A5066865482- Multiple Myeloma Research and Treatments
- Protein Degradation and Inhibitors
- Peptidase Inhibition and Analysis
- Chemokine receptors and signaling
- Cancer, Lipids, and Metabolism
- Computational Drug Discovery Methods
- Cancer Mechanisms and Therapy
- Cell death mechanisms and regulation
- Ubiquitin and proteasome pathways
- Cancer therapeutics and mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Chronic Lymphocytic Leukemia Research
- Retinoids in leukemia and cellular processes
- interferon and immune responses
- Myeloproliferative Neoplasms: Diagnosis and Treatment
- Cancer Treatment and Pharmacology
- Arsenic contamination and mitigation
- Cytokine Signaling Pathways and Interactions
- Synthesis and bioactivity of alkaloids
- RNA Interference and Gene Delivery
- DNA Repair Mechanisms
- Synthesis and Characterization of Heterocyclic Compounds
- Cell Adhesion Molecules Research
- HER2/EGFR in Cancer Research
- Malaria Research and Control
Emory University
2015-2024
Cancer Institute (WIA)
2020-2023
Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori
2023
Istituti di Ricovero e Cura a Carattere Scientifico
2023
Winship Cancer Institute
2011-2020
AID Atlanta
2020
Emory Healthcare
2011
University of Miami
2008-2009
Roswell Park Comprehensive Cancer Center
2009
Sylvester Comprehensive Cancer Center
2009
Abstract Mcl-1 is a member of the Bcl-2 family proteins that promotes cell survival by preventing induction apoptosis in many cancers. High expression causes tumorigenesis and resistance to anticancer therapies highlighting potential inhibitors as drugs. Here, we describe AZD5991, rationally designed macrocyclic molecule with high selectivity affinity for currently clinical development. Our studies demonstrate AZD5991 binds directly induces rapid cancer cells, most notably myeloma acute...
Abstract The BCL-2 antagonist venetoclax is highly effective in multiple myeloma (MM) patients exhibiting the 11;14 translocation, mechanistic basis of which unknown. In evaluating cellular energetics and metabolism t(11;14) non-t(11;14) MM, we determine that venetoclax-sensitive has reduced mitochondrial respiration. Consistent with this, low electron transport chain (ETC) Complex I II activities correlate sensitivity. Inhibition I, using IACS-010759, an orally bioavailable inhibitor...
Abstract Here, we report on the organic arsenical darinaparsin (ZIO-101, S-dimethylarsino-glutathione) and its anti-myeloma activity compared with inorganic arsenic trioxide. Darinaparsin induced apoptosis in multiple myeloma cell lines a dose-dependent manner, addition of N-acetylcysteine, which increases intracellular glutathione (GSH), blocked cytotoxicity both In contrast to trioxide, GSH does not appear be important for metabolism, as an inhibitor synthesis, buthionine sulfoximine, had...
Carfilzomib (Kyprolis®), a second generation proteasome inhibitor, is FDA approved for single-agent use among relapsed/refractory multiple myeloma (MM). To enhance the therapeutic efficacy of carfilzomib, we sought to combine carfilzomib with other novel agents. TG02, multi-kinase targets JAK2 and CDK9. The rationale co-treatment TG02 that both independently target Mcl-1 most cells are dependent on this anti-apoptotic protein survival. We observed at least additive effects using combination...
The connections between metabolic state and therapy resistance in multiple myeloma (MM) are poorly understood. We previously reported that electron transport chain (ETC) suppression promotes sensitivity to the BCL-2 antagonist venetoclax. Here, we show ETC proteasome inhibitors (PIs). Interrogation of ETC-suppressed MM reveals integrated stress response-dependent protein translation ubiquitination, leading PI resistance. gene expression signatures from CoMMpass trial down-regulated patients...
Here, we report the identification of dimethylarsinothioyl glutathione (DMMTA(V)(GS)) as a metabolite in cellular extracts dimethyarsinous (Darinaparsin, DMA(III)(GS)) treated human multiple myeloma (MM) cell lines. Co-elution sulfur and arsenic on inductively coupled plasma mass spectrometer (ICP-MS) indicated presence along with newly observed unidentified molecule speciation chromatograms lines DMA(III)(GS). Liquid chromatography-electrospray ionization-mass spectrometry unknown peak MS...
Multiple myeloma (MM) is a heterogeneous plasma cell malignancy and remains incurable. B-cell lymphoma-2 (BCL2) protein correlates with the survival drug resistance of cells. BH3 mimetics have been developed to disrupt binding between BCL2 its pro-apoptotic family partners for treatment MM, but limited therapeutic efficacy. We recently identified small molecule BDA-366 as BH4 domain antagonist, converting it from an anti-apoptotic into molecule. In this study, we demonstrated that induces...
Multiple myeloma is a malignancy of plasma cells. Extensive genetic and transcriptional characterization has identified subtypes with prognostic therapeutic implications. In contrast, relatively little known about the epigenome.CD138+CD38+ cells were isolated from fresh bone marrow aspirate or same after freezing for 1-6 months. Gene expression chromatin accessibility compared between frozen samples by RNA sequencing (RNA-seq) assay transpose accessible (ATAC-seq). Chromatin regions used to...
Abstract Background The CCL2 chemokine is involved in promoting cancer angiogenesis, proliferation and metastasis by malignancies that express CCR2 receptor. Thus the CCL2/CCR2 axis an attractive molecular target for anticancer drug development. Methods We have generated a novel fusion protein using GMCSF N-terminal truncated version of MCP1/CCL2 (6-76) [hereafter GMME1] investigated its utility as CCR2-specific tumoricidal agent. Results found distinct to full length or N-truncated...
Abstract Spermatocytes normally sustain many meiotically induced double‐strand DNA breaks (DSBs) early in meiotic prophase; autosomal chromatin, these are repaired by initiation of homologous‐recombination processes. Little is known about how spermatocytes respond to environmentally damage after recombination‐related DSBs have been repaired. The experiments described here tested the hypothesis that, even though actively completing recombination, pachytene cultured absence testicular somatic...
Arsenic trioxide (ATO) has been tested in relapsed/refractory multiple myeloma with limited success. In order to better understand drug mechanism and resistance pathways we generated an ATO-resistant cell line, 8226/S-ATOR05, IC50 that is 2–3-fold higher than control lines significantly clinically achievable concentrations. Interestingly found two parallel governing ATO the relevance of these appears be linked concentration used. We changes expression Bcl-2 family proteins Bfl-1 Noxa as well...
Abstract The BCL2 inhibitor venetoclax promotes apoptosis in blood cancer cells and is approved for treatment of chronic lymphocytic leukemia acute myeloid leukemia. However, multiple myeloma are frequently more dependent on MCL-1 survival, conferring resistance to venetoclax. Here we report that mevalonate pathway inhibition with statins can overcome cell lines primary cells. In addition, sensitize induced by inhibitor, S63845. retrospective analysis clinical studies myeloma, background...