Brian Belmontes
A5021750238- Cancer-related gene regulation
- Growth Hormone and Insulin-like Growth Factors
- Ovarian cancer diagnosis and treatment
- Cancer, Hypoxia, and Metabolism
- Cell death mechanisms and regulation
- Immune cells in cancer
- Metabolism, Diabetes, and Cancer
- Melanoma and MAPK Pathways
- CAR-T cell therapy research
- PI3K/AKT/mTOR signaling in cancer
- Fungal Biology and Applications
- Ubiquitin and proteasome pathways
- Synthesis and Catalytic Reactions
- Virus-based gene therapy research
- Immune Cell Function and Interaction
- Neuroblastoma Research and Treatments
- Epigenetics and DNA Methylation
- Acute Myeloid Leukemia Research
- Protein Degradation and Inhibitors
- Cancer-related Molecular Pathways
- Protein Kinase Regulation and GTPase Signaling
- Computational Drug Discovery Methods
- Microtubule and mitosis dynamics
- Immunotherapy and Immune Responses
- Cancer Immunotherapy and Biomarkers
Amgen (United States)
2016-2025
Sidney Kimmel Cancer Center
2014
Johns Hopkins University
2014
University of California, Los Angeles
2014
Howard Hughes Medical Institute
2014
Thomas Jefferson University
2009
Abstract The prosurvival BCL2 family member MCL1 is frequently dysregulated in cancer. To overcome the significant challenges associated with inhibition of protein–protein interactions, we rigorously applied small-molecule conformational restriction, which culminated discovery AMG 176, first selective inhibitor to be studied humans. We demonstrate that induces a rapid and committed step toward apoptosis subsets hematologic cancer cell lines, tumor xenograft models, primary patient samples....
Inhibition of the methyltransferase enzyme PRMT5 by MTA accumulation is a vulnerability MTAP-deleted cancers. Herein, we report discovery and optimization quinolin-2-amine DEL hit that cooperatively binds PRMT5:MEP50 to generate catalytically inhibited ternary complex. X-ray crystallography confirms binding glutamate-444, while simultaneously exhibiting hydrophobic interaction with MTA. Lead produced AM-9747, which selectively inhibits PRMT5-directed symmetric dimethylation arginine residues...
4617 Background: Binding of IGF-1 or IGF-2 to the type I insulin-like growth factor receptor (IGF-1R) activates intracellular signals important in and survival pancreatic tumors. AMG 479 is a fully human monoclonal antibody against IGF-1R currently phase II clinical trials. exerts its anti-tumor activity by blocking ligand binding inducing downregulation vivo. Methods: Insulin Receptor (IR) levels were determined using FACS analysis Meso Scale Detection (MSD). Level AKT phosphorylation...
Pancreatic carcinoma is a leading cause of cancer deaths, and recent clinical trials number oncology therapeutics have not substantially improved outcomes. We evaluated the therapeutic potential AMG 479, fully human monoclonal antibody against insulin-like growth factor (IGF) type I receptor (IGF-IR), in two IGF-IR-expressing pancreatic cell lines, BxPC-3 MiaPaCa2, which also differentially express insulin (INSR). 479 bound to IGF-IR (K(D) 0.33 nmol/L) blocked IGF-I IGF-II binding (IC(50) <...
Purpose: Talimogene laherparepvec, a new oncolytic immunotherapy, has been recently approved for the treatment of melanoma. Using murine version virus, we characterized local and systemic antitumor immune responses driving efficacy in syngeneic models.Experimental Design: The activity talimogene laherparepvec was against melanoma cell lines using an vitro viability assay. Efficacy OncoVEXmGM-CSF (talimogene with mouse granulocyte-macrophage colony-stimulating factor transgene) alone or...
Therapeutic approaches are needed to promote T cell-mediated destruction of poorly immunogenic, "cold" tumors typically associated with minimal response immune checkpoint blockade (ICB) therapy. Bispecific cell engager (BiTE) molecules induce redirected lysis cancer cells by polyclonal and have demonstrated promising clinical activity against solid in some patients. However, little is understood about the key factors that govern responses these therapies. Using an immunocompetent mouse model...
