A5061830496- Cancer Genomics and Diagnostics
- Cancer Cells and Metastasis
- Cancer Research and Treatments
- Cancer, Hypoxia, and Metabolism
- Molecular Biology Techniques and Applications
- Monoclonal and Polyclonal Antibodies Research
- Liver physiology and pathology
- Virus-based gene therapy research
- Cell Image Analysis Techniques
- Cancer therapeutics and mechanisms
- Animal Genetics and Reproduction
- Gene expression and cancer classification
- Advanced Biosensing Techniques and Applications
- 3D Printing in Biomedical Research
- Sarcoma Diagnosis and Treatment
- Hepatocellular Carcinoma Treatment and Prognosis
- CRISPR and Genetic Engineering
- Angiogenesis and VEGF in Cancer
- Renal and related cancers
- Viral-associated cancers and disorders
- Radiomics and Machine Learning in Medical Imaging
- Cancer Mechanisms and Therapy
- HIV/AIDS drug development and treatment
- Renal cell carcinoma treatment
- RNA modifications and cancer
Frederick National Laboratory for Cancer Research
2012-2023
National Cancer Institute
1999-2023
Leidos (United States)
2014-2023
Leidos Biomedical Research Inc. (United States)
2017-2021
Science Applications International Corporation (United States)
1999-2013
Frederick Community College
2010
Center for Cancer Research
2007-2009
Abstract We have previously shown that topotecan, a topoisomerase I poison, inhibits hypoxia-inducible factor (HIF)-1α protein accumulation by DNA damage-independent mechanism. Here, we report daily administration of topotecan HIF-1α expression in U251-HRE glioblastoma xenografts. Concomitant with inhibition, caused significant tumor growth inhibition associated marked decrease angiogenesis and HIF-1 target genes tissue. These results provide compelling rationale for testing clinical trials...
Abstract Inhibition of hypoxia inducible factor-1 (HIF-1) is an attractive therapeutic strategy to target the tumor microenvironment. However, HIF-1 inhibitors may have limited activity as single agents and combination therapies be required. We tested hypothesis that inhibition in a hypoxic-stressed microenvironment, which could generated by administration antiangiogenic agents, result more pronounced effect. The bevacizumab, either alone or with HIF-1α inhibitor topotecan, was evaluated...
Abstract The “Warburg effect,” also termed aerobic glycolysis, describes the increased reliance of cancer cells on glycolysis for ATP production, even in presence oxygen. Consequently, there is continued interest inhibitors as therapeutics. One example dichloroacetate (DCA), a pyruvate mimetic that stimulates oxidative phosphorylation through inhibition dehydrogenase kinase. In this study, mechanistic basis DCA anti‐cancer activity was re‐evaluated vitro using biochemical, cellular and...
The significance of the phenotypic plasticity afforded by epithelial-mesenchymal transition (EMT) for cancer progression and drug resistance remains to be fully elucidated in clinic. We evaluated characteristics across a range tumor histologies using validated, high-resolution digital microscopic immunofluorescence assay (IFA) that incorporates β-catenin detection cellular morphology delineate carcinoma cells from stromal fibroblasts quantitates individual colocalized expression epithelial...
Xenograft samples used to test anti-cancer drug efficacies and toxicities in vivo contain an unknown mix of mouse human cells. Evaluation activity can be confounded by containing large amounts contaminating tissue. We have developed a real-time quantitative polymerase chain reaction (qPCR) assay using TaqMan technology quantify the amount tissue that is incorporated into xenograft samples. The forward reverse primers bind same DNA sequence genome. Using set specially designed fluorescent...
The use of genetically engineered mouse (GEM) models for preclinical testing anticancer therapies is hampered by variable tumor latency, incomplete penetrance, and complicated breeding schemes. Here, we describe validate a transplantation strategy that circumvents some these difficulties.Tumor fragments from tumor-bearing MMTV-PyMT or cell suspensions MMTV-PyMT, -Her2/neu, -wnt1, -wnt1/p53(+/-), BRCA1/p53(+/-), C3(1)T-Ag mice were transplanted into the mammary fat pad s.c. naïve syngeneic...
Development of cancer therapeutics partially depends upon selection appropriate animal models. Therefore, improvements to model are beneficial. Forty-nine human tumor xenografts at in vivo passages 1, 4 and 10 were subjected cDNA microarray analysis yielding a dataset 823 Affymetrix HG-U133 Plus 2.0 arrays. To illustrate mining strategies supporting therapeutic studies, transcript expression was determined: 1) relative other models, 2) with successive passage, 3) during the vitro transition....
Rational development of targeted MET inhibitors for cancer treatment requires a quantitative understanding target pharmacodynamics, including molecular engagement, mechanism action, and duration effect.
In vivo growth of alveolar soft part sarcoma (ASPS) was achieved using subcutaneous xenografts in sex-matched nonobese diabetic severe combined immunodeficiency mice. One tumor, currently at passage 6, has been maintained for 32 months and characteristics consistent with those the original ASPS tumor including (1) histology staining periodic acid Schiff/diastase, (2) presence ASPL-TFE3 type 1 fusion transcript, (3) nuclear antibodies to protein, (4) maintenance t(X;17)(p11;q25) translocation...
