A5003840129- Monoclonal and Polyclonal Antibodies Research
- HER2/EGFR in Cancer Research
- NF-κB Signaling Pathways
- Immune Response and Inflammation
- Lung Cancer Treatments and Mutations
- Synthesis and biological activity
- Cytokine Signaling Pathways and Interactions
- Bioactive Compounds and Antitumor Agents
- Colorectal Cancer Treatments and Studies
- Radiopharmaceutical Chemistry and Applications
- Pharmacological Effects of Natural Compounds
- Cancer Genomics and Diagnostics
- Computational Drug Discovery Methods
- Statistical Methods in Clinical Trials
- Ubiquitin and proteasome pathways
- Cancer therapeutics and mechanisms
- Viral Infectious Diseases and Gene Expression in Insects
- Protein Kinase Regulation and GTPase Signaling
- Immunotherapy and Immune Responses
- Complement system in diseases
- Glycosylation and Glycoproteins Research
- Cancer-related Molecular Pathways
- CAR-T cell therapy research
- Peptidase Inhibition and Analysis
- Medical Imaging Techniques and Applications
Novartis (United States)
2022-2024
Forma Therapeutics (United States)
2020-2021
Columbus Oncology and Hematology Associates
2020
University of Florida
2020
Merrimack Pharmaceuticals (United States)
2011-2019
University of California, San Diego
2006-2015
Center for Systems Biology
2012
Toxicologie, Pharmacologie et Signalisation Cellulaire
2009
Worcester Polytechnic Institute
1981
Covalent inhibitors of KRASG12C have shown antitumor activity against advanced/metastatic KRASG12C-mutated cancers, though resistance emerges and additional strategies are needed to improve outcomes. JDQ443 is a structurally unique covalent inhibitor GDP-bound that forms novel interactions with the switch II pocket. potently inhibits KRASG12C-driven cellular signaling demonstrates selective antiproliferative in cell lines, including those G12C/H95 double mutations. In vivo, induces AUC...
NF-κB signaling is known to be critically regulated by the NF-κB–inducible inhibitor protein IκBα. The resulting negative feedback has been shown produce a propensity for oscillations in activity. We report integrated experimental and computational studies that demonstrate another IκB isoform, IκBε, also provides on activity, but with distinct functional consequences. Upon stimulation, NF-κB–induced transcription of IκBε delayed, relative IκBα, rendering two loops antiphase. As result, role...
TNF-induced NF-kappaB activity shows complex temporal regulation whose different phases lead to distinct gene expression programs. Combining experimental studies and mathematical modeling, we identify two amplification steps-one determined by the obligate negative feedback regulator IkappaBalpha-that define duration of first phase activity. The second is defined A20, inducible provides for a rheostat function which other inflammatory stimuli can regulate TNF responses. Our results delineate...
An oligoclonal antibody overcomes drug resistance in colorectal cancers with EGFR mutations.
Mammalian signaling networks contain an abundance of negative feedback regulators that may have overlapping ("fail-safe") or specific functions. Within the NF-kappaB module, IkappaB alpha is known as a regulator, but newly characterized inhibitor delta also inducibly expressed in response to inflammatory stimuli. To examine delta's roles signaling, we mathematically modeled 4-IkappaB-containing module and developed computational phenotyping methodology general applicability. We found delta,...
In October 2019, Novartis launched brolucizumab, a single-chain variable fragment molecule targeting vascular endothelial growth factor A, for the treatment of neovascular age-related macular degeneration. 2020, rare cases retinal vasculitis and/or occlusion (RV/RO) were reported, often during first few months after initiation, consistent with possible immunologic pathobiology. This finding was inconsistent preclinical studies in cynomolgus monkeys that demonstrated no drug-related...
Immunogenicity against intravitreally administered brolucizumab has been previously described and associated with cases of severe intraocular inflammation, including retinal vasculitis/retinal vascular occlusion (RV/RO). The presence antidrug antibodies (ADAs) in these patients led to the initial hypothesis that immune complexes could be key mediators. Although formation ADAs may a prerequisite, other factors likely contribute some having RV/RO, whereas vast majority do not. To identify...
Abstract Although EGFR is a validated therapeutic target across multiple cancer indications, the often modest clinical responses to current anti-EGFR agents suggest need for improved therapeutics. Here, we demonstrate that signal amplification driven by high-affinity ligands limits capacity of monoclonal antibodies block pathway signaling and cell proliferation these are commonly coexpressed with low-affinity in epithelial tumors. To develop an antibody capable overcoming ligand-mediated...
Lung squamous cell carcinoma (LSCC) is a considerable global health burden, with an incidence of over 600,000 cases per year. Treatment options are limited, and patient's 5-year survival rate less than 5%. The ubiquitin-specific protease 28 (USP28) has been implicated in tumourigenesis through its stabilization the oncoproteins c-MYC, c-JUN, Δp63. Here, we show that genetic inactivation Usp28-induced regression established murine LSCC lung tumours. We developed small molecule inhibits USP28...
Objectives & MethodsThe discovery of trimeric N-galactosamine (GalNAc) conjugation revolutionized the delivery siRNAs to human liver because high specificity GalNAc for asialoglycoprotein receptor (ASGPR) abundantly expressed on hepatocytes [1]. At present, several GalNAc-conjugated oligonucleotides (siRNA or ASO) are approved in clinical development with a subcutaneous bolus (SC) dosing regimen, each mechanism action down-regulate target gene expression liver. Modeling platforms...
The NF-kappaB family member RelB has many properties not shared by other members such as restricted subunit association and lack of regulation the classical IkappaB proteins. We show that protein level is significantly reduced in absence p100 even more when both p105 are absent. stabilizes itself directly interacting with p100, p105, their processed products. However, forms complexes its partners using different interaction modes. Although C-terminal ankyrin repeat domain involved RelB-p105...
The NFκB family of dimeric transcription factors regulate inflammatory and immune responses. While the dynamic control dimer activity via IκB–NFκB signalling module is well understood, there little information on how specific repertoires are generated from Rel polypeptides. Here we report iterative construction—guided by in vitro vivo experimentation—of a mathematical model Rel-NFκB generation module. Our study reveals that IκBβ has essential functions within module, specifically for...
Many cellular stress-responsive signaling systems exhibit highly dynamic behavior with oscillatory features mediated by delayed negative feedback loops. What remains unclear is whether the basis for a code based on frequency modulation (FM) or control modules have evolved to fulfill other functional requirements. Here, we use experimentally calibrated computational models interrogate loops that regulate activity of transcription factor NF-κB. Linear stability analysis model shows hard-wired...
Activation of the Met receptor tyrosine kinase, either by its ligand, hepatocyte growth factor (HGF), or via ligand-independent mechanisms, such as MET amplification overexpression, has been implicated in driving tumor proliferation, metastasis, and resistance to therapy. Clinical development Met-targeted antibodies challenging, however, bivalent exhibit agonistic properties, whereas monovalent lack potency capacity down-regulate Met. Through computational modeling, we found that a antibody...
Quantitative Systems Pharmacology (QSP) modeling is increasingly applied in the pharmaceutical industry to influence decision making across a wide range of stages from early discovery clinical development post-marketing activities. Development standards for how these models are constructed, assessed, and communicated active interest community regulators but complicated by variability structures intended uses underlying diverse expertise QSP modelers. With this mind, IQ Consortium conducted...