target for chimeric receptor (CAR) therapy because its high expression in most MM, with limited other cell types, resulting favorable on-target, off tumor toxicity. The response rate to autologous BCMA CAR-T high; however, it not curative and associated risks cytokine release syndrome (CRS) immune effector cell–associated neurotoxicity syndrome....
Monoclonal gammopathy of undetermined significance (MGUS) is the requisite precursor to multiple myeloma (MM), a malignancy antibody-producing plasma B-cells. The genetic basis MGUS and its progression MM remains poorly understood. C57BL/KaLwRij (KaLwRij) spontaneously-derived inbred mouse strain with high frequency benign idiopathic paraproteinemia (BIP), phenotype similarities including MM. Using haplotype analysis, human SNP array data, whole exome genome sequencing KaLwRij mice, we...
The gene encoding the receptor for macrophage colony-stimulating factor (CSF-1R) is expressed exclusively in cells of myeloid lineages as well trophoblasts. A conserved element second intron, Fms-Intronic Regulatory Element (FIRE), essential macrophage-specific transcription gene. However, molecular details how FIRE activity regulated and it impacts Csf1r promoter have not been characterised. Here we show that agents down-modulate mRNA altered occupancy key cis-acting elements including...
Multiple myeloma (MM) is a cancer of bone marrow (BM) plasma cells, which increasingly treatable but still incurable. In 90% MM patients, severe osteolysis results from pathological interactions between cells and the microenvironment. Delineating specific molecules pathways for their role in supportive BM vital developing new therapies. Very Late Antigen 4 (VLA4, integrin α4β1) key player cell-cell adhesion signaling cells. We evaluated VLA4 selective near infrared fluorescent probe,...
Abstract Dis3 encodes a conserved RNase that degrades or processes all RNA species via an N-terminal PilT N terminus (PIN) domain and C-terminal RNB harbor, respectively, endonuclease activity 3′–5′ exonuclease activity. In Schizosaccharomyces pombe, dis3 mutations cause chromosome missegregation failure in mitosis, suggesting promotes cell division. humans, apparently hypomorphic are found recurrently multiple myeloma, opposes Except for the observation RNAi-mediated depletion of function...