ArticleCancer & metabolism2015
Pyruvate sensitizes pancreatic tumors to hypoxia-activated prodrug TH-302.
Article in Cancer & metabolism, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 48 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
Who cites it
48 citing papers in PubMed, 1 synthesis or guideline pooled it, 81 citations in OpenAlex.
- Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy.Frontiers in oncology · 2021Pooled it
- Advancing Tumor Treatment Through Artificial Intelligence and Mathematical Modeling: A Comprehensive Review.Health science reports · 2026Article
- Understanding Immune Cell Adaptation to Tumor Hypoxia for Maximized Therapeutic Efficacy of Immunotherapy: Biology and Non-invasive Imaging Application.Cancer research and treatment · 2026Review
- Hyperpolarized MRI theranostics in cancer.Frontiers in oncology · 2025Article
- Evaluations of an Early Change in Tumor Pathophysiology in Response to Radiotherapy with Oxygen Enhanced Electron Paramagnetic Resonance Imaging (OE EPRI).Molecular imaging and biology · 2024Article
- Pharmacological Ascorbate Induces Transient Hypoxia Sensitizing Pancreatic Ductal Adenocarcinoma to a Hypoxia Activated Prodrug.bioRxiv : the preprint server for biology · 2024Article
- Hypoxia-activated prodrug and antiangiogenic therapies cooperatively treat pancreatic cancer but elicit immunosuppressive G-MDSC infiltration.JCI insight · 2024Article
- Exploring chronic and transient tumor hypoxia for predicting the efficacy of hypoxia-activated pro-drugs.NPJ systems biology and applications · 2024Article
- In vitro oxygen imaging of acellular and cell-loaded beta cell replacement devices.Scientific reports · 2023Article
- Evofosfamide and Gemcitabine Act Synergistically in Pancreatic Cancer Xenografts by Dual Action on Tumor Vasculature and Inhibition of Homologous Recombination DNA Repair.Antioxidants & redox signaling · 2023Article
- Enhancing Cancer Diagnosis with Real-Time Feedback: Tumor Metabolism through Hyperpolarized 1-Metabolites · 2023Review
- Advances in the Application of Preclinical Models in Photodynamic Therapy for Tumor: A Narrative Review.Pharmaceutics · 2023Review
- Circulating metabolites associated with tumor hypoxia and early response to treatment in bevacizumab-refractory glioblastoma after combined bevacizumab and evofosfamide.Frontiers in oncology · 2022Article
- Hypoxia Imaging As a Guide for Hypoxia-Modulated and Hypoxia-Activated Therapy.Antioxidants & redox signaling · 2022Review
- Hypoxia-Activated Prodrug Evofosfamide Treatment in Pancreatic Ductal Adenocarcinoma Xenografts Alters the Tumor Redox Status to Potentiate Radiotherapy.Antioxidants & redox signaling · 2021Article
- Modulation of cell physiology under hypoxia in pancreatic cancer.World journal of gastroenterology · 2021Review
- Bridging cell-scale simulations and radiologic images to explain short-time intratumoral oxygen fluctuations.PLoS computational biology · 2021Article
- Excess exogenous pyruvate inhibits lactate dehydrogenase activity in live cells in an MCT1-dependent manner.The Journal of biological chemistry · 2021Article
- Hyperpolarized Magnetic Resonance and Artificial Intelligence: Frontiers of Imaging in Pancreatic Cancer.JMIR medical informatics · 2021Review
- Targeting hypoxic tumor microenvironment in pancreatic cancer.Journal of hematology & oncology · 2021Review
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
21 authors at 5 institutions in 1 country.
Funding
Abstract
backgroundHypoxic niches in solid tumors harbor therapy-resistant cells. Hypoxia-activated prodrugs (HAPs) have been designed to overcome this resistance and, to date, have begun to show clinical efficacy. However, clinical HAPs activity could be improved. In this study, we sought to identify non-pharmacological methods to acutely exacerbate tumor hypoxia to increase TH-302 activity in pancreatic ductal adenocarcinoma (PDAC) tumor models.
resultsThree human PDAC cell lines with varying sensitivity to TH-302 (Hs766t > MiaPaCa-2 > SU.86.86) were used to establish PDAC xenograft models. PDAC cells were metabolically profiled in vitro and in vivo using the Seahorse XF system and hyperpolarized (13)C pyruvate MRI, respectively, in addition to quantitative immunohistochemistry. The effect of exogenous pyruvate on tumor oxygenation was determined using electroparamagnetic resonance (EPR) oxygen imaging. Hs766t and MiaPaCa-2 cells exhibited a glycolytic phenotype in comparison to TH-302 resistant line SU.86.86. Supporting this observation is a higher lactate/pyruvate ratio in Hs766t and MiaPaCa xenografts as observed during hyperpolarized pyruvate MRI studies in vivo. Coincidentally, response to exogenous pyruvate both in vitro (Seahorse oxygen consumption) and in vivo (EPR oxygen imaging) was greatest in Hs766t and MiaPaCa models, possibly due to a higher mitochondrial reserve capacity. Changes in oxygen consumption and in vivo hypoxic status to pyruvate were limited in the SU.86.86 model. Combination therapy of pyruvate plus TH-302 in vivo significantly decreased tumor growth and increased survival in the MiaPaCa model and improved survival in Hs766t tumors.
conclusionsUsing metabolic profiling, functional imaging, and computational modeling, we show improved TH-302 activity by transiently increasing tumor hypoxia metabolically with exogenous pyruvate. Additionally, this work identified a set of biomarkers that may be used clinically to predict which tumors will be most responsive to pyruvate + TH-302 combination therapy. The results of this study support the concept that acute increases in tumor hypoxia can be beneficial for improving the clinical efficacy of HAPs and can positively impact the future treatment of PDAC and other cancers.
Indexed as
Identifiers
What OpenQuestion holds
Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.