A5042870042- Cancer, Hypoxia, and Metabolism
- Cancer Research and Treatments
- Nanoplatforms for cancer theranostics
- Acute Myeloid Leukemia Research
- Medical Imaging Techniques and Applications
- Epigenetics and DNA Methylation
- Radiomics and Machine Learning in Medical Imaging
- Sarcoma Diagnosis and Treatment
- RNA modifications and cancer
- RNA Interference and Gene Delivery
- Genomics and Chromatin Dynamics
- Developmental Biology and Gene Regulation
- Protein Degradation and Inhibitors
- Neuroblastoma Research and Treatments
- Multiple Myeloma Research and Treatments
- Cancer therapeutics and mechanisms
- Cancer-related Molecular Pathways
- Hepatocellular Carcinoma Treatment and Prognosis
- Advanced MRI Techniques and Applications
- Animal Genetics and Reproduction
- Cancer Genomics and Diagnostics
- Ubiquitin and proteasome pathways
- Glioma Diagnosis and Treatment
- Advanced NMR Techniques and Applications
- Liver physiology and pathology
Threshold Pharmaceuticals (United States)
2011-2024
University of Auckland
2011-2019
Maurice Wilkins Centre
2019
University Health Network
2019
Princess Margaret Cancer Centre
2019
University of Toronto
2019
Faculty of 1000 (United States)
2017
Case Western Reserve University
2014-2015
Roswell Park Comprehensive Cancer Center
2013
Johns Hopkins Hospital
2013
A series of achiral hypoxia-activated prodrugs were synthesized on the basis DNA cross-linking toxin prodrug, ifosfamide. The hypoxia-selective cytotoxicity several compounds was improved over previously reported racemic mixtures chiral bioreductive phosphoramidate prodrugs. Prodrugs activated by 2-nitroimidazole reduction demonstrated up to 400-fold enhanced toward H460 cells in culture under hypoxia versus their potency aerobic conditions. Compounds further assessed for stability...
TH-302 is a 2-nitroimidazole triggered hypoxia-activated prodrug (HAP) of bromo-isophosphoramide mustard currently undergoing clinical evaluation. Here, we describe broad-spectrum activity, hypoxia-selective activation, and mechanism action TH-302. The concentration time dependence activation was examined as function oxygen concentration, with reference to the prototypic HAP tirapazamine, showed superior inhibition cytotoxicity much improved dose potency relative tirapazamine. Enhanced under...
Tumor hypoxia underlies treatment failure and yields a more aggressive, invasive, metastatic cancer phenotype. TH-302 is 2-nitroimidazole triggered hypoxia-activated prodrug of the cytotoxin bromo-isophosphoramide mustard (Br-IPM). The purpose this study to characterize antitumor activity investigate its selective targeting hypoxic cells in human tumor xenograft models.
Conventional anticancer treatments are often impaired by the presence of hypoxia. TH-302 selectively targets hypoxic tumor regions, where it is converted into a cytotoxic agent. This study assessed efficacy combination treatment and radiotherapy in two preclinical models. The effect oxygen modification on was evaluated fraction (HF) monitored using [(18)F]HX4-PET imaging pimonidazole IHC stainings.Rhabdomyosarcoma R1 H460 NSCLC tumor-bearing animals were treated with (8 Gy, single dose)....
Hypoxic niches in solid tumors harbor therapy-resistant cells. Hypoxia-activated prodrugs (HAPs) have been designed to overcome this resistance and, date, begun show clinical efficacy. However, HAPs activity could be improved. In study, we sought identify non-pharmacological methods acutely exacerbate tumor hypoxia increase TH-302 pancreatic ductal adenocarcinoma (PDAC) models.Three human PDAC cell lines with varying sensitivity (Hs766t > MiaPaCa-2 SU.86.86) were used establish xenograft...
