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Pyruvate sensitizes pancreatic tumors to hypoxia-activated prodrug TH-302
Jonathan W Wojtkowiak1, Heather C Cornnell1, Shingo Matsumoto2
1Department of Imaging and Metabolism, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612 USA.
Background:
Hypoxic 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.
Results:
Three 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.
Conclusions:
Using 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.
Insights
Exogenous pyruvate can enhance hypoxia-activated prodrugs (HAPs) efficacy in pancreatic ductal adenocarcinoma (PDAC) by increasing tumor hypoxia. This combination therapy shows promise for improving cancer treatment outcomes.
Area of Science:
- Oncology
- Cancer Metabolism
- Tumor Microenvironment
Background:
- Hypoxic tumor regions contain therapy-resistant cells.
- Hypoxia-activated prodrugs (HAPs) show clinical promise but require optimization.
- Pancreatic ductal adenocarcinoma (PDAC) presents a therapeutic challenge due to resistant hypoxic niches.
Purpose of the Study:
- To identify non-pharmacological methods to increase tumor hypoxia.
- To enhance the activity of the HAP TH-302 in PDAC models.
- To investigate the role of exogenous pyruvate in modulating tumor hypoxia and HAP efficacy.
Main Methods:
- Utilized three human PDAC cell lines and xenograft models with varying TH-302 sensitivity.
- Performed metabolic profiling using Seahorse XF and hyperpolarized (13)C pyruvate MRI.
- Assessed tumor oxygenation via electroparamagnetic resonance (EPR) oxygen imaging.
Main Results:
- PDAC cell lines Hs766t and MiaPaCa-2 showed a glycolytic phenotype and responded well to pyruvate, unlike the resistant SU.86.86 line.
- Exogenous pyruvate increased oxygen consumption in vitro and modulated hypoxic status in vivo, particularly in sensitive models.
- Combination therapy with pyruvate and TH-302 significantly reduced tumor growth and improved survival in PDAC models.
Conclusions:
- Metabolic manipulation with exogenous pyruvate can transiently increase tumor hypoxia, enhancing TH-302 efficacy in PDAC.
- Biomarkers were identified to predict patient response to pyruvate + TH-302 combination therapy.
- This strategy supports the clinical benefit of acute hypoxia enhancement for HAPs in PDAC and other cancers.