Abstract Chromosomal instability (CIN) is a hallmark of cancer, caused by persistent errors in chromosome segregation during mitosis. Aggressive cancers like high-grade serous ovarian cancer (HGSOC) and triple-negative breast (TNBC) have high frequency CIN TP53 mutations. Here, we show that inhibitors the KIF18A motor protein activate mitotic checkpoint selectively kill chromosomally unstable cells. Sensitivity to inhibition enriched -mutant HGSOC TNBC cell lines with features, including...
One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been dependency on PRMT5 cancer cells with MTAP deletion. We report discovery clinical stage MTA-cooperative inhibitor AMG 193, which preferentially binds presence MTA and potent biochemical cellular activity MTAP-deleted across lineages. In vitro, inhibition induces DNA damage, cell cycle arrest, aberrant alternative mRNA splicing cells. human line patient-derived xenograft models, 193...
Raf inhibitors are under clinical investigation, specifically in patients with tumor types harboring frequent activating mutations B-Raf. Here, we show that cell lines and tumors mutant B-Raf were sensitive to a novel series of (e.g., (V600E)B-Raf A375, IC(50) on cells = 2 nmol/L; ED(50) xenografts 1.3 mg/kg). However, wild-type B-Raf, exposure resulted dose-dependent sustained activation mitogen-activated protein kinase signaling. In some these lines, inhibition led entry into the cycle,...
Abstract Tumor-associated macrophages (TAMs) are abundant in solid tumors where they exhibit immunosuppressive and pro-tumorigenic functions. Inhibition of TAM proliferation survival through CSF1R blockade has been widely explored as a cancer immunotherapy. To further define mechanisms regulating CSF1R-targeted therapies, we systematically evaluated the effect anti-CSF1R treatment on tumor growth microenvironment (TME) inflammation across multiple murine models. Despite substantial...
Abstract Purpose: Insulin-like growth factor 1 receptor (IGF-IR) has been implicated in the pathogenesis of ovarian cancer. Ganitumab is an investigational, fully human monoclonal antibody against IGF-IR. Here, we explore therapeutic potential ganitumab for treatment Experimental Design: The effects were tested vitro a panel 23 established cancer cell lines. ability to inhibit IGF-I–, IGF-II–, and insulin-mediated signaling was examined tumor xenografts using models displaying...
Abstract MCL1 inhibitors are an emerging class of therapeutics targeting key protein-protein interactions between and BH3 domain containing pro-apoptotic BCL-2 family members. Several have entered clinical trials including AMG 176, currently in Phase I development for hematologic malignancies. However, all existing stage being administered intravenously. Here we describe the discovery preclinical evaluation 397, first orally inhibitor development. The pursuit bioavailable with acceptable...
Chromosomal instability (CIN) is a hallmark of cancer that results from errors in chromosome segregation during mitosis. Targeting CIN-associated vulnerabilities an emerging therapeutic strategy drug development. KIF18A, mitotic kinesin, has been shown to play role maintaining bipolar spindle integrity and promotes viability CIN cells. To explore the potential series inhibitors was identified. Optimization initial hit led discovery analogues could be used as chemical probes interrogate...
<p>Supplementary Methods: SDMA Imaging Assay, ELISA, Immunohistochemistry</p>
<p>Supplementary Figure S6. AM-9747 treatment results in increased DNA damage and cellular senescence BxPC-3 cells</p>
<p>Supplementary Figure S8. AMG 193 treatment in BxPC-3 tumors does not affect circulating blood cells</p>
<p>Supplementary Figure S5. <i>In vitro</i> target validation, RNA-seq, and additional cell cycle data in WT MTAP-deleted tumor cells</p>
<p>Supplementary Figure S2. SPR AMG 193 competitive chaser experiment</p>
<p>Supplementary Figure S3. HCT116 isogenic pair validation</p>
<p>Supplementary Figure S1. SPR chaser characterization</p>
<p>Supplementary Figure S7. Time course SDMA analysis, CDX models versus AMG 193, and AM-9747 PDX trial</p>
<p>Supplementary Figure S10. AMG 193 and sotorasib combination is synergistic in the MIAPACA2 MTAP–deleted, KRAS G12C mutant cell line</p>