A5083899578- Lung Cancer Treatments and Mutations
- Computational Drug Discovery Methods
- Cancer Research and Treatments
- S100 Proteins and Annexins
- Metabolomics and Mass Spectrometry Studies
- Adenosine and Purinergic Signaling
- Pharmacogenetics and Drug Metabolism
- Advanced Proteomics Techniques and Applications
- Neutrophil, Myeloperoxidase and Oxidative Mechanisms
- Peptidase Inhibition and Analysis
- Hepatocellular Carcinoma Treatment and Prognosis
- thermodynamics and calorimetric analyses
- Cancer, Hypoxia, and Metabolism
- Cancer therapeutics and mechanisms
- Liver physiology and pathology
- Advanced Biosensing Techniques and Applications
- RNA Interference and Gene Delivery
- Advanced biosensing and bioanalysis techniques
- HER2/EGFR in Cancer Research
- Cell Adhesion Molecules Research
- Protein Degradation and Inhibitors
- Monoclonal and Polyclonal Antibodies Research
- Antibiotics Pharmacokinetics and Efficacy
- Cell death mechanisms and regulation
- Animal testing and alternatives
Leidos (United States)
2014-2025
Frederick National Laboratory for Cancer Research
2015-2025
Leidos Biomedical Research Inc. (United States)
2014-2022
University of Minnesota
2017
Abstract To date, over 100 small-molecule oncology drugs have been approved by the FDA. Because of inherent heterogeneity tumors, these small molecules are often administered in combination to prevent emergence resistant cell subpopulations. Therefore, new strategies overcome drug resistance patients with advanced cancer needed. In this study, we performed a systematic evaluation therapeutic activity 5,000 pairs FDA-approved against panel 60 well-characterized human tumor lines (NCI-60)...
The main clinical problems for dental implants are (1) formation of biofilm around the implant-a condition known as peri-implantitis and (2) inadequate bone implant-lack osseointegration. Therefore, developing an implant to overcome these is significant interest community. Chitosan has been reported have good biocompatibility anti-bacterial activity. An osseo-inductive recombinant elastin-like biopolymer (P-HAP), that contains a peptide derived from protein statherin, induce...
To support clinical pharmacodynamic evaluation of the Smac mimetic TL32711 (birinapant) and other apoptosis-targeting drugs, we describe development, validation, application novel immunoassays for 15 cytosolic membrane-associated proteins indicative induction, onset, commitment to apoptosis in human tumors.
The development of molecularly targeted agents has benefited from use pharmacodynamic markers to identify "biologically effective doses" (BED) below MTDs, yet this knowledge remains underutilized in selecting dosage regimens and comparing the effectiveness within a class. We sought establish preclinical proof-of-concept for such pharmacodynamics-based BED comparisons using MET kinase small-molecule inhibitors. Utilizing biomarker measurements signaling (tumor pY
Abstract Pet dogs with naturally occurring cancers play an important role in studies of cancer biology and drug development. We assessed tolerability, efficacy, pharmacokinetic/pharmacodynamic relationships a first-in-class small molecule inhibitor valosin-containing protein (VCP/p97), CB-5339, administered to 24 tumor-bearing pet dogs. Tumor types included solid malignancies, lymphomas, multiple myeloma. Through stepwise dose schedule escalation schema, we determined the maximum tolerated...
2553 Background: Activation of MET signaling has been proposed as an adaptive response to pharmacological inhibition VEGFR. We compared and phospho-MET levels in paired biopsies collected before after pazopanib treatment patients (pts) with advanced solid tumors enrolled this single-agent arm the Phase I trial a pazopanib/tivantinib combination (NCT01468922). Methods: Eligible pts had histologically confirmed refractory cancers; ≥18 years old; adequate bone marrow, hepatic, renal function....
Abstract Background/Rationale: The combination of the proteosome inhibitor bortezomib (B) and purine analog clofarabine (C) induced synergy in NCI-ALMANAC screen FDA-approved cancer drug combinations; preclinical xenograft studies confirmed this activity suggested a mechanism action involving greater-than-additive effects on markers DNA damage response (DDR) pyroptotic cell death. We conducted phase 1 clinical trial (NCT02211755) to assess safety B C patients (pts) with solid tumors...
e15093 Background: NSC835563 (SM08502, cirtuvivint) is a first-in-class pan CDC-like kinase (CLK) and dual specificity tyrosine (DYRK) inhibitor that targets alternative splicing of genes in multiple pathways modifies their protein expression. Preclinical screening hematologic malignancy models has shown sensitivity to cirtuvivint, leading proposed clinical trials AML combinations with venetoclax. We performed pharmacodynamic studies identify probable mechanisms combination activity models....
