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 13C 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.Electronic supplementary materialThe online version of this article (doi:10.1186/s40170-014-0026-z) contains supplementary material, which is available to authorized users.
Highlights
Hypoxic niches in solid tumors harbor therapy-resistant cells
MiaPaCa-2 tumors had an intermediate response, and SU.86.86 tumors displayed no sensitivity to TH-302 (Figure 1a–c)
As hypoxia is the main determinant for TH-302 activity, immunohistochemistry (IHC) detecting pimonidazole and carbonic anhydrase IX, respectively, markers for physical [20] and biological [21] hypoxia, confirmed the greatest hypoxia in Hs766t tumors (Figure 1d,e)
Summary
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. We sought to identify non-pharmacological methods to acutely exacerbate tumor hypoxia to increase TH-302 activity in pancreatic ductal adenocarcinoma (PDAC) tumor models. A routinely observed phenotype, contributes to chemo- and radioresistance, causing major therapeutic concern [1]. Considerable effort has been devoted to harness its therapeutic potential. A class of hypoxia-activated prodrugs (HAPs) has been developed to selectively target tumor cells residing in hypoxic niches [2,3]. There are 12 clinical trials with TH-302 underway in a variety of cancers (e.g., pancreatic, sarcoma, breast, melanoma) (Additional file 1: Table S1).
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