Metabolic and physiologic imaging biomarkers of the tumor microenvironment predict treatment outcome with radiation or a hypoxia-activated prodrug in mice.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by hypoxic niches that lead to treatment resistance. Therefore, studies of tumor oxygenation and metabolic profiling should contribute to improved treatment strategies. Here we define two imaging biomarkers that predict differences in tumor response to therapy: 1) partial oxygen pressure (pO2), measured by EPR imaging; and 2) [1-13C] pyruvate metabolism rate, measured by hyperpolarized 13C MRI. Three human PDAC xenografts with varying treatment sensitivity (Hs766t, MiaPaCa-2, and Su.86.86) were grown in mice. The median pO2 of the mature Hs766t, MiaPaCa-2, and Su.86.86 tumors was 9.1±1.7, 11.1±2.2, and 17.6±2.6 mmHg, and the rate of pyruvate-to-lactate conversion was 2.72±0.48, 2.28±0.26, and 1.98±0.51 min-1, respectively (n=6, each). These results are in agreement with steady state data of matabolites quantified by mass spectroscopy and histological analysis indicating glycolytic and hypoxia profile in Hs766t, MiaPaca-2, and Su.86.86 tumors. Fractionated radiation therapy (5 Gy x 5) resulted in a tumor growth delay of 16.7±1.6 and 18.0±2.7 days in MiaPaca-2 and Su.86.86 tumors, respectively, compared to 6.3±2.7 days in hypoxic Hs766t tumors. Treatment with gemcitabine, a first-line chemotherapeutic agent, or the hypoxia-activated prodrug TH-302 was more effective against Hs766t tumors (20.0±3.5 and 25.0±7.7 days increase in survival time, respectively) than MiaPaCa-2 (2.7±0.4 and 6.7±0.7 days) and Su.86.86 (4.7±0.6 and 0.7±0.6 days) tumors. Collectively, these results demonstrate the ability of molecular imaging biomarkers to predict the response of PDAC to treatment with radiation therapy and TH-302.

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