Abstract B46: Targeting tumor initiating cells in patient-derived pancreatic xenograft models using the hypoxia-activated prodrug TH-302.

Pancreatic carcinomas have been reported to be some of the most hypoxic of human tumors, although the data supporting this view are limited. Our studies with pancreatic cancer xenografts and initial studies in patients suggest that like other solid tumors, they can display a wide range of oxygenation. We have previously demonstrated that tumor hypoxia correlates with high proliferation rates and metastasis in pancreatic cancer. Furthermore, tumor initiating cells (TIC) are hypothesized to reside in the hypoxic zone. The presence of TICs in pancreatic cancer has a prognostic relevance and influences the response to treatment. Recent publications suggest that metastatic potential is conferred by TICs which receive cues from the microenvironment in which they reside. Hypoxia-activated drugs, such as TH-302, target the hypoxic zone and are therefore theorized to not only increase the treatment response of the primary tumor, but also prevent tumor recurrence and metastasis by reducing the number of TIC. We used 10 patient-derived xenograft models to investigate the relationship between tumor hypoxia, tumor growth, and TIC. These models also examined the efficiency of the hypoxia-activated drug TH-302 in reducing the number of TIC in pancreatic tumors. To specifically examine the effect of TH-302 treatment on pancreatic TIC in vivo, tumor-bearing mice were treated with either TH-302, 10Gy IR, or with the combination of both. The harvested tumors cells were then reinjected into NOD/SCID mice for limiting dilution assays. The patient-derived xenograft models showed a positive correlation between not only tumor hypoxia and tumor growth rates but also between tumor hypoxia and the number TIC. Additionally, TH-302 was an effective treatment of hypoxic pancreatic tumors. Our results suggest that TH-302 efficiency correlates with the extent of tumor hypoxia, showing higher efficiency in highly hypoxic patient-derived models as compared to models with low tumor hypoxia. Although treatment with TH-302 alone was sufficient in reducing the number of TIC, the combination treatment with IR further reduced the number of TIC in all the tested xenografts. These findings demonstrate that the combination of radiation therapy and TH-302 may provide an effective treatment strategy for pancreatic cancer patients. Citation Format: Ines Lohse, Joanna Rasowski, Emin Ibrahimov, Richard Hill, Ming S. Tsao, David W. Hedley. Targeting tumor initiating cells in patient-derived pancreatic xenograft models using the hypoxia-activated prodrug TH-302. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Progress and Challenges; Jun 18-21, 2012; Lake Tahoe, NV. Philadelphia (PA): AACR; Cancer Res 2012;72(12 Suppl):Abstract nr B46.