In vitro growth of alveolar soft part sarcoma (ASPS) and establishment an ASPS cell line, ASPS-1, are described in this study. Using a recently developed xenograft model derived from lymph node metastasis, organoid nests consisting 15 to 25 cells were isolated tumors by capture on 70 μm filters plated vitro. After attachment the substratum, these deposited small aggregates cells. These grew slowly expanded over period 3 years have maintained characteristics consistent with those both...
Background Topoisomerase I (Top1) is a proven target for cancer therapeutics. Recent data from the Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing (FOCUS) trial demonstrated that nuclear staining of Top1 correlates with chemotherapeutic efficacy. Such correlation may help identify patients likely to respond inhibitors illuminate their mechanism action. Cellular response complex, but engagement necessary first step in this process. This paper reports development validation quantitative...
A series of compounds related to oxathiin carboxanilide has been identified as nonnucleoside reverse transcriptase inhibitors (NNRTIs) HIV-1, and structure-activity relationships have described (Buckheit RW, et al.: Antimicrob Agents Chemother 1995;39:2718-2727). Three new analogs (UC040, UC82, UC781) inhibited laboratory clinical isolates including representative the various clades HIV-1 found worldwide, in both established fresh human cells. Virus with amino acid changes L100I, K103N,...
Abstract Oxyphenisatin (3,3‐bis(4‐hydroxyphenyl)‐1H‐indol‐2‐one) and several structurally related molecules have been shown to in vitro vivo antiproliferative activity. This study aims confirm extend mechanistic studies by focusing on oxyphenisatin acetate ( OXY , NSC 59687), the pro‐drug of oxyphenisatin. Results that inhibits growth breast cancer cell lines MCF 7, T47D, HS 578T, MDA ‐ MB ‐468. effect is associated with selective inhibition translation accompanied rapid phosphorylation...
The presence of cancer stem cells (CSCs) and the induction epithelial-to-mesenchymal transition (EMT) in tumors are associated with tumor aggressiveness, metastasis, drug resistance, poor prognosis, necessitating development reagents for unambiguous detection CSC- EMT-associated proteins specimens. To this end, we generated novel antibodies to EMT- CSC-associated proteins, including Goosecoid, Sox9, Slug, Snail, CD133. Importantly, unlike several widely used CD133, anti-CD133 recognize...
Abstract In this article, 5-aza-4′-thio-2′-β-fluoro-2′-deoxycytidine (F-aza-T-dCyd, NSC801845), a novel cytidine analog, is first disclosed and compared with T-dCyd, F-T-dCyd, aza-T-dCyd in cell culture mouse xenograft studies HCT-116 human colon carcinoma, OVCAR3 ovarian NCI-H23 NSCLC HL-60 leukemia, the PDX BL0382 bladder carcinoma. three of five lines (HCT-116, HL-60, BL-0382), F-aza-T-dCyd was more efficacious than aza-T-dCyd. Comparable activity observed for these two agents against...
3042 Background: Deregulation of c-MET (MET), a receptor tyrosine kinase (RTK), signaling has been implicated in the initiation, progression, and metastasis human cancers, therefore represents an attractive target for anticancer therapy. Monitoring phosphorylation status relevant residues provides important method assessing MET modulation. To support clinical development Met inhibitors, we describe pharmacodynamic assays to assess vivo inhibition, which will be suitable use evaluating biopsy...
Abstract The National Cancer Institute (NCI) has developed a Patient-Derived Models Repository (PDMR) comprised of quality-controlled, early-passage, clinically-annotated patient-derived xenografts (PDXs) to serve as resource for public-private partnerships and academic drug discovery efforts. These models are offered the extramural community research use (https://pdmr.cancer.gov/), along with clinical annotation molecular information (whole exome sequence, RNASeq), which is available in...
Abstract The National Cancer Institute’s Patient-Derived Models Repository (NCI PDMR; https://pdmr.cancer.gov) has developed a national repository of (PDMs) comprised patient-derived xenografts (PDXs), in vitro tumor cell cultures (PDCs) and cancer associated fibroblasts (CAFs) as well organoids (PDOrg). These PDMs are clinically annotated with molecular information available an easily accessible database for the extramural community. A key effort developing these models is to develop...
Abstract We previously reported the generation of rabbit monoclonal antibodies to twelve EMT (epithelial-to-mesenchymal transition) transcription factors and cancer stem cell (CSC) markers for development pharmacodynamic assays inform clinical trials new anticancer therapies (Pfister et al., AACR 2013). Here we demonstrate functional utility some these reagents in detecting HGF-induced changes CSC biology a xenograft tumor model. Initial antibody characterization was performed vitro subset...
Wilms Tumor (WT), or nephroblastoma, is the most common pediatric kidney cancer. Most WTs display a "favorable" triphasic histology, in which tumor comprised of blastemal, stromal, and epithelial cell types. Blastemal predominance after neoadjuvant chemotherapy diffuse anaplasia ("unfavorable" histology; 5-8%) portend worse prognosis. Blastema likely provide putative cancer stem cells (CSCs), retain molecular histologic features characteristic nephron progenitor (NPCs), within WTs. NPCs...
Abstract The National Cancer Institute's Patient-Derived Models Repository (NCI PDMR; https://pdmr.cancer.gov) is performing a large-scale multi-year preclinical study with 39 PDX models of rare cancers (mesothelioma, MPNST, osteosarcoma, Merkel cell carcinoma, etc) treated 56 novel therapeutic combinations in an exploratory, n-of-4 arm, design. Combinations that show promising responses (e.g., regression or durable inhibition tumor growth) will be repeated along the single agent arms to...