To characterize the prevalence of hypoxia in leukemic bone marrow, its association with metabolic and transcriptional changes blasts utility hypoxia-activated prodrug TH-302 leukemia models.Hyperpolarized magnetic resonance spectroscopy was utilized to interrogate pyruvate metabolism marrow murine acute myeloid (AML) model. Nanostring technology used evaluate a gene set defining signature normal donors. The efficacy examined vitro vivo models.Metabolic imaging has demonstrated increased...
This review assesses the circumpolar occurrence of emerged marine macrofossils and sediments from Antarctic coastal areas in relation to Late Quaternary climate changes. Radiocarbon ages macrofossils, which are interpreted view complexities radiocarbon reservoir resolution this dating technique, show a bimodal distribution. The data indicate that species inhabited environments at least 35 000 20 yr BP, during Marine Isotope Stage 3 when extensive iceberg calving created ‘meltwater lid’ over...
Abstract Purpose: Acute myeloid leukemia (AML) is an aggressive hematologic neoplasm. Recent evidence has shown the bone marrow microenvironment in patients with AML to be intrinsically hypoxic. Adaptive cellular responses by cells survive under low oxygenation also confer chemoresistance. We therefore asked whether therapeutic exploitation of hypoxia via hypoxia-activated nitrogen mustard prodrug, TH-302, could effectively inhibit growth. Experimental Design: assessed effects and TH-302 on...
Evofosfamide (TH-302) is a clinical-stage hypoxia-activated prodrug of DNA-crosslinking nitrogen mustard that has potential utility for human papillomavirus (HPV) negative head and neck squamous cell carcinoma (HNSCC), in which tumor hypoxia limits treatment outcome. We report the preclinical efficacy, target engagement, preliminary predictive biomarkers initial clinical activity evofosfamide HPV-negative HNSCC. was assessed 22 genomically characterized lines 7 line–derived xenograft (CDX),...
Abstract Recently, we showed that hypoxia is a critical microenvironmental factor in multiple myeloma, and the hypoxia-activated prodrug TH-302 selectively targets hypoxic myeloma cells improves disease parameters vivo. To explore approaches for sensitizing to TH-302, evaluated this study antitumor effect of combination with clinically used proteasome inhibitor bortezomib. First, show bortezomib synergistically induce apoptosis cell lines vitro. Second, confirm synergism related activation...
Tumors often contain hypoxic regions resistant to chemo- and radiotherapy. TH-302 (T) is an investigational hypoxia-activated prodrug that selectively releases the DNA cross-linker bromo-isophosphoramide mustard under conditions. This study evaluated efficacy safety profile of combining T with gemcitabine (G) nab-paclitaxel (nP) in human pancreatic ductal adenocarcinoma (PDAC) xenograft models mice. Antitumor activity G + nP triplet was assessed compared T-alone or doublet Hs766t, MIA...
Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxic niches that lead to treatment resistance. Therefore, studies of tumor oxygenation and metabolic profiling should contribute improved strategies. Here, we define two imaging biomarkers predict differences in response therapy: (i) partial oxygen pressure (pO2), measured EPR imaging; (ii) [1-13C] pyruvate metabolism rate, hyperpolarized 13C MRI. Three human PDAC xenografts with varying sensitivity (Hs766t, MiaPaCa2, Su.86.86)...
Evidence from the Ross embayment, Antarctica, suggests an abrupt cooling and a concomitant increase in sea-ice cover at about 6000 BP (6 ka). Stable-isotope (δD) concentrations Taylor Dome ice core, western edge of decline rapidly after 6 ka, continue to through late Holocene. Methanesulfonic acid show opposite trends δD Sediment cores Sea percentage minimum for diatom Fragilariopsis curta between 9 whenTaylor values are highest, followed by Radiocarbon dates raised beach deposits indicate...
The homeotic genes of Drosophila, which regulate pattern formation during larval development, contain a 180-base-pair DNA sequence termed the "homeo-box." Nucleotide comparisons indicate that homeo-box motif is highly conserved in variety motazoan species. As sequences mammalian species are expressed temporal and tissue-specific embryogenesis. These observations suggest functional homologies between dipteran gene products. To identify possible relationships mice humans, we have compared...