2582 Background: Clinical development of promising small molecule Mcl-1 inhibitors is underway. The act by disrupting complexes with pro-apoptotic proteins such as BAK/BIM/Noxa, leading to formation oligomers BAK and BAX at the mitochondrial membrane activation an apoptosis cascade. Therefore, measurement BAX-BAK heterodimers on considered on-target pharmacodynamic (PD) biomarker for this class drugs. We describe use assay screen prioritize (Taekyu et al, FEBS Let 2017) activity in vivo...
e14539 Background: The AAA (ATPases Associated with diverse cellular Activities) enzyme p97 is an emerging target involved in protein homeostasis. A first-in-class ATP-competitive inhibitor CB-5083 has recently entered phase 1 clinical trials, and non-ATP-competitive inhibitors are being explored. We developed validated quantitative pharmacodynamic (PD) biomarkers to guide preclinical early development of inhibitors. Methods: To measure response inhibitors, we focused on three major steps...
Abstract Background: A direct comparison of drug efficacy for the multiple agents currently in clinical development targeting MET-driven cancers would be useful selection optimal treatment options. Previously, we utilized validated MET pharmacodynamic (PD) assays to compare time course phosphorylated-MET (pMET) suppression five inhibitors (ASCO 2013). In current study, selected three candidates that demonstrated potent inhibition anti-tumor efficacy. Methods: PD and tumor PK data were...
3131 Background: Currently, patient selection criteria for clinical testing of MET inhibitors are limited. Robust studies selecting patients based on protein expression, gene amplification, or mutations have not met their efficacy goals. Development microscopy-based assays to quantify levels phospho-MET (pMET) in tumors has been hampered by poor antibody specificity. Here, we present the development and validation a robust, highly specific multiplex immunofluorescence assay (IFA) that...
<div>Abstract<p>To date, over 100 small-molecule oncology drugs have been approved by the FDA. Because of inherent heterogeneity tumors, these small molecules are often administered in combination to prevent emergence resistant cell subpopulations. Therefore, new strategies overcome drug resistance patients with advanced cancer needed. In this study, we performed a systematic evaluation therapeutic activity 5,000 pairs FDA-approved against panel 60 well-characterized human tumor...
<p>This file contains: Supplementary Methods for pharmacodynamic biomarker analyses, clinicaltrials.gov searches, and molecular correlation analyses; Figures S1 (overview of the NCI-ALMANAC web resource), S2 (apoptotic response to bortezomib-clofarabine), S3 (associations between ABC transporter activity nilotinib-paclitaxel combination activity); Tables (FDA-approved agents used in screen), (tumor doubling time analysis xenograft experiments with clinically tested NCI-ALMANAC-derived...
<p>This file contains supplemental Figure S1: Specificity of antibodies used in multiplex assays</p>
<p>This file contains supplemental Table S1A: Analytical validation- sample dilution linearity, and S1B: accuracy determined by spike recoveries</p>
<p>This file contains supplemental Figure S3: Storage stability of analytes</p>
<p>This file contains supplemental Figure S4: Correlation among multiplexed biomarkers</p>
<p>This file contains supplemental materials and methods describing protein calibrator preparation pre-analytical variability</p>
<p>This file contains supplemental Figure S2: Temperature stability of analytes</p>
<p>This file contains supplemental Table S3: Fitness-for-purpose clinical utility-Intratumoral biological variability</p>
<p>This file contains supplemental Table S2A: Analytical validation- interlaboratory precision, and S2B: Fitness-for-purpose clinical utility- intertumoral biological variability</p>
<div>Abstract<p><b>Purpose:</b> To support clinical pharmacodynamic evaluation of the Smac mimetic TL32711 (birinapant) and other apoptosis-targeting drugs, we describe development, validation, application novel immunoassays for 15 cytosolic membrane-associated proteins indicative induction, onset, commitment to apoptosis in human tumors.</p><p><b>Experimental Design:</b> The multiplex were constructed on Luminex platform with biomarkers...
<div>Abstract<p><b>Purpose:</b> To support clinical pharmacodynamic evaluation of the Smac mimetic TL32711 (birinapant) and other apoptosis-targeting drugs, we describe development, validation, application novel immunoassays for 15 cytosolic membrane-associated proteins indicative induction, onset, commitment to apoptosis in human tumors.</p><p><b>Experimental Design:</b> The multiplex were constructed on Luminex platform with biomarkers...